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Vicepresidency of Research
Finlay Institute, La Habana, Cuba
La
ISBN: 959-7076-12-8
Finlay Ediciones
Ave. 212 No. 3112 e/ 31 y 37,
La Coronela, La Lisa,
Ko A. Annan
INTRODUCTION
after e-mail (93%) and researching a product or service before buying (83%). (Internet Health and Resources, Pew Internet & American Life Project, Susannah Fox and
Deborah Fallows, 16 July, 2003).
There are so many ways to access health information on the web and such a
broad selection of content that the search process can seem overwhelming. However, searching for health information is easy if you know where to start. The following selected tuberculosis Web sites and links list (comprehensive but not exhaustive)
offer some suggestions. We hope that you may nd it useful when looking specically for tuberculosis information on Internet.
THE AUTHORS
La Habana, Cuba, May 2005.
1. ABC de la Tuberculosis - UITB - Unidad de investigacin en ... Informacion sobre tuberculosis, tratamientos, prevencion, vacunas, lineas y proyectos de investigacion, documentos,
casos clinicos, novedades, congresos, ... www.imsb.bcn.es/uitb/
2. About Tuberculosis Public information on the biology of tuberculosis from the Canadian Lung Association http://www.lung.ca/tb
3. Action TB
4. Aeras Global TB Vaccine Foundation http://www.aeras.org/
5. Airborne Disease Weekly
6. A laymans guide to tuberculosis, atypical tuberculosis and ... Offers A to Z of Tuberculosis and includes general, mental health and medication side effects issues. Includes support
and message board chat room. www.tbandu.co.uk/
7. Amedeo.com, The Medical Literature Guide http://amedeo.com/index.htm
8. American Lung Association The American Lung Association (ALA) was founded
in 1904 to combat tuberculosis. Today this organization ghts all forms of lung with special
emphasis on asthma, tobacco control and environmental health. The ALA has worked to
increase federal funding for tuberculosis research and control http://www.lungusa.org/diseases/lungtb.html
9. American Lung Association Tuberculosis Information (on PBS)
10. American Thoracic Society The American Thoracic Society [ATS] is an independently
incorporated, international, educational and scientic society which focuses on respiratory
and critical care medicine. ATS was once called the American Sanatorium Association. It maintains a focus on medical aspects of tuberculosis, whereas the parent organization, American
Lung Association, concentrates on public health issues. Information links on tuberculosis at
this site can identied after using the search button http://www.thoracic.org/
11. Ask NOAH About: Tuberculosis Preguntale a NOAH Sobre la Tuberculosis Information in English and in Spanish presented by the New York Online Access to Health (NOAH)
project.
12. Atlanta Tuberculosis Prevention Coalition Our Mission Collaborating Agencies Projects Screening Education Computerized TB registry Personnel Publications Training Funding
Other TB related Sites TB & Medicaid General TB information Georgia TB reference guide...
13. ATS Journals Online... Ofcial Journals of the American Thoracic Society, Stanford
University
Libraries HighWire Press assists in the publication of ATS Journals Online ... www.atsjournals.org/
14. Bill & Melinda Gates Foundation Grant-making foundation supports initiatives in
education, world health and
population, and community giving in the Pacic Northwest www.gatesfoundation.org/
15. Books on Tuberculosis at Amazon.co.uk Find Genetics and tuberculosis (Novartis
Foundation Symposium) and more at Amazon.co.uk. Read reviews, buy new and used titles...
http://www.amazon.co.uk...
16. Brown University TB-HIV Research Laboratory www.brown.edu/Research/TB-HIV_
Lab/
17. BUBL LINK: Tuberculosis BUBL LINK Catalogue of Internet Resources. Tuberculosis.
Titles. Descriptions. American Lung Association: Diseases A to Z ... cancer, tuberculosis, emphysema ... Internet resources relevant to the respiratory system. Author: OMNI, Nottingham
University. Subjects: asthma, lung cancer, lungs, pneumonia, tuberculosis ... bubl.ac.uk/link/t/
tuberculosis.htm
18. California Tuberculosis Controllers Association
19. Canadas Role in Fighthing Tuberculosis - About Tuberculosis Public information on
the biology of tuberculosis from the Canadian Lung Association. What is tuberculosis and
how is it spread? This resource explains the biology of tuberculosis and the way in which we
deal with it http://www.lung.ca/tb/abouttb/
20. Case Western Reserve University Tuberculosis Research Unit and HIVNET Projects
21. CBC News - Tuberculosis: Anatomy of A Killer Includes facts, videos, reports, and
links on Tuberculosis. Ever heard of White Plague? What about Potts disease? Lupus Vulgaris?
Kings evil? No? Okay then, surely youve heard of Consumption. All of these diseases are
actually the same disease, better known today as Tuberculosis or TB for short http://cbc.
ca/news/indepth/background/tb.html... CBC News - Includes facts, videos, reports, and links
on Tuberculosis
22. CDC Division of Tuberculosis Elimination News, reports, guidelines, and educational
materials for health professionals http://www.cdc.gov/nchstp/tb
23. CDC National Prevention Information Network (NPIN) TB Resources
24. Center for Pulmonary and Infectious Disease Control University of Texas Health Center at Tyler
25. Charles P. Felton National Tuberculosis The goal is to meet the challenge of TB in Harlem by providing innovative prevention, treatment, and training programs to members community and healthcare providers serving the community http://www.harlemtbcenter.org
search
for
BCG
vaccine
http://www.ndarticles.com/p/
47. Florida Department of Health (select Tuberculosis in the Subject Choices box)
48. Francis J. Curry National Tuberculosis Center
49. FREE Internet Encyclopedia - MacroReference MacroReference. Free Internet Encyclopedia. Copyright 2004 by Clifton Davis. Reproduction in whole or part of this arrangement of links only with permission. ... American Lung Association: TB FAQ. Peoples Plague:
Tuberculosis in America (PBS special)(c ... www.cam-info.net/enc/macro.t.html
50. GFATM (PAHO/AMRO) resource page for Latin America and the Caribbean
51. Glaxo Wellcome and Healthcare - Global http://www.glaxowellcome.co.uk/health/odyssey/tuberc/tuberc3.html
52. Global Alliance for TB Drug Development Seeks to develop and ensure equitable access to new tuberculosis drugs. Features organization information, disease information, new
drug development, and news http://www.tballiance.org
53. Global Fund to ght AIDS, tuberculosis and malaria (GFATM)
54. Hardin MD : Tuberculosis From the University of Iowa, the *best* lists of Internet
sources in tuberculosis. www.lib.uiowa.edu/hardin\md/tuberculosis.html
55. Health and Development Initiative
56. healthnder - your free guide to reliable health information AIDS alt med cancer
diabetes food safety Medicare tobacco more . . . the latest government health news health
media online special events calendars prevention and self-care choosing quality care online
health information fraud and...
57. Health Communication Partnership Tuberculosis Related Internet Sites. CDC Division of Tuberculosis Elimination Education and Training Resources Web Site. Tuberculosis ...
87. Multidrug-Resistant Tuberculosis Fact Sheet From the American Lung Association
88. Mycobacterial Genome Workshop, Division of Microbiology and ... ... tuberculosis
research at or near the present level for about another ve years.... The development of an
improved tuberculosis vaccine is of extreme ... www.niaid.nih.gov/dmid/tuberculosis/execsum.
htm
89. MycDB, a Mycobacterium Database
90. Mycobacterium tuberculosis information Diseases Database Mycobacterium Tub
erculosis,TB,Tuberculosis, Disease Database Information ... 3 synonyms or equivalents were
found. Mycobacterium tuberculosis. aka/or ... Search using Internet medical databases; Search
using Internet search engines (non-specialist); ... www.diseasesdatabase.com/ddb8515.htm
91. Mycobacterium tuberculosis : sites et documents francophones ... Dnition [MeSH
Scope Note ; traduction CISMeF] : Espce de bactries, arobies, responsables de la tuberculose chez lhomme, les primates, ... http://www.chu-rouen.fr/ssf/organ/mycobacteriumtub...
92. MYCOS Research - A Colorado limited liability company providing custom mycobacterial research materials. Features products, services, company information, and research.
93. National Center for Infectious Diseases, Division of AIDS, STD, and TB Laboratory Research
94. National Institute of Allergy and Infectious Diseases Home Page (NIAID), National Institutes of Health NIAID Home | About NIAID | News & Information | Activities | Opportunities
NIAID welcomes your comments and suggestions. Please click here to send us an email message, or write to us at: NIAID Ofce of Communications and Public Liaison Buildin...
95. National Institute for Occupational Safety and Health (NIOSH)
96. National Institutes of Health The National Institutes of Health [http://www.nih.gov/]
contains a variety of sites related to tuberculosis research. Most programs lie within the National Institute of Allergy and Infectious Diseases [NIAID, http://www.niaid.nih.gov/]. The
National Heart, Lung and Blood Institute [NHLBI, http://www.nhllbi.nih.gov/] also supports
tuberculosis research. Within the NIAID, there are two divisions supporting tuberculosis research. These are the Division of Microbiology and Infectious Diseases
97. National Jewish Center for Immunology and Respiratory Medicine
98. National Jewish Medical and Research Center
99. National Library of Medicines Online Health Services
100. National Tuberculosis Center in Newark, New Jersey
101. National Tuberculosis Controllers Association - http://www.ntca-tb.org/
The home page of the National Tuberculosis Controllers Association (NTCA) and its associated organization, the National Tuberculosis Nurse Consultant Coalition (NTNCC). The NTCA
and NTNCC were created in 1995 to bring together the leaders of the tuberculosis control
programs of all 50 states as well as many county and city health departments which organize
their own TB control activities
10
Medicine
113. Philippine Tuberculosis Society Inc.... Dedicated to the prevention, treatment and
control of TB in the country. Includes information about the disease and the organization
http://www.ptsi.org.ph
114. PHRI Russian TB Control Program
115. Preguntale a NOAH Sobre la Tuberculosis Information in English and in Spanish presented by the New York Online Access to Health (NOAH) project.
116. Princeton Project 55 Princeton Project 55 Tuberculosis Initiative a wealth of documentation about TB
117. Public Health Laboratory Service (PHLS), UK - Tuberculosis
118. Public Health Research Institute Tuberculosis Center The Public Health Research
Institute (PHRI) Tuberculosis Center was created to address the re-emergence of tuberculosis
11
and the spread of multidrug resistant (MDRTB) strains in New York City. Today it focuses on
understanding and treating tuberculosis with activities in basic research, molecular epidemiology, and treatment of tuberculosis http://www.phri.org/tb.htm
119. Pulmonology Comprehensive database of pulmonological disorders www.fpnotebook.com/LUN.htm
120. PulmonologyChannel In 1993, WHO (the World Health Organization) declared tuberculosis a global emergency. Tuberculosis (TB) is responsible for the deaths of more youths
and adults than any other infectious disease http://www.pulmonologychannel.com/tuberculosis...
121. Quantitative Analysis of TB, Los Alamos National Laboratory...
122. Questions and Answers About TB http://www.cdc.gov/nchstp/tb/faqs/qa.htm
123. Rapid Blood Tests: Infectious Diseases, Tuberculosis, HIV, AIDS, STD Prsentation
dune ligne de tests rapides RAPID 1-2-3 HEMA, sur le sang total proposs par HDS. VIH,
hpatites, dengue, maladie de Chagas, paludisme, ... www.rapid123.com/
124. Registre de Tuberculosi Guia per al compliment del full de declaraci de cas de
tuberculosi. Programa de prevenci i control de la tuberculosi a Andorra. www.col-legidemetges.ad/docs/fulltb.html
125. Research Institute of Tuberculosis Conducts research and treatment of TB. Located
in Kiyose City, Tokyo http://www.jata.or.jp/eindex.htm
126. Research on Tuberculosis, New York State Department of Health
127. Resources for PPD antigens
128. Singapore Anti-Tuberculosis Association
129. Smart Computing Directory Of Web Sites: Diseases ... You will also nd links to
tuberculosis sites, the latest information on conferences, a preventive therapy database, and
numerous reports. ... http://www.smartcomputing.com/input/websites/viewl...
130. Stanford Center for Tuberculosis Research
131. Stanford Center for Tuberculosis Research Guestbook ... Websites with good pictures
related with TB will help very much. ... Near infrared spectroscopy for the analysis of tuberculosis antimicrobials. ... www.stanford.edu/group/molepi/guestbook.html
132. Stop TB Canada Initiative
133. Stop TB Initiative The Stop TB Initiative is a partnership for global action. The mission of Stop TB is to ensure that every person with TB has all the necessary information and
access to treatment and cure; to protect vulnerable populations from TB and http://www.
stoptb.org
134. Texas Center for Infectious Diseases (TCID)
135. Texas Department of Health - Tuberculosis Elimination Division
12
136. Translated Education Materials TB educational material in many languages from the
Minnesota Department of Health
137. TB Alert Details about this charity which supports health projects worldwide and
promotes awareness of tuberculosis. Includes publications, a newsletter and links http://
www.tbalert.org
138. TB Alliance
139. TbandU A laymans guide to Tuberculosis, including all other health and medication issues.
140. TB Control India An information site providing vital information about the status
of the RNTCP, Revised National Tuberculosis Programme being implemented in India. http://
www.tbcindia.org
141. TB Education Center Resources for Patient Care/Management - Texas Center for Infectious Disease
142. TB Education & Training Resources resources from the U.S. CDC
143. TB/HIV Research Laboratory, Brown University
144. TB/HIV WHO activity around tuberculosis and AIDS
145. TB News: Current News Article http://www.hopkins-id.edu/tb_news/tb_news_
17.html
146. TB Patient Incentive Program (American Lung Association of Wisconsin web site)
147. TB Policies: Classication of TB http://www.cpmc.columbia.edu/tbcpp/i-classt.html
148. TB Research at Case Western Reserve University
149. TB Resources on the Internet Text-Only Site. State Directory. Agencies A-Z. About
Oregon.gov. Advanced. Help. Tuberculosis Control. About Us. Contact Us. Tuberculosis Control. Fact Sheets. Guidelines egov.oregon.gov/DHS/ph/tb/links.shtml
150. TB Weekly, a tuberculosis news weekly
151. TBXrays.com - A graphics only site of x-rays and images of patients with tuberculosis
and other lung disease.
152. The Associate of North West TB Nurses The Northwest TB Nurses Association consists of nurses who specialize in the prevention and treatment of Tuberculosis in the North
West of England http://www.tbinfoline.co.uk/
153. The Hong Kong Tuberculosis, Chest and Heart Diseases Association Provides an
introduction to the associations services and patient-oriented information on tuberculosis,
heart diseases and hypertension http://www.ha.org.hk/org/antitb/
154. The Indian Journal of Chest Diseases and Allied Sciences ... www.indegene.com/ijcd/
155. The Indian Journal of Tuberculosis mohfw.nic.in/lrs/IJTB/
13
156. The International Journal of Tuberculosis and Lung Disease a ... ... The International
Journal of Tuberculosis and Lung Diseases... www.ingentaconnect.com/content/ iuatld/ijtld/
157. The International Union Against Tuberculosis and Lung Disease The International
Union Against Tuberculosis and Lung Disease [IUATLD] is a non-prot, non-governmental organization with members throughout the world. It is dedicated to the prevention and control
of tuberculosis and lung disease http://www.iuatld.org/
158. The Lupin Group Tuberculosis Lupin is a national leader in anti-TB drugs. This site
features anti-T.B. drugs produced by the company, frequently asked question, news, directory
of tuberculosis links, and discussion group http://www.lupinworld.com/antitb.htm
159. The Meaning of a Positive Tuberculosis Test / AAFP Patient Inform... http://home.aafp.
org/patientinfo/tbtest.html
160. The Peoples Plague: Tuberculosis in America, PBS Online
161. The Sequella Foundation The Sequella foundation promotes basic and clinical research to facilitate the development new tools for TB control by providing support to the
research community and interested companies http://www.sequellafoundation.org/
162. The TB Investigation Project A 2002 study investigating tuberculosis in Russia, the
USA, and the UK. Analysis of both the human and the scientic stories behind the ght against
TB. Includes TB links http://tbproject.tripod.com
163. The Tuberculosis Coalition for Technical Assistance (TBCTA)
164. The Vaccine Fund - Press Releases ... malaria and tuberculosis vaccines that are so
desperately needed.... www.vaccinefund.org/
165. Tinplate Hospital (BCG Vaccine) BCG Vaccine, Prevention of Tuberculosis, Vaccine,
BCG background, General guideline of BCG, Benets of BCG http://www.tinplatehospital.
com/bcg.asp
166. Treatment of Tuberculosis - revised recommendations (American Thoracic Society web
site) (PDF, 515 KB)
167. TubercuList Database on Mycobacterium tuberculosis genetics. Provides a complete
dataset of
DNA and protein sequences linked to the relevant annotations and functional ...
genolist.pasteur.fr/TubercuList/
168. Tuberculosis Tuberculosis and Public Health for Health Care Professionals. Reviews
on issues in tuberculosis, applied epidemiology, and courses. An afliation of the International
Union Against Tuberculosis and Lung Disease http://www.tbrieder.org
169. Turberculosis A comprehensive resource on tuberculosis and HIV infection, from
AEGIS.
http://www.aegis.com/topics/oi/oi-tb.html
170. Tuberculosis & Airborne Disease Weekly - A weekly publication with searchable ar-
chives
14
171. Tuberculosis and HIV, HIVemir (HIV: An Electronic Media Information Review)
172. Tuberculosis and HIV, Project Inform Hotline
173. Tuberculosis and Related Infections Unit
174. Tuberculosis and Related Infectious Disease - Watson W. Wise ... ... Tuberculosis Sites
(Univ. of Medicine and Dentistry, New Jersey); Tuberculosis & HIV (The Body: An AIDS and HIV
Information Resource) ... http://library.uthct.edu/tb.htm
175. Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF)
176. Tuberculosis Association of Ohio County Provides programs and services to Ohio
County, WV http://www.tboc.org/
177. Tuberculosis Clinical Resources Health: Diseases and Conditions: Tuberculosis. Additional Tuberculosis Sites (These sites have not been reviewed.) ... http://capstoneclinic-dl.slis.
ua.edu/clinical/pulm...
178. Tuberculosis Clinical Resources Additional Tuberculosis Sites (These sites have not
been reviewed.) YAHOO - Health:Medicine:Respiratory Diseases ... http://ruralnurseorganization-dl.slis.ua.edu/clini...
179. Tuberculosis Control in Chicago A comprehensive information site for tuberculosis, a
mycobacterial infectious
disease, that is developed and maintained by local volunteers. www.tbchicago.org/
180. Tuberculosis Control India This site provides information about tuberculosis and
its control in India http://www.tbcindia.org/
181. Tuberculosis Control Program (New York City Department of Health)
182. Tuberculosis Control Program Website internet URL http://www.med.upenn.edu/
TBPA/tbcp.html ... This web site has been created at the University of Pennsylvania Health System as part of a project entitled Tuberculosis Education in an Academic Health System, funded
through the National Heart, Lung and Blood Institute at NIH.
183. Tuberculosis Facts Factsheet with cause, symptoms, risk factors, diagnosis, complications, treatment, and prevention. http://www.astdhpphe.org/infect/tb.html...
184. Tuberculosis Fact Sheet, Maryland Department of Health
185. Tuberculosis Facts Factsheet with cause, symptoms, risk factors, diagnosis, complications, treatment,
and prevention. www.astdhpphe.org/infect/tb.html
186. Tuberculosis http://www.afscme.org/afscme/wrkplace/tbfs1.htm
187. Tuberculosis http://www.seanet.com/~tzhre/tuber.htm
188. Tuberculosis in Children - Keep Kids Healthy Tuberculosis information and answers
to common questions about TB in children, including the difference between tuberculosis
infection and disease, ...
www.keepkidshealthy.com/welcome/ infectionsguide/tuberculosis.html
15
189. Tuberculosis - Index- Pulmonology In 1993, WHO (the World Health Organization)
declared tuberculosis a global emergency. Tuberculosis (TB) is responsible for the deaths of
more youths and adults ... www.pulmonologychannel.com/tuberculosis/
190. Tuberculosis Information ... and Site Hosting - Web Hosting - Internet Store and
Ecommerce Solution Provider - High Speed Internet. Popular Searches: Tuberculosis Information ... ccfdca.www1.50megs.com/TB.htm
htm
tb.html
16
http://www.niaid.nih.gov/dmid/tuberculosis/tbvacci...
215. Tuberculosis Vaccine Action Plan, Blueprint for Tuberculosis Vaccine Development,
National Institute of Allergy ... http://www.niaid.nih.gov/publications/blueprint/pa...
216. Tuberculosis Web Sites http://www.lib.siu.edu/websites/health/tb.html
217. Tuberculosis Web Sites ... Consumer Health Sites. Enfermedades - Tuberculosis. This
Spanish language page from the Centers for Disease Control contains links to pamphlets including Tuberculosis - !Enterese! ... Core Curriculum on Tuberculosis is updated periodically.
Therefore, the Internet version may differ ... www.lib.siu.edu/hp/divisions/sci/health/tb.html
218. Tuberculosis - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Tuber-
culosis
219. Tuberculosis workplace standards related to TB from the U.S. Occupational Safety
and Health
220. www.tuberculosis.ru/
221. Understand and Fight Tuberculosis - Information for health care professionals From
the Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease
(IUATLD) http://www.tbrieder.org/
17
222. Unidad de investigacin en Tuberculosis de Barcelona... Informacion sobre tuberculosis, tratamientos, prevencion, vacunas, lineas y proyectos de investigacion, documentos, casos
clinicos, novedades, congresos, eventos y cursos http://www.imsb.bcn.es/uitb/
223. Unit de Gntique Molculaire Bactrienne ... projects is also available via the web
sites at Integrated Genomics, live tuberculosis vaccines Mycobacterium bovisBCG and Mycobacterium microti. ... www.pasteur.fr/recherche/unites/Lgmb/mycogenomics.html
224. USDA Funded Projects ... Develop candidate tuberculosis vaccines for cattle and deer;
3. ... www.nal.usda.gov/awic/pubs/TB/USDAFunded.htm
225. Vaccines, Division of Microbiology and Infectious Diseases http://worldaidsday.nih.
gov/dmid/vaccines...
226. Veiled Face of Tuberculosis - Find the authors attitude towards diagnostics of renal
tuberculosis, the way the investigations were performed, studied samples, and a note on the
author. Site is in English and Croatian
227. Wadsworth Center (New York State Department of Health)
228. Welcome on the TB Vaccine Cluster Site Click on to enter. Updated : Tue, Jun 13,
2000. Site realised by Marie Guibert. http://www.pasteur.fr/recherche/EC_TBvaccine/
229. WHO Tuberculosis - Prevention and Control Web Site This World Health Organization
site includes several publications and fact sheets with an international focus, including the
2002 Global Tuberculosis Control Report, Treatment of Tuberculosis: Guidelines for National
Programmes (available in English, French, and Spanish), TB/HIV: A Clinical Manual, Tuberculosis
in Prisons (available in English and Russian), and information about drug-resistant TB.
230. World Bank - tuberculosis
231. World Health Organization Tuberculosis http://www.who.int/tb/en/
232. World Health Organization Global Tuberculosis Programme
233. World TB Day, March 24, 2005 information from the U.S. CDC
18
19
Others:
Niels Abel, mathematician Rene Adore, Beulah Annan, Frdric Bastiat, Alexander Graham Bell, Sarah Bernhardt, Louis Braille, James Burke, Anders Celsius,
Cheng Man-ching, Tai Chi Chuan master, Charlie Christian, Arline Feynman, W. C.
Fields, Augustin-Jean Fresnel, Brenda Fricker, Abel Gance, Jay Gould, Emmett Hardy,
Richard Harris (actor)?, Doc Holliday, Immanuel Kant, Freddie Keppard, Ren Lannec French physician; inventor of the stethoscope, Vivien Leigh, Christy Mathewson,
Dmitri Mendeleev?, James Bubber Miley jazz trumpeter, Barry Morse?, Anne Neville (queen consort of Richard III) (probably), Florence Nightingale, Mabel Normand,
Etti Plesch?, Joseph Mary Plunkett, Virginia Eliza Clemm Poe (wife of Edgar Allan
Poe), Herman Potonik, Gavrilo Princip, Jimmie Rodgers, Bernhard, Riemann, mathematician Erwin Schrdinger, Takasugi Shinsaku (1839-1867), samurai Okita Soji
(1844-1869), Japanese swordsman and troop captain in the Shinsengumi, Baruch
Spinoza, Adrianus Turnebus, Georges Vezina, Lev Vygotsky, Rube Waddell, William
Winchester (son of Oliver Winchester, husband of Sarah Winchester), Link Wray,
Eugene Wigner?.
Note: ? died of something unrelated to tuberculosis.
Fictional characters:
Ukyo Tachibana from the Samurai Shodown video game series Sayo from the
Rurouni Kenshin anime, Hyatt from the Excel Saga anime, Helen Burns from Jane
Eyre by Charlotte Bront, Little Nell from The Old Curiosity Shop (Charles Dickens),
Mimi from La Bohme (Giacomo Puccini et. al.), Violette from Verdis La Traviata,
Buddy Willard from The Bell Jar by Sylvia Plath, Lin Dai-yu from The Story of Stone
by Cao, Satine from Moulin Rouge.
Reference:
Rothman, Sheila M. (1994). Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness
in American History. ISBN 0801851866 .
20
Tuberculosis
22
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Tuberculosis
Advocacy report
WHO/CDS/TB/2003.321
ISBN 92 4 259070 3 (NLM classification: WF 310)
The publication, prepared for the World
Health Organization by editors and
photographers from Colors magazine,
puts a human face on the TB epidemic
and the deadly interaction between TB
and HIV. Outlining the efficacy of the
DOTS programme, the report makes clear
that continued commitment and
expanded resources are vital to combat
TB.
Links
Despite eight million new cases of TB being reported annually and
two million deaths a year the report reveals the many
misconceptions people have about the disease and how this
ignorance is reflected in the misery of those infected with TB across
the world.
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"The images are disturbing," said Colors editor-in-chief Renzo di Renzo, "but in fact they give just a mere
glimpse of the enormous challenges faced every day by TB health care workers."
WHO | TB cases and deaths linked to HIV now at alarming levels in Africa
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Even Uganda, an African HIV reduction success story, is today curing fewer TB patients than it did four
years ago. More than half of all people with TB in Uganda remain without access to life-saving DOTS*
services due to strained general health facilities.
"Evidence in this report provides real optimism that TB is beatable, but it is also a clear warning," said
WHO Director-General Dr LEE Jong-wook. "As Nelson Mandela has said, we can't fight AIDS unless we do
much more to fight TB, and it is time to match his words with urgent action in Africa on the two
epidemics together."
There has been major progress in China and India, which account for one third of the global TB burden.
Both are leading the accelerated response to TB control by rapidly scaling up DOTS. As a result, the
number of cases treated under DOTS worldwide rose 8% in 2003 compared to the previous year. Other
countries such as Indonesia and the Philippines are showing similar progress.
Assuming strong commitment and resources are sustained, four regions - the Americas, Eastern
Mediterranean, South East Asia and Western Pacific - are on track to reach the United Nations Millennium
Development Goal of reducing TB incidence by 2015. The two exceptions are Africa due to the TB/HIV coepidemic, and Europe where there are high levels of multidrug-resistant TB and slow advances in DOTS
in countries of the former Soviet Union.
WHO | TB cases and deaths linked to HIV now at alarming levels in Africa
"Dedicated frontline health workers are making a difference, reaching out to the most vulnerable," said
Dr Mario Raviglione, Director of WHO's Stop TB Department. "But we need to push even further, to work
with new partners in both public and private health sectors, and in all regions, to reach more than half of
all patients that are still without access to DOTS treatments."
Since 1995, over 17 million people with TB have benefited from effective treatment under DOTS. But
more could be achieved within countries, and in research into new diagnostics, drugs and vaccines, if the
annual US$ 1 billion funding gap for TB control was filled.
The urgency of addressing TB has been highlighted in the UK-led Commission for Africa, which linked
improved TB control to strengthened health systems, as well as calling for full funding of WHO's 'Two
Diseases, One Patient' strategy for improved TB and HIV intervention.
"It is a remarkable achievement that we are on target to reach the goal of halving TB cases by 2015 in
most places," said the UK's International Development Secretary, Hilary Benn. "The Department for
International Development is a strong supporter of TB programmes in some of the countries which have
been making the fastest progress. However, as both the Global TB Control report and the Commission for
Africa report stress, the destructive link between TB and AIDS in Africa is causing an increase in cases. I
call on the international community to step up efforts to tackle both of these diseases together."
*DOTS is the internationally recommended strategy for controlling TB, consisting of five elements:
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Strenuous physical labor is important as a cause of elevated alanine aminotransferase levels in Japanese
patients with chronic hepatitis C viremia.
Eur J Epidemiol 2005;20:251-61.
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17. JAIN A, Rana SS, Chakravarty P, Gupta RK, Murthy NS, Nath MC et al
The prevalence of hepatitis C virus antibodies among the voluntary blood donors of New Delhi, India.
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19. REDA AA, Arafa MA, Youssry AA, Wandan EH, Ab de Ati M, Daebees H
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Objetivos de la UITB
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En 1994, el fondo de Investigaciones Sanitarias de la Seguridad social abra la posibilidad de
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Ya en 1987, en una reunin cientfica sobre Programas de Vigilancia y Control celebrado en
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Conferencia Nacional de Consenso de 1991 tambin puso de manifiesto esta necesidad. En
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Taller
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absence of potential PCR inhibitors, thus defining an optimal method for DNA extraction from bird fecal
samples. The first experiment compared three DNA extraction methods and heat treatment of the
extracted fecal DNA samples for their ability to overcome fecal PCR inhibition. Methods for extracting
DNA from feces of healthy Japanese quail (Coturnix coturnix japonica) included (a) bead beating + EL
(BB+EL), (b) bead beating + silicone dioxide (BB+SiO2), and (c) bead beating + phenol/chloroform. To
evaluate each extraction methods' ability to overcome PCR inhibition, extracted fecal DNA samples were
spiked with control M. avium subsp. avium DNA and quantitative real-time TaqMan PCR analysis was
performed. The BB+EL and BB+SiO2 methods returned positive PCR results. BB+EL resulted in the
highest purity and number of mycobacteria. Heating samples before PCR analysis decreased the mean
number of mycobacteria for all fecal DNA extraction methods. In the second experiment, living M.
avium subsp. avium cells were mixed with feces from healthy Japanese quail at concentrations of 1 x 106
CFU/g, 10 x 106 CFU/g, or 60x 106 CFU/g. Samples underwent DNA extraction using BB+EL,
followed by quantitative TaqMan PCR. Heated and unheated samples were analyzed. The mean number
of mycobacteria detected in feces with a spiking concentration of M. avium subsp. avium of 1 x 106
CFU/g was only 1 (range, 0 to 2.3) for both heated and unheated samples. Thus, the lower limit of
detection for quantitative PCR using the methods described is approximately 1x106 CFU/g or less. In
summary, this study demonstrated that DNA extraction methods used in sample preparation can have a
substantial impact on the DNA yield, purity, and amplification during subsequent PCR analysis on avian
fecal samples. The best preparation method tested incorporated bead beating and enzymatic lysis using a
commercial kit designed for use on stool samples. The lower limit of detection on avian fecal samples
spiked with M. avium subsp. avium was 1 million CFU/gram, so this test may be of most use in
identifying highly infective birds.
IMPACT: 2001/09 TO 2002/08
Mycobacteriosis is a bacterial disease that causes morality in birds and can cause human disease as well.
Affected birds shed organisms in their feces that may remain viable in the environment for months to
years. Currently, infected birds are identified by culturing mycobacteria from fecal samples, a process
taking weeks for results. This study assessed a DNA based assay system that could detect high numbers
of the bacteria within one day of sample processing, and thus could help in the rapid screening of
contagious animals.
PUBLICATIONS: 2001/09 TO 2002/08
Lisa A. Tell, Wayne L. Smith, Christian M. Leutenegger, Janet E. Foley, Richard L. Walker, Martha L.
Needham, Katheryn J. Jones, and James C. Cullor 2003. The suitability of polymerase chain reaction
testing for the identification of Mycobacterium avium subsp. avium in avian feces. Submitted to Journal
of Veterinary Diagnostic Investigation
PROJECT CONTACT:
Name: Tell, L. A.
Phone: 530-752-1363
Fax: 530-752-0414
Email: latell@ucdavis.edu
marcescens, and Escherichia coli. The S. Newport class 1 integron was found to encode resistance to
trimethoprim, spectinomycin/streptomycin, and sulfonamides; and contained a defective version of the
quaternary ammonium compound resistance gene. The resident plasmid in these isolates also contained
genes for tetracycline and b-lactam and cephalosporin resistance, although these genes were not
contained within the class 1 integron. The results of these studies indicate that, unlike multidrug resistant
S. typhimurium DT104 (whose antibiotic resistance is encoded within an integron located on the
chromosome), multidrug resistance of S. Newport isolates is due to genes encoded on a resident plasmid.
The significance of this finding is that these resistance markers could presumably be transferred to other
Salmonella serotypes by conjugation and emphasizes the need to understand transfer of drug resistance in
Salmonella. Range and feedlot cattle with a high intake of sulfur can develop polio-encephalomalacia
(PEM), a neurological condition of ruminants characterized by necrosis of the cerebral cortex. An
important factor in the development of PEM is the sulfur reducing capacity of the ruminal microflora.
Little is known about the microbial population(s) involved in the production of neurotoxic concentrations
of H2S. In this study, the natural ruminal ecosystem was studied by comparative 16S ribosomal RNA
analysis followed by specific analysis of sulfate-reducing bacteria using DNA extracted from rumen fluid
collected from test cattle before, during, and after transition to high sulfur water. 16S rDNA was cloned
and 50 clones were analyzed from each rumen sample with restriction enzymes. Extreme diversity was
observed both within a time point among different animals and between time points. Sulfate-reducing
bacteria (SRB) belonging to the genera Desulfovibrio and Desulfomicrobium were detected in all of the
animals. In addition, Desulfobulbus species were detected in animals during the second time point when
ruminal H2S became maximal. Reverse Southern Analysis to determine the abundance of bacterial
species in the rumen failed to reveal any particular dominant species in cattle consuming high sulfur
concentrations.
IMPACT: 2002/01 TO 2002/12
Drug resistant bacteria are becoming more of a health concern in animal products. The finding that
multidrug resistance occurs in S. enterica serotyp Newport indicates that such resistance is spreading to
several genera of bacteria. The occurrence of drug resistance in this species indicates that the resistance
may be transferred to other species of Salmonella and indicates the importance of developing a better
understanding of the transfer of drug resistance across species. It was demonstrated that the many
microbes in the rumen of cattle are associated with production of toxic levels of hydrogen sulfide.
Therefore, strategies to control complex populations of ruminal microbes, rather than a single species
will be necessary to control polioencephalomalacia in cattle.
PUBLICATIONS: 2002/01 TO 2002/12
1. Kurowski, P., Locke, A., and C. Gentry-Weeks. May 19, 2002. Characterization of integrons in
Salmonella enterica serovar Newport, Abstract A-106. In Abstracts of the 102nd General Meeting of the
American Society for Microbiology, 102nd General Meeting of the American Society for Microbiology,
Salt Lake City, UT.
2. Allen, T.E., Sherrill, K.J., Crispell, S.M., Perrott, M., Carlson, J.O., DeMartini, J.D. The Jaagsiekte
Sheep Retrovirus Envelope Gene Induces Transformation of the Avian Fibroblast Cell Line DF-1 but
Does Not Require a Conserved SH2 Binding Domain. Journal of General Virology., 83: 2733-2742
(2002)
http://nal.usda.gov/awic/pubs/TB/USDAFunded.htm (4 of 38) [04/01/06 2:04:35]
3. M.J. Magill1, D.H. Gould1, J.J. Wagner2, N.M DuTeau1; Characterization of Ruminal Microflora
Associated With Pathologic Hydrogen Sulfide Production in Cattle Exposed to High Levels of Dietary
Sulfur. American Society for Microbiology 102nd General Meeting, May 19-23, 2002, Salt Lake City,
UT 1Colorado State University, Fort Collins, CO, 2Continental Beef Research, Lamar, CO
4. Thesis; Colorado State University: Magill, Molly Jean. Characterization of ruminal microflora
associated with pathologic hydrogen sulfide production in cattle exposed to high levels of dietary sulfur /
submitted by Molly Jean Magill. 2002.
PROJECT CONTACT:
Name: Nett, T. M.
Phone: 970-491-7051
Fax: 970-491-2250
Email: tnett@cvmbs.colostate.edu
brain tissue. Montior for illness. Screen palpebral lymph nodes for prions at 18 and 24 months, and full
necropsy at 36 months post inoculation. 2. Inoculate elk and mule deer with Mycobacterium avium
organisms. Compare hypersensitive reactions to tuberculin intradermal inoculation made in the upper
eyelids, to those standard test sites in the cervical region. 3. Elk will be fed Brucella RB51 vaccine as a
top dressing in four, five-day series. Blood samples will be taken and evaluations conducted to determine
if, and when an immune response is achieved.
PROGRESS: 1999/07 TO 2002/06
Nothing was accomplished in this time period because we were awaiting the availability of mule deer
fawns from Fish and Game in the late spring.
IMPACT: 1999/07 TO 2002/06
The results of the investigation will have significant impact on disease management of range sheep and
wildlife management.
PUBLICATIONS: 1999/07 TO 2002/06
No publications reported this period
PROJECT CONTACT:
Name: Zaugg, J. L.
Phone: 208-454-8657
Fax: 208-454-8659
Email: jzaugg@uidaho.edu
in animals; and develop improved methods for differentiation of M. bovis isolates. NEW FUND OBJ:
Identify candidate antigens that would be efficacious in a mucosal vaccine for prevention of tuberculosis
in cattle, cervids (deer), and other wildlife.
APPROACH: Animals will be experimentally challenged w/M. bovis and blood and tissue samples will
be collected at different times to determine response of host to the organisms. Bacteriologic,
histopathologic, and immunologic methods will be used to characterize host responses. Tissue samples
w/b collected from naturally infected animals to determine distribution/characteristics of lesions. A
gamma interferon assay for diagnosis of TB in deer and elk is being developed; w/b evaluated to
determine test sensitivity/specificity. Blood samples from infected and noninfected animals w/b used for
test evaluation. A method using the polumerase chain reaction w/b developed for rapid detection of M.
bovis in tissue samples. Methods for DNA finger- printing M. bovis isolates will be improved by using
different DNA probes and enzymes. A method using PCR for direct detection and typing of M. bovis in
fresh tissue samples w/b modified for use w/formalin-fixed tissues. NADC,AmesIA:Bldg2A12,BL1-3
IBC-0193 Apprvd to 6/29/00;-0224 Apprvd to 6/3/00; -0239 Apprvd to 12/26/00
PROGRESS: 2000/10 TO 2001/09
1. What major problem or issue is being resolved and how are you resolving it? Bovine tuberculosis,
which is caused by Mycobacterium bovis, is an infectious disease that affects many species of animals as
well as human beings. Animals infected with M. bovis can shed organisms as they exhale or cough and in
various secretions including saliva, milk and urine. Elimination of animals infected with M. bovis is
important to prevent the spread of disease among animals and to human beings. The United States
initiated a program to eradicate tuberculosis from cattle in 1917 when the prevalence of disease was
approximately 5%. In general, the eradication program has been successful and today, less than 0.002%
of cattle are infected with M. bovis. However, a low prevalence of disease has persisted over the last 1015 years and it has not been possible to eradicate bovine tuberculosis from the United States using
available technology. Improved diagnostic tests and control measures are needed to detect and eliminate
the few remaining cattle and herds that have bovine tuberculosis. In addition, tuberculosis has been
detected in captive deer and elk and in wild white-tailed deer, coyotes, raccoons, bear, bobcat, opossum,
and fox. In some cases, there is epidemiological evidence to suggest that tuberculosis has been
transmitted from deer to cattle. The presence of tuberculosis in wildlife poses a serious threat to the
national eradication program. Other countries with tuberculosis in wildlife species have been unable to
eradicate the disease from the domestic livestock population. The Bovine Tuberculosis research project
at the National Animal Disease Center (NADC)is conducting research to develop a better understanding
of the interactions between various host species and M. bovis. This information will be used to develop
improved diagnostic tests and vaccines. Methods to identify and differentiate strains of M.bovis are being
developed and used to aid in epidemiological investigations of outbreaks of tuberculosis in animals. 2.
How serious is the problem? Why does it matter? Bovine tuberculosis is considered a public health
threat because human beings can become infected with M. bovis through contact with infected animals or
by ingestion of contaminated food and milk. Elimination of tuberculosis from cattle is important to
provide food and milk to the public that is free of M. bovis. Eradication of tuberculosis from wildlife is
important to prevent transmission of disease from wildlife to domestic livestock. Elimination of bovine
tuberculosis from domestic livestock also is important to maintain free trade with the many trading
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partners of the United States. Trade restrictions between the United States and Canada and between
Mexico and the United States have occurred because of bovine tuberculosis in animals. 3. How does it
relate to the National Program(s) and National Component(s)? The Bovine Tuberculosis research
project is assigned to the Animal Health National Program (103) and relates to the vision of this program
to ensure animal health through improved disease detection and control. The objectives of the project are
to 1) develop and evaluate improved tests for diagnosis of tuberculosis in cattle, deer and other
species,which relates to the National Program Component on Pathogen Detection; 2) develop improved
methods for differentiation of M. bovis isolates, which relates to the National Program Component on
Epidemiology of Disease; 3) define the interactions between various host species and M. bovis, which
relates to the National Program Component on Host/Pathogen Interactions and 4) develop and evaluate
vaccines for control and prevention of tuberculosis in animals, which relates to the National Program
Component on Disease Control Strategies. 4. What were the most significant accomplishments this
past year? A. Single Most Significant Accomplishment during FY 2000 year: Improved tests for
diagnosis of tuberculosis are needed so that animals infected with M. bovis can be identified and
eliminated as a source of infection to other animals and human beings. ARS scientists at NADC
conducted experiments to examine the immune responses of animals infected with M. bovis to identify
characteristics that could be used for diagnosis of infection. We developed a rapid diagnostic test that can
be used for detection of M. bovis infection in multiple species of animals. After further validation and
approval, the test may be used for the national program to eradicate tuberculosis from animals in the
United States. B. Other Significant Accomplishment(s), if any: In order to conduct controlled studies on
tuberculosis in animals, a system to experimentally infect animals with M. bovis is needed so that they
develop signs of disease that are similar to those observed in naturally infected animals. ARS scientists at
NADC developed a method to experimentally infect white-tailed deer, cattle, and other animals with
aerosolized M. bovis. We determined that animals experimentally infected with aerosolized develop
lesions and other signs of disease that mimic those seen in naturally infected animals. M. bovis The new
method for experimentally infecting animals with M. bovis is being used for controlled studies on
tuberculosis in animals. C. Significant Accomplishments/Activities that Support Special Target
Populations: None to report. 5. Describe the major accomplishments over the life of the project
including their predicted or actual impact. Since 1998, bovine tuberculosis has been detected in 16
herds of cattle in northeast Michigan where tuberculosis is endemic in the wild white-tailed deer
population. ARS scientists at the NADC experimentally infected white-tailed deer and allowed cattle to
have access to feed that had been offered to the deer and to pens that had been soiled by the deer. We
determined that cattle can become infected with M. bovis through indirect contact with experimentally
infected white-tailed deer. These results provide evidence that cattle do not need to have direct contact
with infected white-tailed deer in order for them to develop bovine tuberculosis and helps explain how
cattle in Michigan became infected with M. bovis. ARS scientists at the NADC experimentally infected a
group of deer and monitored routes of shedding and transmission to other deer. We determined that deer
infected with M. bovis shed organisms in saliva, nasal secretions, urine and feces and that infection is
readily transmitted from experimentally challenged deer to other deer sharing the same pen. These results
explain how tuberculosis is transmitted within a population of deer and will be used to develop strategies
for control of the disease. Current surveys to determine the prevalence of tuberculosis in wild whitetailed deer are based on examination of tissues in the head to detect lesions. In a study that involved
detailed examination of the entire deer carcass, we determined that about 50% of the infected deer did
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not have lesions in the head. These results indicate current methods to detect tuberculosis in wild whitetailed deer underestimate the prevalence of disease by 50% and that improved methods for detection are
needed. Supplemental feeding and baiting of white-tailed deer in the winter in Michigan has been
practiced for many years and is thought to contribute to the spread of M. bovis among deer. ARS
scientists at the NADC experimentally inoculated samples of six feeds typically used for baiting deer and
stored them for various lengths of time at different temperatures. We determined that M. bovis survives
on all feeds when frozen for at least 4 months. These results have been used by regulatory officials to
make recommendations regarding feeding and baiting of deer in Michigan. A new test for detection and
identification of M. bovis in tissue samples that are collected for microscopic examination was
developed. When animals are slaughtered, meat inspectors collect tissue samples from animals that are
suspected of having tuberculosis. Tissue samples are examined for microscopic evidence of tuberculosis
and for the presence of organisms. Stains used to detect M. bovis in a tissue sample also stain other
organisms so that it is not possible to identify the organism in the sample. The new test detects a specific
piece of DNA that is present only in organisms that cause tuberculosis. The new test permits more
accurate and rapid identification of animals with tuberculosis than was previously possible. The test is
used extensively at the request of state and federal regulatory officials to confirm suspected cases of
tuberculosis in animals. We adapted and standardized methods for differentiation of strains of M. bovis.
Differences among various strains of M. bovis can be identified by using specific genetic markers. Using
these markers, it is possible to determine if different animals are infected with a common strain or
different strains of M. bovis. This information is used by epidemiologists to determine possible sources
of infection in outbreaks of tuberculosis in animals. 6. What do you expect to accomplish, year by
year, over the next 3 years? FY 2002: 1) Further characterize the disease produced when cattle and deer
are experimentally challenged with aerosolized M. bovis. 2) Determine if M. bovis can be transmitted
from experimentally infected raccoons to uninfected penmates. 3) Determine routes of transmission of
M. bovis from does to fawns. 4) Begin to characterize immune response of white-tailed deer to M. bovis.
5) Determine the sensitivity and specificity of a new diagnostic test 6) Continue research to develop
improved methods for differentiation of M. bovis isolates. FY 2003: 1) Further characterize the
progression of disease and immune responses of white-tailed deer infected with M. bovis. 2) Continue
research to determine the sensitivity and specificity of a new diagnostic test. 3) Identify potential
vaccines that can be used for prevention and control of tuberculosis in wildlife and domestic animals. 4)
Continue research to develop improved methods for differentiation of M. bovis isolates FY 2004: 1)
Determine the safety and effectiveness of candidate vaccines. 2) Continue research to develop and
evaluate improved diagnostic tests. 7. What science and/or technologies have been transferred and to
whom? When is the science and/or technology likely to become available to the end user (industry,
farmer, other scientists)? What are the constraints if known, to the adoption & durability of the
technology product? ARS scientists assigned to the Bovine Tuberculosis Research Project routinely
presented research findings to scientists, state and federal action agencies, and industry groups. In some
cases, results of research conducted by ARS scientists are used as the basis for regulatory action. ARS
scientists received invitations to present results of research to specfic groups, such as the Michigan
Department of Natural Resources, because of the direct impact that the research findings have on
recommendations of the group. ARS scientists are members of several organizations, committees, and
working groups and provide scientific expertise on a broad range of issues relating to bovine
tuberculosis. A patent has been approved for a new test that was developed by ARS scientists for
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diagnosis of tuberculosis. (Invention Report No. 0152.01 "Diagnosis of Tuberculosis Infection Through
Analysis of Nitrite Production of Leukocytes Stimulated with Mycobacterial Antigens") 8. List your
most important publications in the popular press (no abstracts) and presentations to non-scientific
organizations and articles written about your work Presented results of research on CMU Public
Television program "Bovine Tuberculosis in Michigan: The Controversy," Spring, 2001. Presented talks
entitled "Use of the gamma-interferon assay for diagnosis of tuberculosis in cattle," "Naturally occurring
tuberculosis in white-tailed deer" and "Raccoons and Mycobacterium bovis: Maintenance or Spill-Over
Host" to participants of Bovine Tuberculosis in Michigan, conference 2001, March 5- 6, 2001, Lansing,
Michigan. Registered participants of the conference included state and federal animal health officials,
departments of natural resource and community health, livestock industry groups, private land owners,
hunt clubs, state legislators, congressional representatives, and members of the press. Presented talk
entitled "Emergence of tuberculosis in wildlife: Impact on animal agriculture and public health" at
Beltsville Symposium "Healthy Animals 2000", September, 2000.
PUBLICATIONS: 2000/10 TO 2001/09
1. Palmer, M.V., Whipple, D.L., Waters, WR. Experimental deer to deer transmission of Mycobacterium
bovis. American Journal of Veterinary Research. 2001. v. 62. p. 692-696.
2. Palmer, M.V., Whipple, D.L. Deer to deer transmission of Mycobacterium bovis. 43rd annual meeting
of the American Association of Veterinary Laboratory Diagnosticians. 2000. p. 22.
3. Waters, W.R., Palmer, M.V., Pesch, B.A., Olsen, S.C., Wannemuehler, M.J., Whipple, D.L. MHC
class II-restricted, CD4+ T cell proliferative responses of peripheral blood mononuclear cells from
Mycobacterium bovis-infected white-tailed deer. Veterinary Immunology and Immunopathology. 2000.
v. 76 p. 215-229.
4. Waters, W.R., Palmer, M.V., Pesch, B.A., Olsen, S.C., Wannemuehler, M.J., Whipple, D.L.
Lymphocyte subset proliferative responses of Mycobacterium bovis-infected cattle to purified protein
derivative. Veterinary Immunology and Immunopathology. 2000. v. 77. p. 257-273.
5. Waters, W.R., Palmer, M.V., Pesch, B.A., Olsen, S.C., Wannemuehler, M.J., Whipple, D.L.
Lymphocyte subset proliferative responses of Mycobacterium bovis-infected cattle: gd TCR+ and CD4+
cells are the predominant cells responding. The Great Lakes International Imaging and Flow Cytometry
Association Meeting, Detroit, MI 2000. Abstract No. 14.
6. Waters, W.R., Palmer, M.V., Whipple, D.L. Lymphocyte subset proliferative responses of tuberculous
cattle and white-tailed deer to Mycobacterium bovis purified protein derivative. In: Proceedings of the
Keystone Symposia entitled Molecular and Cellular Aspects of Tuberuclosis Research in the Post
Genome Era, Taos, NM. 2001. Abstract p. 98.
7. Whipple, D.L., Palmer, M.V., Slaughter, R.E., Jones, S.L. Comparison of purified protein derivatives
and effect of skin testing on results of a commercial gamma interferon assay for diagnosis of tuberculosis
in cattle. Journal of Veterinary Diagnostic Investigation. 2001. v. 13. p. 117-122.
Performing Institution:
Agricultural Research Service
Ames, Iowa 50010
DIAGNOSIS AND PATHOGENESIS OF TUBERCULOSIS IN ANIMALS
OBJECTIVES: Evaluate immune responses of reindeer sensitized to Mycobacterium bovis BCG;
Evaluate immune responses and diagnostic tests in reindeer experimentally infected with pathogenic M.
bovis; Evaluate lesions in reindeer experimentally infected with M. bovis; Evaluate immune respones and
lesion development in white-tailed deer experimentally infected with M. bovis.
APPROACH: A group of reindeer will be sensitized with M. bovis BCG and matched with a group of
non-sensitized control animals. Blood samples will be collected and skin tests will be conducted
periodically throughout the study period. Various immune function assays will be conducted to monitor
immune responses. In the second study, reindeer will be challenged with virulent M. bovis. Blood
samples will be collected and skin tests will be conducted similar to the first study. In addition, tissue
samples will be collected at various times to characterize the progression of disease in reindeer. Whitetailed deer will be experimentally challenged with M. bovis using two routes of inoculation and three
dosages. Immune responses will be monitored by evaluating blood collected at various times and
conducting skin tests. Lesions will be characterized at the conclusion of the study. BSL-1-3-N; Certified
through April 10, 2002.
Pathobiological Sciences
Louisiana State University
Baton Rouge, Louisiana 70893
MAINTENANCE OF AN ARMADILLO COLONY FOR LEPROSY RESEARCH
OBJECTIVES: The nine-banded armadillo is a permissive host for leprosy and is essential for
providing enormous numbers of Mycobacterium leprae as a research resource. The production of M.
leprae allows for the purification and production of skin test antigens for detecting new cases of clinical
disease. The objective of this project is to identify, condition and screen armadillos to determine their
suitability for in vivo propogation of M. leprae.
APPROACH: Armadillos will be captured in the wild from areas non-enzootic for armadillo leprosy.
Animals' suitability for inclusion in the colony will be determined by normal hematology, serology and
fecal exams, freedom from Mycobacterium sp infections, and negative for M. leprae based on antibody
titer and PCR. An assisted breeding program will be developed for captive armadillos.
PROGRESS: 2002/01 TO 2002/12
Leprosy is a chronic debilitating infectious disease caused by Mycobacterium leprae. Though significant
progress has been made in its treatment using multiple drug regimes, more than 850,000 new cases
occurred globally in 1999. Thus technologies are needed to interrupt the transmission of leprosy and
eliminate it as a public health problem. In addition, with recognition of persistence of leprosy in human
populations.there has been new appreciation for the importance of detection of sub-clinical infection and
occult reservoirs. A major obstacle to these lines of investigation is the fact that the leprosy bacillus
cannot be cultrured in vitro. However, M. leprae can be propagated in the tissues of the infected nine
banded armadillo, the only animal host known to be highly susceptible to leprosy. Through contact with
NIAID we maintain a colony of more than 100 M. leprae-infected armadillos to provide the scientific
community with its principal source of Mycobacterium leprae and associated research reagents. Several
different strains of M. leprae are maintained and we continue a quality assurance testing program on
these tissues and are refining our protocols with new research on aspects of inoculum control, animal
selection, susceptibility to leprosy and testing and management of experimental infections. The highly
bacilliferous tissues produced are shared principally with another contractor at Colorado State University
and secondarily with other investigators around the world.
IMPACT: 2002/01 TO 2002/12
The leprosy bacillus cannot be cultured in vitro. We are the world's sole source of sufficient batches of
armadillo-derived M. leprae for development of skin test antigens, a potential leprosy vaccine and
immunologically specific antigens required to study the basic pathogenesis of this disease.
PUBLICATIONS: 2002/01 TO 2002/12
No publications reported this period
PROJECT CONTACT:
Name: Klei, T. R.
Phone: 225-578-9903
Fax: 225-578-9916
Email: klei@vetmed.lsu.edu
and/or prokaryotic expression systems will be used for detection of antibody against viruses that do not
grow in cell culture. The baculovirus expression system has proven very useful for expression of foreign
proteins and will be used extensively for production of recombinant protein. C) Nucleic acid based
diagnostic tests including PCR tests and in situ hybridization will be developed for newly emerged
diseases. D) Standard procedures for determining pathogenetic mechanisms, modes of disease
transmission, and disease distribution will be applied to newly emeerged diseases such as postweaning
multisystemic wasting syndrome and Michigan rabbit viral heaptitis. E) Determine the effects of sample
handling on laboratory tests for bovine tuberculosis. The gamma interferon whole blood test for bovine
TB requires viable and functional white blood cells. Blood will be subjected to conditions that affect
viability white blood cells or function of white blood cells. Pokeweed mitogen will be used as a positive
control to assess effects of harsh conditions on white blood cell function.
PROGRESS: 2002/01 TO 2002/12
In January of 2001, an outbreak of fatal disease occured in a rabbitry in Michigan. A calicivirus was
detected in tissue emulsions using negative staining and transmission electron microscopy. The nucleic
acid sequence for the virus has been derived and it indicates a new group of rabbit caliciviruses has been
identified. The virus did not replicate in cell culture; therefore, the gene encoding the capsid protein for
that virus was cloned into a baculovirus expression system for production of intracellular antigen in
cultured insect cells. This has allowed development of a diagnostic test for detection of antibody against
the calicivirus in rabbit serum. The whole blood gamma interferon test for bovine tuberculosis, a reemerging disease in Michigan, was recently approved in the U.S. for use as an ancillary diagnostic
procedure. During 2002, 30 cattle were sensitized with antigen from Mycobacterium bovis to evaluate
effects of sample handling on performance of the gamma interferon test. Optimal holding and transport
temperature for blood used in the gamma interferon test was determined to be between 4 and 15 degrees
celsius. West Nile Virus (WNV) emerged in Michigan in 2001 with minimal impact on human or animal
health, other than death of several crows. However, in 2002, there were numerous fatal cases of WNV
infection in humans and in horses. Fatality rates also were high in several avian species in zoological
collections in Michigan. Equipment has been obtained and facilities modified to allow serological
surveys for WNV acitivity in 2003.
IMPACT: 2002/01 TO 2002/12
The development of a diagnostic test for rabbit calicivirus has allowed screening of rabbits for viral
infection before purchase for research purposes. Determining the effects of sample handling, especially
holding and transport temperature for blood, has been reported to the Tuberculosis Committee of the U.S.
Animal Health Association. Blood obtained as part of the tuberculosis control program in Michigan is
now held between 4 and 15 degrees celsius. This has had a beneficial impact on testing cattle for
tuberculosis.
PUBLICATIONS: 2002/01 TO 2002/12
No publications reported this period
PROJECT CONTACT:
Name: Bolin, S. R.
Phone: 517-432-9926
Fax: 517-353-4426
Email: bolins@ahdl.msu.edu
90 days post-inoculation, from fecal culture and various organ tissues. Organ tissues will be evaluated
microscopically at 30, 60, and 90 days post-inoculation. Project 3: Risk analysis of bovine TB for
surveillance and control programs Risk assessment: A prospective stochastic simulation model will be
developed to estimate the risk of a dairy or beef cattle herd developing TB infection, utilizing cattle herdrelated factors, deer-related factors, and other geographic factors. Results from the risk assessment model
will be forwarded to federal and state agencies, which can use this information to improve TB
eradication programs, and extension which can disseminate this information to the public. The results
will also be used in a proposed farm-level risk management model which will interface with the risk
simulation model.
PROGRESS: 2000/06 TO 2002/05
Project 1: Epidemiological study of M. bovis in wild and domestic animals Specific aims: determine 1)
spatial relationships of bovine TB to deer feeding, environmental conditions, and location-specific
human activity; 2) environmental survivability of M. bovis; 3) conduct studies of naturally infected hosts;
4) determine factors that influence the transmission of M. bovis in domestic and wild animals. A study
was conducted to examine the association between TB in deer and location, environment, and
supplemental feeding. Spatial clusters of TB were seen, and associations between risk factors and TB
prevalence were found. Preliminary results have been presented at conferences, and final results are
being prepared for submission to a refereed journal. Environmental samples (soil, feed, water, feces)
collected at feeding sites and TB-positive farms were tested for the M. bovis by the National Veterinary
Services Laboratories: 200+ samples were tested for and none yielded M. bovis. The lag time from
sample collection to processing may have affected our ability to recover M. bovis. Data on other wildlife
species from TB surveillance were reported (Bruning-Fann et al., 2001). Results of an epidemiological
study of a cat with M. bovis will be published (Kaneene et al., 2002b). Cats and other wildlife species
may contract TB through consumption of infected deer carcasses. Project 2: Experimental inoculation of
M. bovis into pigeons Specific aims: 1) study the susceptibility of pigeons inoculated with M. bovis by
oral and intraperitoneal routes; 2) isolate M. bovis from inoculated pigeons from feces and various organ
tissues; 3) evaluate organ tissues microscopically to understand the pathogenesis of M. bovis infection in
pigeons; 4) compare results on pigeons with previous studies on crows and starlings. 12 pigeons
inoculated with M. bovis (6 by oral gavage and 6 by intratracheal injection) and 6 control birds were in
the study. Two birds shed M. bovis 1 day post-inoculation and 0 were shedding at 30 days. One
intratracheally-inoculated bird developed granulomatous pneumonia with acid-fast bacilli, and tissues
were culture-positive for M. bovis. Pigeons can passively shed M. bovis in feces following inoculation.
Pigeons appear refractory to oral infection, but intratracheal inoculation may lead to active disseminated
infection. Results have been prepared for publication (Zwick et al., 2002). Project 3: Risk analysis of
bovine TB for surveillance and control programs Specific aims: 1) develop a risk analysis model of M.
bovis in Michigan livestock; 2) capture dynamic spatial aspects of disease in wildlife and livestock; 3)
use results from Project 1 to parameterize the risk model. An epidemiological study of M. bovis in cervid
ranches was conducted and has been published (Kaneene et al., 2002a). A case-control study of cattle
herds with M. bovis was done to identify risk factors for inclusion in the risk model, and results of the
study have been accepted for publication (Kaneene et al., 2002c). The risk analysis model has been
developed, and a stochastic simulation model to predict herd risk for TB based on management practices
is being developed.
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Email: kaneene@cvm.msu.edu
effector capabilities following DNA immunization under the various protocols. Thus, the first sets of
experiments we performed in the chimeric mouse model were proof of concept experiments related to the
practical limitations of obtaining sufficient numbers of cells of the appropriate specificity to generate T
cell lines or clones. We have successfully generated antigen-specific T cell lines from immunized
animals.
IMPACT: 1996/10 TO 2001/09
DNA vaccines are an ideal platform for delivering antigens into the class I pathway and thus eliciting
potent CTL responses. Species differences in responsiveness to CpG motifs and the resulting
inflammatory response suggest the potential need for added costimulation. This series of studies have
examined this requirement in part and set the stage for continuing studies in large animals.
PUBLICATIONS: 1996/10 TO 2001/09
1. Zhang, Y., L.K.M. Shoda, D.M. Estes, G.H. Palmer and W.C. Brown. 2001. Activation of B
lymphocytes, monocytes and macrophages of cattle by a CpG oligoedeoxynucleotide (ODN 2059)
containing the GTCGTT motif. J. Inter.& Cytokine Research 21:871-881
2. 5th Annual Conference on Vaccine Research, Baltimore, MD., May 2002. Mycobacterium bovis BCG
vaccination of cattle: activation and proliferation of lymphocyte subsets upon stimulation with
mycobacterial antigens. W.R. Waters, B.J. Nonnecke, T.E. Rahner, M.V. Palmer, D.L. Whipple, M.R.
Foote, A.C. Maue, and D.M. Estes.
OBJECTIVES: We hypothesize that bison neutrophils contain mobilizable proteins, which have direct
antimicrobial properties with therapeutic potential against persistent bison diseases such as tuberculosis.
To address this hypothesis, we propose the following aims: 1) Characterize biochemically and
functionally the types of antibacterial proteins present in bison neutrophils and 2) Probe for and clone
selected bison neutrophil antimicrobial proteins.
APPROACH: Objective 1 will require the collection of blood from captive bison and further isolation
and purification of neutrophils. We will then use one or more procedures to extract a subset of proteins,
which is likely to contain neutrophil antimicrobial proteins (AMPs), as determined by bacterial killing
assays. Finally, we will systematically screen the proteins we have extracted, for killing activity against
E. coli, S. aureus, and M. bovis BCG. Following completion of objective 1, we hope to have identified
one or more proteins that have interesting antimicrobial activity; we then propose to find and clone the
gene(s) for these proteins, so that they can be produced as recombinant proteins for further detailed
mechanistic and microbiological testing. One possibility is that the protein of interest is one of the bison
bactenecins, which we have already begun to characterize, and we will continue cloning these genes as
described below. If the protein does not appear to be one of the bactenecins, we will use N-terminal
sequencing to obtain sufficient code to design primers for further sequencing/cloning.
PROJECT CONTACT:
Name: Quinn, M. T.
Phone: 406-994-5721
Fax: 406-994-4303
Email: mquinn@montana.edu
NON-TECHNICAL SUMMARY: Mycobacterial species are important pathogens in both animals and
humans. Study into the lifestyles of mycobacteria species pathogenic to animals and humans such as M.
tuberculosis, M. leprae, M. bovis and M. avium reveals extensive parallels in their mechanisms of
intracellular survival and persistence. The laboratory is devoted to the study of microbial pathogens that
exploit the macrophage as their host cell.
OBJECTIVES: The laboratory is dedicated to the study of pathogen mycobacteria. The primary area of
interests are as follows: 1. Analysis of the biology of the interaction between the macrophage and the
bacillus with respect to the intracellular environment and the regulation of host cell function. 2. The
elucidation of the metabolism of the intracellular bacillus and its exploitation as possible targets of drug
action. 3. The appreciation of the modulation of the infection foci and the role of the granuloma in the
persistence of infection.
APPROACH: Cell Biology of Intracellular Infections by Mycobacterium avium: This delicate interplay
between the bacterium, and its potentially microbicidal host cell is little understood. Previous work in the
laboratory has fostered the belief that, with respect to the interaction with macrophages and the immune
responses at site of infection, there are many parallels between pathogenic mycobacteria species,
including Mycobacterium bovis. For this reason emphasis is also placed on exploitation of genetic
approaches available for other mycobacterial species, notably M. tuberculosis and M. bovis, for the
resolution of mechanisms common to all pathogenic mycobacteria. 2. Elucidation of Intermediate
Metabolism and Carbon Source Acquisition by M. bovis and M. tuberculosis: We have extensive
experience in modelling intracellular infections by both prokaryote and eukaryote pathogens and propose
to apply this expertise to determining the contribution of the glyoxylate shunt pathway to infection. 3.
Formation and Maintenance of the Granuloma and it role in Infection by Mycobacterium spp: We have
carried out a systematic analysis of bacterial lipidoglycans released and trafficked through infected
macrophages. These comprise 7 major species of lipids some, or all, capable of inducting granulomas in
mice. The ability of these lipids to expand the influence of the bacteria beyond the infected macrophages
and induce granuloma formation suggest that they play roles key to the evolution of this response. Our
recent development of an in vivo model exploiting these lipids will enable the functional determination
of the roles of these molecules in granuloma induction.
PROGRESS: 2002/01 TO 2002/12
Mycobacterium tuberculosis is a phenomenally successful pathogen that infects approximately 1/3 of its
host species, mankind. Its success lies in its capacity to establish and maintain its infection within the
hosts' phagocytes. In the short term this is achieved through arresting the normal maturation of its
phagosome and blocking its fusion with acidic, hydrolytic lysosomes. We have been studying this aspect
of the pathogen's biology through the isolation of transposon-mutagenized bacteria defective in arresting
the maturation of the phagosome. Mutants isolated in this screen demonstrate an altered intracellular
distribution and are attenuated for survival inside macrophages. In the longer term the continuation of
infection relies on the bacterium's capacity to respond to and to modulate the changing environment
within the immune host. The bacterium's metabolism appears geared to respond to environmental shifts
experienced in activated versus resting macrophages. In resting macrophages the bacterium replicates
freely and appears to rely extensively on the TCA cycle, however upon activation of the macrophage the
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bacterium mobilizes the glyoxylate cycle, usually associated with a dependence on fatty acids as primary
carbon source. The promoter for the gene encoding the glyoxylate cycle enzyme isocitrate lyase appears
regulated tightly by factors such as oxygen tension and carbon source. We have adopted a genetic
approach that exploits this regulation to identify environmental factors and the bacterial sensors and
effectors responsible for this shift. Finally, the tissue surrounding the infected macrophages develops into
a granuloma. This structure, the tubercle, fulfills functions for both pathogen and host. For the host the
granuloma walls off the infection and restricts spread, but for the bacterium the granuloma actually
ensures persistence of the infection. The bacterium is able to persist because the granuloma structure
ensures that the lymphocytes capable of activating the macrophages are maintained as a mantle or cuff
around the periphery of the granuloma, away from the infected macrophages in the center. Bacterial cell
wall lipids are released by intracellular bacteria and appear to play an active role in the formation and
maintenance of this structure. The biological activities of these lipids are being explored in an in vivo
granuloma model.
IMPACT: 2002/01 TO 2002/12
Infections by Mycobacterium spp. continue to be a serious problem for the health of both humans and
livestock. Results of these studies will provide a better understanding of the pathogen's biology through
the isolation of transposon-mutagenized bacteria defective in arresting the maturation of the phagosome.
PUBLICATIONS: 2002/01 TO 2002/12
1. Beatty, W., Rhoades, E.R., and Russell, D.G. 2002. Association of a macrophage galactose-binding
protein with Mycobacterium-containing phagosomes. Cell. Microbiol. 4. 167-176.
2. Smith, C.V., Huang, C-C., Miczak, A.M., Russell, D.G., Sacchettini, J.C., and Honer zu Bentrup, K.
2003. Biochemical and Structural studies of Malate synthase from Mycobacterium tuberculosis. J. Biol.
Chem. 278. 1735-1743.
3. Russell, D.G., Mwandumba, H.C., and Rhoades, E.R. 2002. Mycobacterium and the coat of many
lipids. J. Cell. Biology. 158. 421-426
4. Liu, K., Yu, J. and Russell, D.G. 2003. pckA-deficient mutants of Mycobacterium bovis BCG show
attenuated virulence in mice and in macrophages. Microbiology. 149. 1829-1835
5. Rhoades, E.R., Hsu, F-F., Torrelles, J.B., Chatterjee, D. and Russell, D.G. 2003. Identification and
macrophage-activating activity of glycolipids released from intracellular Mycobacterium spp. Mol.
Microbiol. 48. 875-888
PROJECT CONTACT:
Name: Wood, J. R.
Phone: 607-253-3759
Fax: 607-253-3756
Email: jrw7@cornell.edu
APPROACH: rDNA sequences.. We will obtain rDNA sequences using both direct PCR from tissues
and PCR from isolated colonies In addition, we will continue to use our new primers for amplification of
problematic samples, especially fish tissue samples, as they amplify smaller products and thus appear to
be more sensitive for certain samples These primer sets provide SSU sequence, and to more precisely
characterize and differentiate our isolates (e.g., the closely related salmonid isolates), we will examine a
more variable region of the gene (the ITS) using published primers After the various isolates are
sequenced, we will compare sequences using BLAST Search to compare with existing strains in
GenBank. Furthermore, we will conduct phylogenetic comparisons using standard molecular systematics
programs available through PAUP, etc. Virulence. We will characterize the virulence of representative
strains obtained from our epidemiological and taxonomy studies using in vitro macrophage assays. To
evaluate the ability of the bacterium to infect and survive in macrophages, we propose to employ the
systems currently in use in Dr. Bermudez's laboratory. We plan to determine: (1) efficiency of invasion
and (2) the ability of survive and replicate inside macrophages. For those experiments we propose to use
carp macrophage cell line, the zebrafish macrophage cell line we have recently established from
zebrafish spleens, and mouse macrophage cell line RAW 246.7. We also plan to use as controls for the
experiments a human isolate of Mycobacterium avium, a fish derived Mycobacterium marinum (also a
human isolate) and a non-virulent Mycobacterium smegmatis. The strain to be tested and the controls will
be cultured and then used to infect macrophages in a ratio of 0.1 to 1, 1 to 1 and 10 to 1
(bacteria:macrophage). Invasion will be determined after 1 hour. The inoculum will be plated onto 7H11
agar plates to determine the number of bacteria. Infected macrophage monolayers will be washed several
times with buffer in order to remove extracellular bacteria and then the monolayers will be lysed by
incubating them with water for 10 min as described (Bermudez and Young 1988; Bermudez et al. 1994).
Then 0.025% SDS will be added to the suspension for 10 additional minutes to prevent clumping. The
suspension will be plate onto 7H11 plates to determine the number of viable intracellular bacteria. The
efficiency of invasion will be calculated as a percentage of the initial inoculum used to infect the
monolayers. To determine the ability of the bacteria to grow intracellularly, monolayers will be
established and infected in a similar manner as described above. The intracellular bacteria will be
allowed to grow and 4 and 7 days after infection the monolayers will be lysed and the number of
intracellular bacteria quantified as reported (Wagner et al. 2002). The bacterial growth or decrease of the
number of intracellular bacteria will be calculated as the variation of the number of bacteria inside
macrophages 1 h after infection.
PROGRESS: 2002/01 TO 2002/12
NEW PRIMERS: We have had moderate success amplifying 16s rDNA using the Talaat primers which
worked well for cultures, but we obtained mixed results with tissue samples. We designed new primer
sets, dividing this region into two sections. These sets proved to be more sensitive and we were able to
obtain product from difficult tissues. ZEBRAFISH ISOLATES: (Facility 1) Using the 16S primers and
restrictive enzyme approach for identification of fish mycobacteria we identified the first zebrafish
isolates that we investigated as M. marinum. In contrast, when we sequenced this specimen, it clustered
as a sister taxon to M. haemophilum, a human pathogen not recognized as a pathogen of fishes. We
considered that this may be a terrestrial contaminant, but refuted this hypothesis as we obtained identical
sequence from a PCR product amplified from the heart of additional fish from the same colony. Infected
fish exhibited massive invasion and associated tissue reaction in the visceral organs. In addition, some of
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the fish with the M. haemophilum-like infection showed an unusual pathological condition with
numerous mycobacteria colonies within the central nervous system not associated with inflammatory
changes. (Facility 2.) A second research facility suffered a massive outbreak of mycobacteriosis in which
the entire colony was ultimately destroyed. Using our new 16s rDNA primers and those of Talaat et al.
(1997), we also obtained 16s rDNA sequence from two zebrafish from this epizootic. This isolate cluster
within a clade was comprised of M. septicum and M. peregrinum. These species are related to M.
fortuitum, forming a clade of fast growing bacteria known to be pathogens of humans. (Facilty 3.) We
maintain a sentinel fish monitoring program at the two zebrafish facilites at the University of Oregon
Zfish Facility - i.e., exposing zebrafish to effluent water from the entire system. Although no outbreaks
have been observed, we recently detected mycobacteiosis in a few sentinel fish based on histology. We
have obtained an isolate from these fish in culture, and it will be added to our phylogenetic analyses.
(Salmon Isolates.) We obtained five isolates from salmonids from the OSU fish pathogen culture culture
at the Hatfield Marine Science Ctr . All salmonid isolates, including one from Australia were very
closely related, showing only a maximum sequence difference of 4 bp over about 850 bp of the 16S
rDNA. These isolates cluster together as a group, near M. chelonae, a recognized pathogen of fishes.
(Marine Fish Isolates.) We obtained a culture from a moribund sable fish maintained at the Hatfield
Marine Science Ctr. which was clustered with the salmonid isolates near M. chelonae. We have several
kidneys (frozen) from rockfishes with Mycobacterium infections. To date we have not been able to
culture Mycobacterium spp. from these tissues. However, direct PCR using new primers that we
designed allowed us to obtain about 850 of reliable sequence. This specimen was identical to M.
monteflorense, a recently described Mycobacterium species from moray eels from Florida. This is the
first report of the infection in another fish species and from the Pacific Ocean.
IMPACT: 2002/01 TO 2002/12
The genus Mycobacterium causes several diseases in animals, including tuberculosis in humans (i.e. M.
tuberculosis). Particularly with emergence of AIDS, in recent years many new Mycobacterium species
have been recognized as virulent or opportunistic human pathogens. Our study has revealed that several
other species of Mycobacterium can cause disease in fishes than what was previously recognized,
including human pathogens such as M. haemophilum. These results provide further evidence that fishes
may be reservoirs for Mycobacterium infections that are potential pathogens for humans.
PUBLICATIONS: 2002/01 TO 2002/12
Kent, M.L., V. Watral, J.L. Matthews, C.M. Whipps. Proceedings of the 43rd Western Fish Disease
Workshop. 25- 26 June 2002. Corvallis, Oregon, p. 11.
PROJECT CONTACT:
Name: Kent, M. L.
Phone: 541-737-5088
Fax: 541-737-2166
Email: Michael.Kent@orst.edu
differential expression of eight clones was confirmed by reverse Northen blot and ribonuclease
protection assays. Most of the genes identified were associated with an overexpression pattern after
infection. Differential gene expression was observed at all the time points studied (0, 12, 24h), however
the majority of the changes in gene expression occurred at the early stages post-infection. A GenBank
sequence database search identified the differentially expressed genes as the putative bovine homologues
of serum amyloid A protein (SAAP), legumain, signaling lymphocytic activation molecule (SLAM),
alveolar macrophage-derived chemotactic factor II, ferritin heavy-chain and osteopontin. Results from
this study reveal that M. bovis modulates the gene expression of bovine macrophages shortly after
infection.
IMPACT: 2002/01 TO 2002/12
Better understanding of the regulation of gene expression in the bovine host target cell, the macrophage,
particularly genetically controlled factors controlling survival of Mycobacterium bovis, provide the
rationale for improved control of tuberculosis.
PUBLICATIONS: 2002/01 TO 2002/12
1. Adams, L. G. 2001. In vivo and in vitro diagnosis of Mycobacterium bovis infection. Rev. sci. tech.
Off. Int. Epiz. 20:302-324.
2. Gutierrez-Pabello, Jose A., David N. McMurray, and L. Garry Adams. 2002. Upregulation of
Thymosin of B-10 by Mycobacterium bovis Infection in Bovine Macrophages is Associated with
Apoptosis. Infection & Immunity, 70:2121-2127.
3. Chacon, O., Z. Feng, N.B. Harris, N.E. Caceres, L.G. Adams, and R.G. Barletta. 2002. Mycobacterium
smegmatis D-alanine racemase mutants are not dependent of D-alanine for growth. Antimicrobial Agents
and Chemotherapy. 46:47-54.
PROJECT CONTACT:
Name: Adams, L. G.
Phone: 979-845-9816
Fax: 979-862-1088
Email: gadams@cvm.tamu.edu
ice. The tubes will be centrifuged immediately and the plasma removed to analyze the following with an
automated chemistry analyzer: total protein, albumin, globulin, creatinine, total bilirubin, alkaline
phosphatase, aspartate aminotransferase, glucose, cholesterol, sodium, chloride, potassium, calcium,
magnesium, and phosphorus. Hematologic reference intervals will be determined for the stock group of
fish and will be used as the standard of comparison for any changes in blood values due to the bacterial
infections. Macrophages will be isolated from the spleen and pronephros of control and exposed fish at
the 7 sampling times. Flow cytometry will be used to determine macrophage function and activation by
monitoring chemiluminescence and phagocytic activity. Additionally, tissue samples will be collected
and fixed in 10% neutral buffered formalin, paraffin embedded, sectioned, and stained with hematoxylin
and eosin and Gram stain. Tissue sections will be analyzed for the presence of bacteria and pathological
changes associated with the bacterial infection. The general linear model function of SAS System will be
used to perform analysis of variance to test for treatment effects, time effects and treatment time
interactions. Correlation will be used to associate tissue pathology with hematologic changes.
PROGRESS: 2001/10 TO 2002/09
Cultured juvenile hybrid striped bass and cultured juvenile summer flounder were exposed to
Mycobacterium marinum by inoculation and water borne routes, respectively. At various times postexposure, a sample of fish was collected, humanely euthanized and necropsied. Tissues were submitted
for standard histopathology and a pathological description developed for the time course of the pathology
associated with the infection. Both species of fish had tissue pathology as a result of the infection, but
had differing courses and amounts of pathology. The hybrid striped bass typically had the classical
granulomas, while the summer flounder typically had a severe granulomatous inflammatory response
without discrete granuloma formation. The time course for pathology in both species was described.
IMPACT: 2001/10 TO 2002/09
This study documents the progressive pathological changes in fish associated with a specific bacterial
disease, mycobacteriosis, and provides a diagnostic description for assessing the health of fish in the face
of this infection. As a result, veterinarians and other fish health professionals will have a method for
evaluating chronic disease changes in hybrid striped bass and summer flounder.
PUBLICATIONS: 2001/10 TO 2002/09
1. Hughes, K.P, R.B. Duncan. and S.A. Smith. 2002. Renomegaly associated with a mycobacterial
infection in summer flounder, Paralichthys dentatus. Fish Pathology 37:83-86.
2. Hughes, K.P., R.B. Duncan, S.A. Smith. 2002. Mass in oral cavity of cultured summer flounder,
Paralichthys dentatus. Lab Animal 31:25-27.
3. Wolf, J.C. and S.A. Smith. 1999. Comparative severity of experimentally-induced mycobacteriosis in
striped bass Morone saxatilis and hybrid tilapia Oreochromis spp. Diseases of Aquatic Organisms.
38:191-200.
PROJECT CONTACT:
Name: Schurig, G. G.
Phone: 540-231-4992
Fax: 540-231-5815
the 85A antigen is threefold: 1) the 85A antigen is one of the major secreted fibronectin binding proteins
of all mycobacterial species including M. bovis and M. marinum, 2) the 85A antigen induces an effective
protection against infection in other mycobacterial species, and 3) the 85A antigen shows high homology
with various mycobacterial species suggesting that the antigen may be cross-protective against other
mycobacterial species. Expression of sodC will be driven by its own promoter while that of fbpA will be
driven by the groE heat shock promoter of Brucella. The fbpA from M. marinum will be obtained by
amplification via PCR from the genomic DNA. Overexpression of SOD and expression of the 85A
antigen in the recombinant RB51 strain will be confirmed by Western blot analysis. The recombinant
strain will be subjected to heat-shock by incubating the cultures for 30 minutes at 42 degrees C to upregulate the production of the mycobacterial protein. After treatment, the bacteria will be washed in PBS,
resuspended to obtain approximately 1011 colony forming units (CFU) per ml, and frozen at -80 degrees
C. When the fish are ready for immunization, the bacteria will be subjected to 300 krad of radiation
which renders the bacteria completely inactivated without any effect on its adjuvant and antigenic
properties. Thus, the mycobacterial recombinant vaccine will be rendered completely non-infectious
without changing its immunomodulatory effects. Two routes of immunization, intraperitoneal injection
(IP) and water immersion (WI) will be tested. Juvenile striped bass will be divided into 5 groups/route of
140 fish each and individually identified. One group for each route will be sham-immunized with sterile
saline, while the other four groups will receive concentrations of x10E8, x10E9, x10E10, and x10E11.
On Days 0, 14, 28, and 42, fish will be bled and the serum analyzed by indirect ELISA for humoral
antibodies to the RB51 strain of B. abortus and the M. marinum 85A antigen. The cell-mediated response
will be evaluated by a lymphoproliferative assay where splenocytes will be harvested on Days 28, 42, 90,
and 120 and cultured in 96-well plates in the presence of M. marinum 85A antigen, B. abortus RB51
crude extract, concanavalin A (positive control), or no additives (negative control). The cells will be
cultured for 3-5 days and then pulsed with 1 micron Ci of [3H] thymidine/well for 18 hours, harvested,
and placed in a liquid scintillation counter to evaluate [3H] thymidine incorporation. On Days 42, 90, and
120, fish from each group will also be challenged with M. marinum. Tissue samples of fish from this
study will be routinely processed, stained with hematoxylin and eosin (H & E) and Zeihl-Neelson stain,
and examined by microscopy for granulomas or other pathology.
PROGRESS: 2001/10 TO 2002/09
A DNA vaccine for fish mycobacteriosis was constructed against the M. marinum 85A protective antigen
using standard protocols. The basis for the selection of the 85A antigen is threefold: 1) the 85A antigen is
one of the major secreted fibronectin binding proteins of all mycobacterial species including M. bovis
and M. marinum, 2) the 85A antigen induces an effective protection against infection in other
mycobacterial species, and 3) the 85A antigen shows high homology with various mycobacterial species
suggesting that the antigen may be cross-protective against other mycobacterial species. Two routes of
immunization, intraperitoneal injection (IP) and intrmuscular injection (IM) were tested. Juvenile striped
bass were divided into 5 groups/route of 140 fish each and individually identified. One group for each
route was sham-immunized with sterile saline, while the other four groups received concentrations of
108, 109, 1010, and 1011. On Days 0, 14, 28, and 42, fish were bled and the serum analyzed by indirect
ELISA for humoral antibodies to the M. marinum 85A antigen. The cell-mediated response were
evaluated by a lymphoproliferative assay where splenocytes were harvested on Days 28, 42, 90, and 120
and cultured in 96-well plates in the presence of M. marinum 85A antigen, concanavalin A (positive
http://nal.usda.gov/awic/pubs/TB/USDAFunded.htm (37 of 38) [04/01/06 2:04:36]
control), or no additives (negative control). The cells were cultured for 3-5 days and then pulsed with
1uCi of [3H] thymidine/well for 18 hours, harvested, and placed in a liquid scintillation counter to
evaluate [3H] thymidine incorporation. On Days 42, 90, and 120, fish from each group were challenged
with M. marinum. Tissue samples of fish from this study will be routinely processed, stained with
hematoxylin and eosin (H & E) and Zeihl-Neelson stain, and examined by microscopy for the presence
of granulomas or other pathology. To date, hybrid striped bass have been immunized with the DNA
vaccine and their humoral and cell-mediated immune responses have been documented. These responses
appear to be dose-dependant, with higher vaccine doses eliciting stronger immune responses. Preliminary
histopathology results suggest that the vaccine may have some protective effects against live bacterial
challenge.
IMPACT: 2001/10 TO 2002/09
As mycobacteriosis is a serious bacterial disease of cultured fish, the construction of an effective vaccine
against this pathogen will protect the fish ensuring that healthier and greater numbers of fish reach
marketable size. In addition, since these bacteria are potential zoonotic pathogens, a vaccine should
decrease the exposure of humans to this infectious agent.
PUBLICATIONS: 2001/10 TO 2002/09
No publications reported this period
PROJECT CONTACT:
Name: Schurig, G. G.
Phone: 540-231-4992
Fax: 540-231-5815
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JULY 2003
CONTENTS.
Contents
Chairmans
Introduction
Recommendations
Badger Vaccines
Cattle Vaccines
References
Appendix 1
Appendix 2
Appendix 3
Appendix 4
Appendix 5
Appendix 6
Appendix 7
Appendix 8
Appendix 9
Appendix 10
Appendix 11
Appendix 12
Appendix 13
Appendix 14
Appendix 15
PAGE
2
3
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8
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17
23
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39
45
48
53
58
62
69
72
82
101
106
108
1. CHAIRMANS INTRODUCTION.
1.1 Bovine TB is a serious disease of cattle in Great Britain. The incidence of
the disease is increasing and extending beyond the traditionally TB infected
areas in the West Country. It is a disease of complex epidemiology involving
a wildlife reservoir of infection, the size and contribution of which to the
disease in cattle, is not known. Control of the disease is ultimately likely to
require a multi-faceted approach which will require a better scientific
understanding of the disease in both cattle and wildlife. To achieve this, Defra
has put in place a broad based programme of research on which it can be
expected that future control policy options will be based.
1.2 Vaccination of either cattle or wildlife is considered to be a potential, long
term, policy option. The Independent Scientific Group on Cattle TB (ISG) has
previously commented on the importance of vaccine research and advised
that this option should be kept under active consideration. Vaccines are often
talked about in simplistic terms that ignore the paucity of scientific information
available, and the financial and time dimensions required for developing a
successful vaccine. This reflects a presumption that a vaccine strategy, for
cattle or badgers, is scientifically, technically and operationally easy to put in
place. In response to a request from ministers to better inform them on the
development needs and potential value of vaccines the ISG established a
Sub-Committee comprising some ISG members plus external experts
(Appendix 15) to carry out an objective review of the feasibility for pursuing a
TB vaccination strategy for either cattle or wildlife. Consideration was given to
ongoing research and to identify further research which would be needed to
develop and test vaccines and successfully extend their use into the field.
1.3 The Sub-Committee approached the task by identifying questions and
issues that needed to be considered and inviting members of the SubCommittee and other external experts to prepare position papers to aid its
discussions and deliberations. To fully record the approach adopted by the
Sub-Committee and to illustrate the breadth of its discussions these
documents form Appendices to this report.
The Sub-Committee also
recognised that as technology develops and new scientific data become
available, further reviews are likely to be needed; the prepared position
papers will form a useful reference point for future deliberations.
1.4 From an operational perspective the field use of a cattle vaccine should
present few problems since there is direct access to the target species and
the vaccine could be given directly to each individual animal by injection.
However there are difficult scientific questions that need to be considered as
well as policy issues before use of a vaccine in the field could be
contemplated; it is worthy of note that all other countries with an intransigent
cattle TB problem have rejected the option of using currently available cattle
vaccines (in effect, only BCG is available) on the grounds of its relatively poor
efficacy and that its use would limit the ability to export breeding cattle.
1.5 We recognise that the demands of an ideal cattle vaccine are particularly
severe since the vaccine would need to prevent the establishment of
2. RECOMMENDATIONS.
2.1 Badgers.
2.1.1 BCG may be of value to protect badgers but before a field trial of BCG
can be put in place it is essential to await the outcome of vaccine protection
studies that are currently being carried out on a population of housed wild
badgers in the Republic of Ireland (RoI). We advise that even if a degree of
protection is shown in these studies that success in the field cannot be
guaranteed and that a field trial would inevitably have to be put in place and
designed on a large scale and continue for an extended time period, in order
to demonstrate its effect on the incidence of TB in cattle.
2.1.2 It will also be necessary to await the outcome of the RBCT in order to
obtain essential epidemiological data on TB in the badger and the impact of
badger culling on cattle TB before deciding on whether or not to proceed with
a field trial.
2.1.3 A field vaccine for badgers will need to be delivered as an oral bait.
Priority needs to be given to development of oral/respiratory delivery systems
that are effective in stimulating protective immune responses without capture
of badgers.
2.1.4 There is additional preparatory work that could be undertaken in order
to enable a field trial to be in place as soon as badger vaccine protection and
field trial data become available. We recommend that oral bait formulation
studies be continued, and that field studies be initiated on bait uptake and bait
targeting in badgers and the level of bait uptake by non-target species
including cattle.
2.2 Cattle.
2.2.1 BCG is the only currently available vaccine candidate that could be
considered for practical use. Experimental challenge of vaccinated cattle has
demonstrated very variable protection of up to 70%, as judged by reduction in
pathology, but lower levels of protection against establishment of infection.
Field trials have generally provided poor protection. It is our view that BCG in
its present form would not provide an effective cattle vaccine and that cattle
vaccination could only be considered when an improved vaccine is available.
2.2.2 It will be imperative to maintain the current effort on development and
testing of vaccines, which relates to both cattle, including neonates, and
badgers, with emphasis on testing in the target species (cattle). The well
developed and effective international collaborations with scientists working on
vaccines for both animal and human TB must be maintained and built on.
2.2.3 We also recommend studies on the oral sensitisation of cattle with BCG
and on the effect of vaccinating already infected animals particularly with
respect to lesion development.
3. BADGER VACCINES.
3.1 Introduction.
3.1.1 In its report of 1997, the Kreb's Committee recommended1 that a
research programme aimed at developing a vaccine against tuberculosis for
use in cattle should be implemented, although the option of developing a
vaccine for use in wildlife (badgers) should also be retained. A vaccine
targeted at badgers would not be required to protect individual badgers
against TB, but would need to reduce transmission to cattle. Thus a vaccine
which reduces the severity of the disease and/or reduces shedding of the
bacteria from infected badgers could have the desired effect of reducing
transmission to cattle. Of course, such a vaccine would have the additional
requirement of being safe, both for the target species (badgers) and for nontarget species including domestic animals, wildlife and humans (Appendix 1).
In principle developing a wildlife vaccine may be regarded as a more realistic
and less long-term option than developing a cattle vaccine. However, it
should be noted that, implementing a field trial to measure the effect of a
wildlife vaccine on TB in cattle presents considerable challenges, and cannot
be done quickly. Moreover, while there is reasonable evidence that virtual
elimination of badgers has been shown to have an impact on TB in cattle, the
influence of reducing the numbers of infected badgers and/or the severity of
disease in affected badgers on the risk of TB in cattle is not known. Thus, any
decision to proceed towards a field trial of a vaccine targeted at badgers (or
other wildlife species) should await the outcome of the ongoing RBCT. We do
however advise that preparatory work is put in place to inform on matters such
as bait uptake and improved vaccine formulations, and thus prepare for the
possibility of a trial.
3.2 Epidemiological considerations and vaccination strategies.
3.2.1. Developing and testing a vaccine for badgers remains a considerable
undertaking. Even with an appropriate vaccine candidate, many hurdles
remain, and even if these hurdles are overcome, there can be no guarantee of
success. The development of a vaccine strategy targeted at badgers would
need to address the following issues:
3.2.1.1 The expected efficacy of the vaccine, as determined by experimental
protection studies.
3.2.1.2 The extent of the badger population to be covered and the optimal
area of coverage required to have a measurable impact on the disease in
cattle.
3.2.1.3 The route of delivery of the vaccine would need to be easy and
inexpensive, and while providing the maximum possible take-up rate in
badgers, it should avoid immunisation of non-target species and particularly
cattle.
3.2.1.4 How would a badger vaccine be used in the field? What are the
frequency and duration of vaccine application that would be required. What
proportion of badgers would eat the bait? What is the duration of immunity?
3.2.2
Given the extent of the TB problem in cattle, it is likely (assuming
current studies confirm that badgers are an important source of infection) that
vaccination would need to be applied over large areas to have a significant
impact on the problem. The rapid turnover of the badger population and the
fact that vaccination is unlikely to confer complete protection also means that
a vaccine would need to be administered at regular intervals (probably at least
annually) over a prolonged period of time. While trapping of badgers in order
to administer vaccine by injection may be justifiable under certain
circumstances (e.g. to deal with small, well-circumscribed pockets of disease),
it would be impractical for the more extensive application of vaccination that is
required to address the problem. Such a vaccination programme would
require an oral vaccine that could be delivered in the form of a bait.
3.2.3 There is currently insufficient knowledge of the epidemiology of the
disease in badgers and the route and frequency of transmission to cattle, to
produce simulation models for predicting the level of vaccine efficacy and
determining the optimal vaccination strategy required to interrupt transmission
to cattle (Appendix 2). While the RBCT will provide useful epidemiological
data, quantitative information on a number of parameters relating to
transmission of infection, which would be particularly useful for model
construction, are extremely difficult to obtain. For these reasons the only
realistic way of determining whether or not a vaccine (even if effective in
badgers) has an impact on TB in cattle is to conduct a field trial to measure
the effect of vaccination on the incidence of cattle herd breakdowns. The
limitations in producing precise mathematical models for TB in badgers also
make it impossible, at present, to predict the long-term impact of vaccination
on TB in the badger population, and whether or not it might be possible to
achieve eradication in local populations of badgers.
3.2.4 Considering the current situation regarding vaccine candidates, the only
vaccine which is currently available and which is likely to be available within
the medium term is the human vaccine, BCG (Bacille Calmette-Guerin). BCG
was developed during the early part of the 20th Century. It was derived from a
strain of virulent Mycobacterium bovis which became attenuated following
prolonged passage in laboratory culture medium. BCG was introduced as a
human vaccine on a large scale during the second half of the 20th Century and
is currently one of the most extensively used vaccines available (Appendices
3 and 4).
3.2.5 Unfortunately, it has now become evident that the efficacy of BCG
against the major form of TB in humans is extremely variable, ranging from
0% to approximately 80% in different trials. The basis for this variability is not
fully understood. BCG has been tested in experimental conditions in a wide
variety of animal species, both for efficacy against TB and for possible
virulence (Appendices 3 and 4). This extensive testing of BCG in a wide
variety of mammalian species has failed to reveal any substantive evidence
that the organism can cause disease (Appendix 3). At the same time, most
species which have been used in experimental efficacy studies have been
found to exhibit some level of protection against challenge with virulent M.
tuberculosis or M. bovis.
3.2.6 The most relevant information on the potential of BCG to protect wildlife
against M. bovis infection, and interrupt transmission to cattle comes from
work carried out (Appendix 5) in New Zealand (NZ). In NZ the Brushtail
possum is a major wildlife reservoir for M. bovis infection. In preliminary
experimental studies, BCG administered to Brushtail possums by a variety of
routes, including orally, gave low level protection against experimental
infection with M. bovis. Subsequently a field study was carried out in which
vaccinated and unvaccinated control possums were released into a study
area and the amount of TB in the possum population was monitored for 2
years. The results, which because of inadequate experimental design are
difficult to interpret, confirmed that BCG gave some protection to possums
against M. bovis infection in this field situation although the effects on cattle
TB could not be measured. Thus, these limited studies are the only grounds
for considering trialing BCG for protection against TB in badgers. However,
even with evidence of significant protection in badgers, it would be difficult to
predict how this translates to protection of cattle. Therefore, it would be
critical to design a trial to measure the impact of badger vaccination on TB in
cattle.
3.3 Towards a trial of BCG vaccination of badgers.
3.3.1 Given that there is some available evidence to suggest that BCG might
have a rle in the vaccination of badgers, the Sub-Committee felt it would be
useful to document the steps required in developing a field trial protocol. In
many ways this represents a best case scenario. Given the widespread use
of BCG in the human population and the considerable background information
on its safety in many species and optimal modes of administration, gaining
approval to implement a field trial is likely to be considerably more
straightforward than would be the case for a completely novel vaccine.
3.3.2 Regulatory considerations.
3.3.2.1 The fact that BCG has been so widely used in man, and has been
extensively studied for efficacy and toxicity in a large number of wildlife and
domestic species, means that many of the steps involved in authorising its
use in field trials will be considerably less demanding than would be the case
for a completely novel vaccine formulation. The probable steps required for
authorisation have been set out (Appendix 6).
3.3.2.2 As part of the regulatory requirements for the use of BCG as a wildlife
vaccine, it would be necessary to demonstrate safety and efficacy against the
target species under laboratory conditions (see below); this would mean
obtaining uninfected badgers from the wild for experimental purposes. The
legal aspects of the Badger Act on the procurement of badgers for research
purposes (see below) have been described (Appendix 7). It would also be
10
11
12
13
14
Defra, is currently being devoted to the development of TB-specific interferongamma (IFN-) assays incorporating defined M. bovis antigens. As with the
skin test, the IFN- assay measures the immunological response to M. bovis;
however using state-of-the-art genomic analysis it has been possible to
identify antigens which are present in M. bovis but absent in environmental
mycobacteria and also absent in BCG. Thus, such an assay is likely to be
more specific in defining TB infection than the existing skin test. In the short
term, it is envisaged that such assays could be used in conjunction with the
skin test to improve the efficiency of herd testing. It is likely that an IFN-
assay with similar or superior sensitivity to that of the skin test will be
developed over the next few years. If sensitivity can be achieved along with a
high level of specificity, serious consideration should be given to replacing the
skin test with the IFN- assay as the primary diagnostic assay for herd testing.
Such a laboratory-based assay would allow improved standardisation of TB
testing and require only one farm visit per test (as compared to two at
present).
4.3.2.2 A diagnostic assay based on the use of defined M. bovis antigens
would also potentially allow the use of vaccines that did not contain the
antigens used in the diagnostic assay. For example, many of the candidate
diagnostic antigens are absent from BCG but present in wild-type M. bovis, so
using such a test should differentiate between infection with M. bovis and
vaccination with BCG. Thus, either live attenuated or sub-unit vaccines could
be considered. However, as discussed elsewhere (see 4.1.1), the diagnostic
assay would not only need to distinguish infected from vaccinated animals but
also infected from vaccinated immune animals that have been exposed to
challenge with M. bovis. The latter might be difficult to achieve but is
amenable to experimental investigation.
4.3.3 Vaccination without herd testing. Current resources for control of TB
are focused on identification of animals once they have become infected with
the causative organism. If wildlife is confirmed as a major source of infection
and if measures to control infection in wildlife prove to be impractical,
unacceptable or ineffective, this control strategy will have a limited impact on
the problem and will continue to consume a large amount of resource. An
alternative, though radical approach would be to use vaccination of cattle as
the primary means of control in affected regions, dispense with routine herd
testing and focus resources on detection of infected carcasses in
slaughterhouses coupled with a ban on the consumption of raw milk. Such a
strategy would require a highly effective vaccine, which reliably prevents
systemic infection and substantially reduces pathology and bacterial
excretion. The principal aim would be to protect human health, by reducing
bacterial excretion to a level that poses negligible risk to humans in contact
with the live animal and limits pathology to avoid lesions that would lead to
condemnation of the carcass at post mortem, slaughterhouse, inspection.
This approach would require a vaccine with a protective effect superior to that
of BCG.
4.3.4 An advantage of vaccine development in cattle is that any vaccine
candidate considered suitable for field use can be tested rigorously for
15
16
APPENDIX 1.
EPIDEMIOLOGICAL INVESTIGATIONS INTO BOVINE TB THE
POTENTIAL FOR THE USE OF VACCINES IN CATTLE AND WILDLIFE.
John Bourne
ISG, Location 105, 1A Page Street, London SW1P 4PQ
1. INTRODUCTION.
1.1 The ISG in co-operation with Defra has put in place a range of studies to
gain more information on the epidemiology of TB in both cattle and wildlife
since it is our view that only through this knowledge can sustainable control
policies be developed.
1.2 Full details of the scientific approach taken and the research now in
place, which includes vaccine research, can be found in the Groups reports to
Ministers (2000, 2001).
1.3 The use of vaccines in either cattle or badgers remains a potential policy
option, although we regard this option as offering prospects only in a long
term context and also caution that success cannot be guaranteed. The
demands of an acceptable cattle vaccine are particularly severe since it would
need both to prevent the establishment of persistent infection and to eliminate
transmission. Additionally, it should not give a positive reading in the
tuberculin skin test since this would confuse the regular herd testing
procedure and create serious regulatory problems. However, an additional
concern about the use of cattle vaccination in Great Britain relates to the
strong likelihood that a wildlife reservoir of TB infection will persist in the
countryside environment, and exposure of cattle protected by a successful
vaccine to this source of infection would result in immunological responses
which may compromise the skin test.
1.4 Any diagnostic test based upon detecting an immune response would
need therefore to distinguish immune responses generated following infection
from those elicited following challenge of a protected vaccinated animal. This
would be difficult to achieve. In addition, to being highly sensitive such a test
would have to have a high level of specificity for it to be acceptable, since
false positive reactions would trigger a herd breakdown control response.
1.5 Nonetheless, we support continuation of the cattle vaccine research and
its co-ordination with human TB research, since new technologies are
continually developing which may be applicable to cattle vaccine
development. Experimental infection of cattle with TB also provides a model
of the natural disease, which will provide information on the immunology and
pathogenesis of bovine TB relevant to vaccine development for both cattle
and badgers and also to the development of improved diagnostics.
17
1.6 By contrast with the cattle situation, vaccination of wildlife would require a
less demanding vaccine since, although widespread coverage would be the
target, protection of each individual animal would not be essential. The
primary rle of a wildlife vaccine would be to reduce the severity of disease in
the target species and the consequent rate of transmission to cattle.
However, a wildlife vaccine would only be effective in controlling TB in cattle if
most cattle TB infections derived from wildlife, a point that at present is in
doubt.
1.7 If an effective vaccine was available for wildlife, the logistics of
vaccinating a badger population in the wild presents enormous challenges.
The effectiveness of vaccination is likely to be greatly influenced by the route
of administration, but there are practical constraints on which route can be
employed; oral vaccination is likely to be the preferred route for use in the
badger but by this route it may be difficult to achieve a protective immune
response.
1.8 If the strategy of badger vaccination is to be seriously pursued,
experimental facilities to conduct pathogenesis and vaccination challenge
studies would have to be made available. This will necessitate sourcing TBfree badgers and possibly rearing offspring that can be used for experimental
studies in disease secure high containment facilities. A more demanding
requirement will be to validate the potential vaccine in the field and to
determine how its success would be measured particularly as we currently
have no reliable rapid live test for TB infection in badgers. A further
consideration is the possibility of transmission of a wildlife vaccine to other
wildlife, domestic animals, man and also to cattle, and the impact that that
might have on tuberculin testing in cattle.
1.9 While there is strong pressure from some groups for successful
vaccination of cattle or badgers to be considered as the preferred strategy
there are many difficult issues to be addressed if this policy is to be pursued.
1.10 The purpose of the present exercise is to consider these issues and to
assist the ISG in further advising Ministers on the requirements for pursuing
the vaccination strategy.
1.11 There are two issues to consider, namely a badger vaccine and a cattle
vaccine.
2. BADGER VACCINE.
2.1 We must consider the factors that could influence the impact of
vaccination and these are listed below.
2.1.1 The contribution badgers make to bovine TB.
2.1.2
The extent of reduction in transmission to cattle achieved by
vaccination.
18
19
20
21
22
APPENDIX 2.
BADGER VACCINATION:
CONSIDERATIONS
ECOLOGICAL
AND
EPIDEMIOLOGICAL
23
below one, and the pathogen will die out. The higher R0, the greater the
proportion of hosts that must be vaccinated to achieve eradication. Estimation
of R0 is therefore vital to determine the proportion of hosts that must be kept
immune through vaccination in order to achieve eradication.
2.3 Eradication of TB infection from closed badger populations is clearly
theoretically possible. However, several technical barriers make it unlikely
that eradication could be achieved at present.
2.3.1 The only vaccine currently available BCG has not been shown to
confer immunity to experimental challenge with M. bovis. Twelve badgers
vaccinated with BCG in captivity showed immune responses to vaccination
(Stuart et al., 1988). However, when seven of these were subsequently
challenged by intradermal injection of M. bovis they did become infected
(though they lived longer, and shed fewer bacteria), than did three
unvaccinated controls (Stuart et al., 1988), although it is not clear to what
extent experimental intradermal infection mimics natural exposure. It is
possible that reduced bacterial excretion by infected but vaccinated badgers
could reduce transmission and help to control the disease; however, in the
absence of any data on TB transmission routes among badgers, and on how
bacterial excretion influences infectiousness, it is impossible to make
quantitative predictions.
2.3.2 Estimation of the proportion of animals to be vaccinated requires an
estimate of R0.
This requires basic epidemiological data which are,
unfortunately, not currently available for TB in badgers. Existing models (e.g.
White & Harris, 1995; Smith et al., 1995) do predict population density and
group size thresholds for the persistence of TB in badgers. Unfortunately
these models largely fail to capture the observed distribution of infection
(disease persists in much lower-density populations than predicted). This
suggests either that some component of disease dynamics, such as social
perturbation effects (Swinton et al., 1997) or infection from alternative host
species, is important in the natural system but missing from the base models,
or that models have been incorrectly parameterised, due for example to the
sparse data available from a limited number of badger studies. In either case,
these models currently have limited predictive value but data generated by the
randomised badger culling trial (RBCT) may lead to the use of more accurate
parameter values of similar models, and may allow estimation of the
proportion of badgers that would have to be made immune to TB to reduce
transmission rates below the required threshold. Such estimates would then
need to be combined with measures of vaccine efficacy to allow approximate
calculation of the vaccine coverage required to achieve eradication. In the
absence of reliable data on either TB transmission rates within badger
populations, or vaccine efficacy, it is impossible to know whether the bait
uptake rates (and hence the potentially achievable vaccination coverages)
reported in Appendix 11 are acceptably high.
2.3.3
Classical disease eradication through vaccine-induced immunity
requires vaccinating individual hosts before they are exposed to infection. If
initial exposure occurs in young cubs that have not yet emerged from the sett,
24
25
26
One firm conclusion can be drawn: vaccinating badgers is not a quick fix that
could be implemented outside the RBCT with any expectation of effectiveness
in the short or medium term.
5.2 These discussions highlight the fact that many of the concerns about the
potential effectiveness of badger vaccination stem from lack of data on the
transmission of TB among badgers, and between badgers and cattle. Some
of the necessary data will be provided by the ongoing RBCT and associated
research. Hence, the outcome of the trial might inform expectations of the
potential success of any vaccination programme and the extent to which
vaccinating badgers might potentially influence cattle TB. In addition, the trial
will provide much-needed data on TB epidemiology in badger populations that
would help in the design of vaccination programmes. However even with trial
data we will still lack some important information on transmission.
5.3 Given (i) a lack of confidence in the possible effectiveness of badger
vaccination in controlling cattle TB; (ii) the cost and timescale of the field trial
that would be necessary to evaluate the effectiveness of this measure; and
(iii) the expectation that data from the ongoing RBCT, and associated
research, will provide better estimates of what might be achievable, and how
that might best be achieved, I recommend that field trials of badger
vaccination are not to be carried out at this point, but that the situation be reassessed when results of the RBCT and other work become available.
6. ACKNOWLEDGEMENTS.
6.1 I would like to thank Sir David Cox for epidemiological advice during the
preparation of this Appendix.
7. REFERENCES.
Artois, M., Delahay, R., Guberti, V., Cheeseman, C. (2001). Control of
infectious diseases of wildlife in Europe. Veterinary Journal, 162, 141-152.
Barlow, N.D. (1996). The ecology of wildlife disease control: simple models
revisited. Journal of Applied Ecology, 33, 303-314.
Hughes, M.S., Neill, S.D., Rogers, M.S. (1996). Vaccination of the badger
(Meles meles) against Mycobacterium bovis. Veterinary Microbiology, 51,
363-379.
Plowright, W. (1982). The effects of rinderpest and rinderpest control on
wildlife in Africa. Symposia of the Zoological Society of London, 50, 1-28.
Smith, G. C., Richards, M. S., Clifton-Hadley, R. S., Cheeseman, C. L. (1995).
Modelling bovine tuberculosis in badgers in England: Preliminary results,
Mammalia, 59, 639-650.
27
28
APPENDIX 3.
BCG VACCINATION OF WILDLIFE.
Glyn Hewinson
Veterinary Laboratories Agency, New Haw, Addleston, Surrey KT15 3NB
1. INTRODUCTION.
1.1 This appendix reviews current knowledge on the use and efficacy of BCG
in wildlife species. It concentrates on the use of BCG in possums, ferrets and
badgers although subcutaneous vaccination with between 104 to 107 cfu BCG
has also been shown to confer significant protection against infection and
disease in domesticated deer (Griffin et al, 1999).
2. BCG VACCINATION IN POSSUMS.
2.1 Challenge Model.
2.1.1 Two models have been developed for the evaluation of vaccines in
possums. The first consists of an intratrachael inoculation of 100 - 1000 cfu of
M. bovis (Aldwell et al, 1995 a & b). In this model lesions are confined to the
lungs and lymph nodes of the thorax, except in the advanced stage of disease
(Cooke et al, 1999). However, disease progression is more rapid than
observed for natural infection and possums develop severe pneumonia six to
eight weeks after challenge. More recently a low dose aerosol challenge
model has been developed using an aerosol-generating chamber in which a
dose of 104 cfu in the nebuliser produces eight to fifteen primary lesions
resulting in a more natural time scale for disease progression (Skinner et al,
2001). In an attempt to develop a natural challenge model, vaccinated and
non-vaccinated possums were housed with possums that had been
experimentally infected with M. bovis using the intratrachael challenge model.
In these experiments transmission of disease was highly variable with
infection rates for in-contact possums ranging from 10% to 60%. This level of
variation prevented interpretation of the protection results (Skinner et al, 2001;
Corner, 2001).
2.2 BCG vaccination.
2.2.1 A number of vaccination studies have been undertaken in possums
using BCG which have demonstrated a significant level of protection to
experimental challenge. These studies have also indicated that the route of
vaccination affects the protective efficacy achieved. In all of these studies
vaccination has not prevented animals from developing tuberculous lesions
but has conferred a significant reduction in the dissemination of M. bovis to
the spleen and liver. Vaccination with BCG has also been shown to influence
the immunopathology associated with M. bovis challenge. In comparison with
the predominantly necrotic lesions present in non-vaccinated animals, the
29
30
31
2.7.1 The very high susceptibility of possums to M. bovis infection and limited
protection of possums against experimentally-induced infection provides
opportunities to identify tuberculosis vaccines that are more effective than
BCG. In one study, killed Mycobacterium vaccae mixed with live BCG and
administered intranasally induced significantly greater protection than BCG
alone (Skinner et al., 2002). In another study, vaccination with two newly
derived attenuated M. bovis strains induced a higher degree of protection than
that seen with BCG (Buddle et al., 2002).
3. BCG VACCINATION IN FERRETS.
3.1 Challenge Model.
3.1.1 The route of transmission of M. bovis to ferrets is usually by ingestion
through the scavenging of infected carrion. Consequently an oral M. bovis
challenge model has been used to assess the efficacy of BCG in ferrets. In
this model ferrets are infected orally with 5 x 106 cfu by feeding with infected
lung tissue (Qureshi et al, 1999; Cross et al, 2000). The outcome of challenge
is determined twenty weeks after challenge by autopsy, histology and
bacterial culture. This route of infection gives rise to progressive disease with
lesions primarily in the mesenteric lymph nodes where the bacterial burden is
highest and also in the head region lymph nodes. The pathology observed in
this model mimics natural infection in the ferret.
3.2 BCG Vaccination Studies.
3.2.1 In a recent study ferrets were orally vaccinated with two doses of 5 x
108 cfu live BCG incorporated into dietary meat administered 4 weeks apart
(Qureshi et al, 1999). Although oral vaccination did not prevent infection,
significant manifestations of protection were observed most notably a
reduction in the bacterial burden, incidence and severity of TB in the head
lymph nodes. Interestingly, blood from only 2/9 vaccines gave tuberculin
specific lymphocyte responses suggesting that systemic immune responses
may have been less important than local immunity in mediating protection in
this study. Subcutaneous vaccination of ferrets with 5 x 106 cfu BCG between
the shoulder blades also induced protection against oral challenge but again
did not prevent infection (Cross et al, 2000). In this case protection was
characterised by a significant reduction in bacterial burden, the prevention of
gross lesions in the mesenteric lymph nodes and reduced bacterial spread to
thoracic lymph nodes. In contrast, to the favourable results in possums,
vaccination by intraduodenal inoculation of 5 x 107 cfu BCG was not effective
in reducing disease (Cross et al, 2000). Both subcutaneous and intraintestinal vaccination with BCG induced tuberculin-specific lymphocyte
reactivity.
4. BCG VACCINATION IN BADGERS.
4.1 Introduction.
32
4.1.1 The early observation that badgers may survive for a number of years
after natural or experimental infection (Mahmood et al., 1987; Newell et al,
1997) suggests that they are not especially susceptible to M. bovis infection.
Preliminary studies of the badger immune response to experimental infection
led to the conclusion that badgers exhibit an immune spectrum during
tuberculosis akin to other mammalian species (Thorns and Morris, 1983).
More recent studies on the pathology and immunology of tuberculous badgers
suggest that they are capable of mounting a vigorous cell-mediated immune
response even when heavily infected and that they can contain infection,
possibly for several years (Newell et al, 1997; Gavier-Widen et al, 2001).
4.2 Challenge Model.
4.2.1 Protocols for the experimental infection of badgers with M. bovis have
been developed at VLA in previous studies (Pritchard et al, 1988; Mahmood et
al, 1987). Two groups of four badgers were challenged with either 103 or 104
M. bovis either intradermally or intratracheally. Two animals thus received
each dose/route combination. The intratracheal challenge route failed to lead
to tuberculosis in all cases and their immunological responses were the same
as the control, uninfected animals. The four intradermally challenged animals
all developed miliary tuberculosis accompanied by positive skin test and
increases in lymphocyte transformation and anti-mycobacterial antibodies.
These studies highlighted the need to develop an improved challenge model
for badgers.
4.3 Development of a badger challenge model in the Republic of Ireland.
4.3.1 Development of an experimental M. bovis challenge model for badgers
has started at the Badger Research and Observation Complex (BROC) facility
in Abbotstown. In the first instance, groups of uninfected badgers held in the
BROC facility were challenged intratracheally with M. bovis over a range of
doses (ca. 100 10,000 cfu). After a set interval (15 weeks), all animals were
sacrificed and the presence and extent of infection determined at post
mortem. Lung lesions were observed in all animals receiving 10,000 cfu.
This challenge dose of M. bovis is now being used to infect further groups of
badgers in order to determine the reproducibility of the model and to examine
the progression of disease over time. This will be measured immunologically,
physiologically and pathologically by serial necropsy. VLA is providing
support for the immunological aspects of this study through a Defra funded
project.
4.4 BCG vaccination.
4.4.1 In a previous study performed at VLA, Stuart et al. (1988) reported the
protective effect of BCG against M. bovis in badgers. An intradermal
inoculation of 106 cfu of BCG was found to be non-pathogenic, was not
excreted by the badgers and was not transmitted to in-contact animals. There
was an increase in LTT response but no skin-test reaction or antibody
increase in all vaccinated badgers. When seven of these badgers were
subsequently challenged intradermally with 104 M. bovis, between 5 and 25
33
months after vaccination, the LTT response tended to fall and the antibody
response rose. Skin-test responses became positive. The vaccinated
badgers were shown to live longer, shed fewer tubercle bacilli and their
inoculation sites healed more rapidly after challenge than a group of three
control badgers. Thus, although only small numbers of badgers were
involved, cell-mediated immunity did seem to be enhanced by BCG
vaccination, leading to prolonged survival of the badgers and delayed
excretion of tubercle bacilli.
4.4.2 In a recent study in the Republic of Ireland, the immunological
responses were measured in a resident population of badgers following
subcutaneous vaccination with BCG (Southey et al, 2001). Three doses of
vaccine were administered 1 cm above right ear. An initial dose of 5 x 104 cfu
BCG was followed 17 weeks later with a boost of 5 x 104 cfu and a second
boost of 5 x 105 cfu at week 30. Cellular immune responses were only
observed after the third dose of BCG (at week 42) and were characterized by
lymphocyte blastogenic responses to PPD-B. Antibody responses to MPB83
(the Brock Test) were minimal. This study highlighted the need to optimise
the dose and route of BCG vaccination for badgers before further field
evaluation could be performed. It is clear that the testing of BCG in badgers is
lagging some way behind that in possums and ferrets, not least because of
the lack of facilities to perform such work.
5. POST-EXPOSURE VACCINATION.
5.1 Vaccination of badgers in the field will inevitably result in the vaccination
of many badgers that have already been infected with M. bovis and have
clinical or subclinical disease. It is possible that the ensuing immune
response to vaccination may result in exacerbation of the disease (the Koch
phenomenon).
This might have two effects.
First, if post-exposure
vaccination exacerbates disease it might result in increased spread of
infection. Second, vaccination might reveal occult disease which could
confound interpretation of a field trial since the number of TB cases in the
vaccinated population would be selectively increased compared to that in the
untreated population.
5.2 A number of post-exposure experiments have been performed in mice
using BCG (Turner et al, 2000; Moreira et al., 2002). When administered to
mice already infected with M. tuberculosis a single dose of BCG did not
exacerbate disease nor effect the bacillary loads in the organs of the infected
mice. Neither did it have a therapeutic effect on the pre-existing infection.
However, repeated BCG vaccination of infected mice resulted in exacerbation
of the granulomatous response with detrimental pathologic changes in the
lungs. The effect became more prolonged and severe if the vaccine was
given twice or three times (at 15 day intervals) although there was no effect on
the bacillary load in the lungs (Turner et al., 2000).
5.3 Exacerbation of TB following post-exposure vaccination with BCG has not
been reported for any other species including man. There have not been
reports of significant harm associated with boosters or revaccination with BCG
34
35
36
37
Pritchard D.G., Stuart F.A., Brewer J.I., Mahmood, K.H. (1987). Experimental
infection of badgers (Meles meles) with Mycobacterium bovis. Epidemiology
and Infection, 98, 145-154.
Qureshi T., Labes R.E., Cross M.L., Griffin J.F., Mackintosh C.G. (1999).
Partial protection against oral challenge with Mycobacterium bovis in ferrets
(Mustela furo) following oral vaccination with BCG. Int J Tuberc Lung Dis., 3,
1025-33.
Skinner, M. A., Keen D. L., Parlane N. A., Yates G. F., and Buddle B. M..
2002. Increased protection against bovine tuberculosis in the brushtail
possum (Trichosurus vulpecula) when BCG is administered with killed
Mycobacterium vaccae. Tuberculosis 82,15-22.
Skinner M.A., Wedlock D.N., Buddle B.M. (2001). Vaccination of animals
against Mycobacterium bovis. Rev Sci Tech, 20, 112-32
Southey A., Sleeman D.P., Lloyd K., Dalley D., Chambers M.A., Hewinson
R.G., Gormley E. (2001). Immunological responses of Eurasian badgers
(Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette
guerin). Vet Immunol Immunopathol., 79,197-207.
Stuart F.A., Mahmood K.H., Stanford J.L., Pritchard D.G. (1988).
Development of diagnostic tests for, and vaccination against, tuberculosis in
badgers. Mammalian Review, 18, 74-75.
Thorns C.J., Morris J.A. (1983). The immune spectrum of Mycobacterium
bovis infections in some mammalian species: a review. Veterinary Bulletin,
53, 543-550.
Turner J., Rhoades E.R., Keen M., Belisle J.T., Frank A.A., Orme I.M. (2000).
Effective preexposure tuberculosis vaccines fail to protect when they are
given in an immunotherapeutic mode. Infect Immun. 68, 1706-9.
38
APPENDIX 4.
BCG IN WILD-LIFE AND DOMESTIC LIVESTOCK; VIRULENCE AND
EFFICACY.
Jo Colston (deceased)
National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7
1AA
1. INTRODUCTION.
1.1 Extensive testing of virulence was carried out by Calmette and his
colleagues during their development of BCG in the early part of the 20th
century. In addition to this there has been extensive work carried out in wildlife or domestic livestock to investigate protective efficacy or immunogenicity
of BCG, rather than virulence; these studies allow us to draw some
conclusions about the virulence of BCG in these species. Calmette and
colleagues also carried out experiments in which large doses of BCG were
administered to animals which were already infected with M. tuberculosis;
because of the potential importance of these studies, these have been
included in the discussion (see section 3).
2. EXPERIMENTS ON THE VIRULENCE OF BCG CARRIED OUT BY
CALMETTE AND COLLEAGUES.
2.1 Cattle.
2.1.1
In Calmette and Guerins original work, 100mg of BCG was
administered intravenously to cattle. The recipients were reported to have
developed a typhoid-like disease (Le seul effet de cette injection massive est
de provoquer une maladie generale dallure typhique, qui gurit spontanement
aprs 15 a 20 jours de fievre, sans produire la moindre lesion folliculair), but
all recovered and remained healthy.
2.2 Guinea pigs.
2.2.1
Guinea pigs given 5-10mg of BCG intradermally or 3-5mg
intraperitoneally remained healthy. 50-100mg administered into the stomach
resulted in lymph node swelling but again the animals remained healthy.
2.3 Rabbits.
2.3.1 1-5mg BCG injected sub-cutaneously had no effect on the health of the
rabbits. Intravenous injection of 100mg also had no effect.
2.4 Dogs.
2.4.1 A single 4Kg dog was given 0.5mg BCG intravenously, followed five
days later with 1mg by the same route, and three months later 10mg
39
40
al, 1999; Hook et al, 1996). As with cattle vaccination, all of these studies
reported some level of protection and there were no reports of adverse affects
from the vaccination.
3.4 Possums.
3.4.1 Possums have been vaccinated with BCG by a variety of routes,
including subcutaneous, aerosol and intraduodenal (Aldwell et al, 1995;
Buddle et al, 1997). One study involved a combination of intranasal aerosol
and conjunctival instillation. No adverse effects of vaccination have been
reported. In all experiments, there was a reduction in disease severity in the
BCG vaccinated animals following challenge with viable M.bovis.
3.5 Ferrets.
3.5.1 BCG has been given orally to ferrets, followed by oral challenge with
virulent M.bovis. There was significant reduction in gross lesions, and in
culture and acid fast positive lymph nodes in the vaccinated groups. No
adverse side effects of vaccination were reported (Qureshi et al, 1999).
3.5.2 In another series of experiments, ferrets were vaccinated with live BCG
via subcutaneous injection or intra-duodenal inoculation.
Only the
subcutaneous route was effective in reducing disease (Cross et al, 2000).
3.6 Badgers.
3.6.1 Numbers of experimental studies have been carried out on vaccination
of badgers with BCG (Stuart et al, 1988; Southey et al, 2001). Generally the
route of administration has been intradermal or subcutaneous. No adverse
effects have been reported and the experiments reveal an increase in cellmediated immunity against M.bovis.
3.7 Rabbits.
3.7.1 Tuberculosis in rabbits is claimed to resemble human TB more closely
than TB in other common laboratory animals. Immunisation of rabbits with
BCG has been carried out by a number of workers (Lurie et al, 1952;
Dannenberg et al, 2001). BCG was usually administered intradermally using
106 107 viable bacilli. No adverse affects were reported and significant
levels of protection against subsequent challenge with M.bovis observed.
3.8 Guinea pigs.
3.8.1 Guinea pigs have been widely used for experimental tuberculosis
studies, and there are many reports of vaccination with BCG (e.g. Chambers
et al, 2000). There are no reports demonstrating that BCG can cause
progressive infections or have adverse side effects.
3.9 Mice.
41
3.9.1 Mice are the most commonly used experimental animals for testing
vaccination against tuberculosis. BCG does not cause progressive infections
in these animals.
4.
ADMINISTRATION
TUBERCULOSIS.
OF
BCG
TO
ANIMALS
INFECTED
WITH
4.1 Calmette and colleagues carried out a number of studies in which large
doses of BCG were administered to animals already infected with M. bovis.
Their general conclusion was that this did not produced aggravation of the
tuberculosis (Lintroduction de bacilles bilies, meme a fortes doses plusieurs
fois repetees, dans lorganisme des animaux deja tuberculises ne produit
aucune aggravation de la maladie).
4.2 A PPD-positive cow was given 10mg of BCG intravenously, followed nine
days later with 50mg, again intravenously. The animal was sacrificed and
subjected to post mortem examination two and a half months later. Two
small, caseous lung lesions were found, along with a number of calcified
lesions in mediastinal lymph nodes; however these were considered to be old
lesions, and there was no evidence of recent tuberculosis.
Similar
experiments carried out with guinea pigs and rabbits failed to reveal evidence
of aggravation of the disease.
5. CONCLUSIONS.
5.1 Extensive testing of BCG in a variety of mammalian species has failed to
reveal any evidence that the organism can cause disease or can exacerbate
pre-existing tuberculosis. Many of these tests were carried out with very large
doses of BCG given by a variety of different routes. However, it should be
noted that lack of virulence of BCG is related to the immunological status of
the host. Thus people with congenital defects in type 1 cytokines or their
receptors may develop a disseminated, lethal BCG infection. Thus individual
animals which are immunosuppressed, or species with more primitive immune
systems could be highly susceptible to BCG infection.
6. REFERENCES.
Aldwell F.E., Keen D., Stent V.L.C. et al. (1995). Route of BCG administration
in possums effects protection against bovine tuberculosis. New Zealand Vet.
Rec., 43, 356-359.
Bergeen S.A. (1977) Incidence of tuberculosis in BCG vaccinated and control
cattle in relation to age distribution in Malawi. Br. Vet. J., 133, 490-494.
Buddle B.M., Keen D., Thomson G. et al. (1995). Protection of cattle from
bovine tuberculosis by vaccination with BCG by the respiratory or
subcutaneous route, but not by vaccination with killed Mycobacterium vaccae.
Res. Vet. Sci., 59, 10-16.
42
Buddle B.M., Aldwell F.E., Keen D., et al. (1997). Intraduodenal vaccination
of brushtail possums with bacille Calmette-Guerin enhances immune
responses and protection against Mycobacterium bovis infection. Int. J.
Tuberc. & Lung Dis., 1, 377-383.
Chambers M.A., Williams A., Gavier-Widen, D. et al. (2000). Identification of
a Mycobacterium bovis BCG auxotrophic mutant that protects guinea pigs
against M. bovis and hematogenous spread of Mycobacterium tuberculosis
without sensitisation to tuberculin. Infect. Immun., 68, 7094-7099.
Cross M.L., Labes R.E., Griffin J.F.T., Mackintosh C.G. (2000). Systemic but
not intra-intestinal vaccination with BCG reduces the severity of tuberculosis
infection in ferrets (Mustelo furo). Int. J. Tuberc. & Lung Dis., 4, 473-480.
Calmette A., Boquet A., Negre L. (1921). Contributions a letude du bacille
tuberculeux bilie Extrait des Annales de lInstitut Pasteur. Septembre 1921,
Tome XXXV.
Dannenberg A.M., Bishai W.R., Parrish N. et al. (2001). Efficacies of BCG
and vole Bacillus (Mycobacterium microti) vaccines in preventing clinically
apparent pulmonary tuberculosis in rabbits: a preliminary report. Vaccine, 19,
796-800.
Griffin J.F.T., Chinn D.N., Rodgers C.R., Mackintosh C G. (2001). Optimal
models to evaluate the protective efficacy of tuberculosis vaccines.
Tuberculosis, 81, 133-139.
Hook S., Griffin F., MacKintosh C., Buchan G. (1996). Activation of an
interleukin-4 mRNA-producing population of peripheral blood mononuclear
cells after infection with Mycobacterium bovis or vaccination with killed, but
not live, BCG. Immunology, 88, 269-274.
Lurie M.B., Zappasodi P., Cardona-Lynch E., Dannenberg A.M. (1952). The
response to the intracutaneous inoculation of BCG as an index of native
resistance to tuberculosis. J. Immunol., 68, 369-387.
Miller L.A., Johns B.E., Elias D.J., Killian G.J. (1999). Oral vaccination of
white-tailed deer using a recombinant Bacillus Calmette-Guerin vaccine
expressing the Borrelia burgdorferi outer surface protein A: prospects for
immunocontraception. Am. J. Rep. Imm., 41, 279-285.
Qureshi T., Labes R.E., Cross M.L., et al. (1999). Partial protection against
oral challenge with Mycobacterium bovis in ferrets (Mustelo furo) following
oral vaccination with BCG. Int. J. Tuberc. & Lung Dis., 3, 1025-1033.
Slobbe L., Lockhart E., ODonell M.A., et al. (1999). An in vivo comparison of
bacillus Calmette-Guerin (BCG) and cytokine-secreting BCG vaccines.
Immunology, 96, 517-523.
43
44
APPENDIX 5.
PROTOCOLS FOR THE DEVELOPMENT AND EVALUATION OF BCG
VACCINATION AGAINST M. BOVIS INFECTION IN BADGERS.
Glyn Hewinson and Mark Chambers
Veterinary Laboratories Agency, New Haw, Addleston, Surrey KT15 3NB
1. INTRODUCTION.
1.1 Vaccinating badgers against infection with M. bovis is one possible
strategy with which to break the transmission of tuberculosis, by reducing the
burden of infection within the badger population and the level of shedding of
the bacterium by infected individuals.
1.2 In Appendix 3 was outlined a number of steps that would be required for
the development of BCG vaccination regimes for badgers. The main purpose
of the study would be to provide proof of principle that BCG can protect
against a stringent challenge with M. bovis and to determine the level of
protection conferred by BCG in this model. Previous studies in other wildlife
species have shown that, to date, the optimum level of protection for BCG has
been achieved by subcutaneous vaccination (Appendix 3). Therefore it would
be prudent to provide proof of principle that BCG can protect against M. bovis
infection in badgers using this route of vaccination before embarking on the
development of formulations and delivery systems for oral vaccination. The
aim of this Appendix is to discuss the development of protocols to achieve this
goal.
2. M. BOVIS CHALLENGE MODEL FOR BADGERS INCLUDING STUDIES
ON PATHOGENESIS AND KINETICS OF THE IMMUNE RESPONSE.
2.1 The first objective would be to develop an M. bovis challenge model for
badgers. The optimum dose for intratrachael challenge is being determined in
the Republic of Ireland (RoI) by titrating doses of M. bovis (10, 100, 1000 cfu).
The kinetics of the immune response and shedding during infection are being
measured and pathology will be defined by post mortem examination.
2.2 The second objective would be to define the variation in the parameters
that would be used for measuring protection against M. bovis challenge in this
model. This would ensure that a minimum number of animals were used for
subsequent vaccination and challenge studies.
2.3 Ideally, the experimental design would include a badger group size of
between twelve and twenty animals. At least two pre-bleeds should be taken
for each badger. The dose of M. bovis given would be determined from the
experiments performed in RoI outlined above (2.1). All badgers would be kept
12-18 weeks after challenge or until they showed severe clinical signs of
disease. A full post mortem would be carried out on each animal and
45
pathology, histopathology and cfu in lung, lymph nodes and other tissues
would be determined. Pathology scores would be determined for lungs and
lymph nodes using scoring systems developed for the bovine model of M.
bovis infection.
2.4 The clinical markers to assess disease progression would be weight,
haematology, blood biochemistry, survival, clinical signs (include lymph node
enlargement).
2.5 Regarding immune markers of disease progression, badgers would be
sampled at two to three-weekly intervals and tested for the following:
2.5.1 Serum IgG response (using the Brock Test, MAPIA/Lateral flow assays
and Dachs ELISA; Appendix 9).
2.5.2 IgA response in tracheal aspirates and serum.
2.5.3 Lymphocyte transformation assay (Appendix 9) using PPD-M, PPD-A
and specific M. bovis antigens that are present in M. bovis and absent from
BCG (e.g. ESAT-6 and CFP10).
2.5.4 IFN ELISA and ELISPOT using PPDM, PPDA, ESAT-6, CFP10 and
other antigens that might be useful in determining disease progression
(Appendix 9).
2.6 Shedding of M. bovis would be detected by culturing urine, faeces and
tracheal aspirates and by PCR.
2.7 The information gathered as a result of this experiment would be used to
determine which parameters would be useful in determining protective
efficacy, the variation in these parameters and hence the group size required
for subsequent vaccination and challenge experiments.
3. PROOF OF PRINCIPLE EXPERIMENTS TO SHOW THAT BCG CAN
GIVE DEMONSTRABLE PROTECTION AGAINST M. BOVIS CHALLENGE
IN BADGERS AND REDUCE BACTERIAL EXCRETION.
3.1 Group size for a BCG vaccination and challenge experiment would be
determined from the data obtained from the experiment outlined in 2. It should
be noted that groups of six cows were sufficient to demonstrate 80 %
protection (i.e. reduction in lesions) in BCG vaccinated animals compared to
controls. This is the minimum group size that could demonstrate a statistically
significant protective effect in cattle.
3.2 It is suggested that a commercial preparation of BCG that is licensed in
GB (i.e. BCG Copenhagen; see Appendix 6) be used at a dose that has been
efficacious for a wide range of species i.e. 106 cfu (Appendix 3).
3.3 Shedding of BCG prior to M. bovis challenge would be detected by
culturing urine, faeces and tracheal aspirates and by PCR.
46
47
APPENDIX 6.
VACCINES FOR THE CONTROL OF BOVINE TUBERCULOSIS:
COMMERCIAL
PRODUCT
DEVELOPMENT
AND
REGULATORY
APPROVAL.
Steve Houghton
Hoechst Roussel Vet Ltd., Walton Manor, Walton, Milton Keynes, MK7 7AJ
1. INTRODUCTION.
1.1 The expertise necessary to develop and license commercial TB vaccines
lies with animal health companies collaborating with research institutes or
laboratories. A commercial company involved in the development of vaccines
will seek to make a return on investment whilst at the same time having to
comply with regulatory requirements. This involves compliance with Good
Manufacturing Practice (GMP) for production, Good Laboratory Practice
(GLP) for experimental studies and Good Clinical Practice (GCP) for field
studies.
2.
PROJECT EVALUATION: HOW COMPANIES CHOOSE WHAT
PRODUCTS TO DEVELOP.
2.1 In deciding what projects to progress, the following are taken into
consideration:
2.1.1 The market. How many countries are involved and how widespread is
the disease? What is the likely uptake of the vaccine (prohibition or
prescription for use by control policies?), what are the manufacturing costs
and anticipated selling price?
2.1.2 Technological feasibility. How likely is it that a useful vaccine can be
developed?
2.1.3 Product profile. This sets the objectives for the project which primarily
involves defining the following:
2.1.3.1 Type of vaccine: live, inactivated whole cells, subunit, extract,
recombinant etc.
2.1.3.2 Adjuvant (usually only for inactivated vaccines).
2.1.3.3 Dosage regimen.
2.1.3.4 Method and route of application (by injection, oral etc).
2.1.4 Production methods/costs.
48
2.1.4.1 The more complicated the production process, the higher the costs. It
is easier to predict the costs of a simple process, similar to established
methodology.
2.1.4.2 The vaccine strain(s), notably the history (particularly with respect to
culture conditions and TSE), and any IP issues are essential to address early
on.
2.1.5 Consumer concerns. The release of live strains with potential zoonotic
implications and perhaps the release of Genetically Modified Organisms
(GMOs) as live vaccine strains in particular will undoubtedly present problems
with consumer and regulatory acceptance.
3. RESEARCH AND DEVELOPMENT OF CANDIDATE TB VACCINES.
3.1 A successful project team is multidisciplinary consisting of R&D,
Marketing, Registration, QA, QC and Production personnel throughout the
duration of the development.
3.1.1
First and foremost Transmissible Spongiform Encephalopathy
compliant production master and working seeds must be established and the
method of production of the vaccine defined, otherwise all subsequent studies
might be invalidated.
3.1.2
A validated, consistent, method of production is essential.
Fermentation, culture conditions etc must be set. Culture media used at all
stages of manufacture have to comply with Transmissible Spongiform
Encephalopathy guidelines of the Committee for Veterinary Medicinal
Products.
An initial stage of vaccine development is undertaken with
candidate vaccines prepared to a documented method and used to inoculate
animals in challenge studies to evaluate efficacy and safety. This phase may
also involve dose ranging. Data on vaccine stability are required and are
initiated as soon as possible in development.
3.1.3 The seeds have to be tested for identity and purity. The maximum and
minimum titre (for live vaccines) of the final product is set. If a range of titres
is specified for the product, all efficacy studies are carried out using minimum
titre and all safety studies at maximum titre.
3.1.4 Safety studies are carried out under GLP conditions and conducted in
the most susceptible category of animal (e.g. neonates, pregnant) and
include:
3.1.4.1 Safety of a single dose.
3.1.4.2 Safety of a repeated dose.
3.1.4.3 Safety of a 10 times (live) or double (inactivated) overdose.
3.1.4.4 Reversion to virulence (live).
49
50
5. BCG.
5.1 From all the studies conducted so far BCG is the only realistic vaccine
candidate currently available.
5.2 BCG is a licensed product for humans in the UK, therefore there are no
significant zoonotic implications.
5.3 Adopting this vaccine for use in badgers or cattle is likely to save years in
development time. Collaboration and consent of the manufacturer would be
necessary.
5.4 For badgers the oral route in bait is likely to be the method of application
of choice. Efficacy and stability work would be necessary to develop this.
5.5 Ecology and the Environment. For any product a key part of the dossier
is the assessment (called the ecotoxicity section) of impact on the
environment and spread to other species. This assessment method is clearly
described in regulatory guidelines and involves key studies of the vaccine and
its stability. There is a wealth of published data on the safety and efficacy of
BCG in numerous species, including man, cattle and laboratory animals and
some in badgers.
6. REGULATORY STEPS.
6.1 The sequence involved depends on which of a number of options
provides the best route:
6.1.1 Article 8 of Directive 2001/82/EC. As there is no licensed vaccine for
animals it is possible (but, vide infra) that the human BCG vaccine could be
used in badgers and cattle to combat a disease emergency, and the EU
commission informed of this action. Given the current levels of TB in GB this
route should not be ignored and for a badger vaccine this may be the ideal
route to pursue as long as data on stability in bait can be developed. For
cattle, tuberculin testing is required by Directive 64/432 and evidence that
BCG does not interfere with this test would be necessary. However it is
unlikely that TB in cattle would constitute a disease emergency and oral
administration of BCG to badgers would not be a direct correlate of the use of
BCG in other species and is unlikely to be approved without data to support
its likely efficacy.
6.1.2 Cascade. Where there is no licensed product available, a veterinary
surgeon may be permitted to administer to a small number of animals on a
particular holding a product authorised for human beings. For badgers and
selected cattle herds this would be acceptable. The same issues as in 6.1.1
above would apply but it is unlikely that this would be considered an option for
justifying the use of BCG in badgers. The key point is that the animals are
under the care of the prescribing veterinary surgeon, which is unlikely to
apply to wildlife. This point is also relevant to 6.1.1.
51
52
APPENDIX 7.
ISSUES RELATING TO THE PROCUREMENT OF BADGERS FOR
VACCINE RESEARCH.
Chris Cheeseman, Des Delahay & Gavin Wilson
CSL Woodchester Park, Nympsfield, Stonehouse, Glos, GL10 3UJ
1. INTRODUCTION.
1.1 Captive badgers will be required for experimental research related to the
development of a TB vaccine for badgers. Consequently badgers will need to
be procured from the wild by live trapping.
2. GENERAL.
2.1 Badgers are social animals and therefore cannot be housed individually in
captivity on a long-term basis. However, although housing singly is not
desirable for welfare reasons, housing in pairs or groups will have implications
for cross-infection between individuals in the course of the vaccination
studies. Advice will be required from the relevant immunologists and
statisticians on the desired characteristics of badgers to be procured for
vaccine research, as this will influence the strategy for their capture. Are
badgers to be kept in pairs? If so what age and sex distribution is required?
Alternatively, will it be possible to house whole social groups? Will the
badgers be required to come from locations of varying history of exposure to
M. bovis?
3. AGE AND SEX.
3.1 There is likely to be a requirement for the sample of procured badgers to
have a particular age and sex structure. One scenario is that badgers are
held in pairs. In order to minimise disruption to existing social groups from
which badgers are being removed, a small number of individuals should be
taken. A maximum removal of one male and one female could probably be
sustained by a normal group of five to eight individuals, as this is a minimal
increase over the natural background mortality rate of approximately 30% per
annum. However, this approach will require trapping of many setts in order to
procure sufficient badgers, which will be labour intensive. There may be limits
to the months when trapping can be carried out, to avoid the breeding season.
It is obviously undesirable to bring pregnant females into captivity and
lactating females cannot be removed from their cubs. It may also be
necessary to carry out bait-marking surveys in the areas of interest to
determine social group territories.
3.2 The intention only to partially deplete social groups to avoid disruption
carries with it the need to assess group size, age and sex composition. For
example, it would not be desirable to remove two badgers from a group of
less than say five individuals. A possible alternative to this, if there were
53
54
55
should also be noted that removal of badger from the wild by cage trapping is
not 100% effective.
9. STRESS - WILD ANIMALS IN CAPTIVITY.
9.1 Experience suggests that there is a great deal of individual variation in
how easily badgers accept captivity. In general, cubs seem better at settling
into captivity than adults. Adults tend to spend more of their time and energy
attempting to escape, and sometimes never settle completely. If they are to
be held in pairs, the chances of them accepting each other are increased if
they are introduced to their accommodation at the same time. Some badgers
in captivity may remain intolerant of each other. This does not seem to be
determined by whether they came from the same or different social groups, or
whether they are males or females. Therefore there is likely to be an element
of trial or error in successfully housing badgers in pairs.
9.2 The exact design of the accommodation needs to be considered carefully.
The stress levels of the animals may affect their immune response. Therefore
it will be very important to house the badgers in a way which reduces stress
as much as possible. Before committing to the construction of a large number
of enclosures, it may be worth considering a small-scale pilot study to
establish a successful design for the accommodation (see Appendix 8,
Section 6).
10. GENETIC CONSIDERATIONS.
10.1 Preliminary work suggests that the levels of genetic variability are very
similar between trial areas. No such information is available for non TB hotspot areas. Also, it is as yet unknown what implications differences in genetic
variability between areas would have for the immune response, or TB
pathogenicity in badgers. Therefore genetic composition is an issue which
cannot currently be resolved, and it is assumed that it will not be a
consideration for badger procurement.
11. LEGAL CONSIDERATIONS.
11.1 Under the Protection of Badgers Act 1992, the killing or taking of
badgers and/or interference with their setts is prohibited. Section 10 of the
Act, however, makes provision for the issue of licences for specific purposes
to carry out otherwise unlawful activities against badgers and their setts.
Section 10(1) of the Act provides for the licensing of certain activities,
including the killing or taking of badgers, and interference with setts, for
scientific or educational purposes, or for the conservation of badgers. English
Nature is the licensing authority for licences issued under this Section.
11.2 In addition, the Act provides an exemption to the above offences for the
purpose of doing anything which is authorised under the Animals (Scientific
Procedures) Act 1986 e.g. experimental procedures approved under licence
to advance biological or behavioural knowledge.
56
11.3 One part of the Crown is, strictly speaking, unable to apply to another
part of the Crown for a licence and it may be a Crown laboratory that would
wish to carry out the research. In circumstances such as these it is usual for
Crown staff to operate within the spirit of the law, and should a "licence" prove
necessary, to submit an "application" and to comply with the conditions
attached to any "licence" subsequently issued.
12. SECURITY CONSIDERATIONS.
12.1 Removal of animals from the wild for experimental purposes will attract
the attention of animal rights activists, both in the field and at the captive
facility. Consideration should be given to the possibility of procuring badgers
from a secure, perhaps Ministry of Defence, site.
13. REFERENCE.
Forrester G.J., Delahay R.J., Clifton-Hadley R.S. (2001). Screening badgers
(Meles meles) for Mycobacterium bovis infection by using multiple
applications of an ELISA. Veterinary Record, 149, 169-172.
14. BIBLIOGRAPHY.
Pope and Burke, preliminary report 6th March 2002. Report to Defra.
57
APPENDIX 8.
FEASIBILITY AND COSTS FOR PROVIDING ACCOMMODATION FOR
BADGERS.
1. INTRODUCTION.
1.1 Work with badgers infected with bovine tuberculosis would require
containment at Level 3. Appropriate containment is also required to protect
local farming interests. As the work would require animals to be maintained in
captivity for an extended period particular attention needs to be paid to their
welfare and the conditions under which they would be held.
1.2 Given the containment and animal welfare considerations of this work a
new facility would be required. Existing secure facilities are available which
include sufficient open ground to accommodate a new unit while providing
access to trained animal technicians and scientists.
2. STANDARDS.
2.1 To comply with Level 3 containment and Home Office Procedures the
facilities must meet the following standards.
2.1.1 All rooms must be maintained to an air pressure negative to the
atmosphere.
2.1.2 Extracted air must be filtered by a HEPA (high efficiency particulate
absorption) filter.
2.1.3 Liquid waste should be discharged via a sealed and leak-proof drainage
system into an impermeable holding or treatment enclosed tank within the
designated area.
2.1.4 All areas must be sealable to permit disinfection.
2.1.5 An autoclave must be available within the facilities and all bedding,
animal waste and bodies must be autoclaved before disposal.
2.1.6 When undertaking procedures, such as post mortem, a class 1
microbiological safety cabinet is required; the exhaust must go into the room
extract system via a HEPA filter.
2.1.7 A dedicated staff changing area is required.
3. SERVICES.
3.1 Under The Animal (Scientific Procedures) Act 1986 all services should be
installed in such away that they are either buried within the fabric of the
building or clear of wall surfaces. Maintenance required to any services might
disturb the animals. Therefore the design for services such as lighting must
58
be accessible from outside the holding area. All holding areas should have
temperature and relative humidity control, which are carefully maintained.
The temperature should be within the range appropriate for the species and
the relative humidity would be maintained at 55%. Ventilation should provide
sufficient air of an appropriate quality and reduce the levels and spread of
odours, dust and infection; in order to comply with this recommendation 15-20
air changes per hour distributed throughout the holding area should be
adequate. No procedures or euthanasia must be performed in the normal
holding areas where animals are housed, i.e. there must be an adequate area
provided to carry out these.
4. HOLDING AREA.
4.1 These requirements mean that infected badgers will need to be kept in an
enclosed facility with no access to outdoor or grass runs. There is currently
no available information on the welfare requirements of badgers to be kept
under such containment conditions for an extended period of time. However,
working on the assumption of two animals to be kept in each enclosure, and
from experience with other species, it is suggested a holding area of 4.5m x
10m be an appropriate minimum. This area should be concrete floored with
steel walls. Within this area the animals would be kept on a deep litter system
and be provided with nest boxes.
4.2 A series of such enclosures would require access through a central
corridor leading to a procedures room, post mortem area, autoclave facility
and changing area. The area would require secure drainage.
5. COSTS.
5.1 Commercial construction of Category 3 facilities costs approximately
4,400 per square meter. Adding 15% to the floor area for corridors and
circulation and each enclosure built to existing standards would involve a cost
of 227,700. Such area-based costs might be higher than necessary given
the large enclosed spaces required by the animals and should be viewed as a
maximum. It might be possible to use cheaper alternatives or modular preconstructed units although these would require further investigation. A low
end cost of 3,000 per square meter might be a minimum in these
circumstances producing a cost of 155,250 per enclosure. The central
procedures, autoclave, post mortem and changing areas would have an
additional cost of approximately 440,000.
No
Enclosures
each
containing
two badgers
10
25
50
Cost of
Enclosures at
4,400 per
m2
Cost of
Enclosures at
3,000 per
m2
2,277,000
5,692,500
11,385,000
1,552,500
3,881,250
7,762,500
59
Cost of
Central
Facilities at
4,400 per
m2
440,000
440,000
440,000
Total price
range
2.25-2.72m
4.32-6.13m
8.20-11.82m
5.2 In addition to the capital costs of construction there would also be staff,
veterinary consultancy and running costs associated with the facilities.
Approximate annual costs are outlined below.
No
Enclosures
each
containing
two badgers
10
25
50
Staff Costs
Veterinary
Costs
Running
Costs
Total
40,000
60,000
85,000
2,000
2,500
3,000
30,000
75,000
150,000
72,000
137,500
238,000
5.3 Holding animals in existing facilities while checking disease status would
not change the above costs; these are largely determined by the number of
simultaneous challenges that are required, not by how long the animals are
held. If animals were to be held for a brief period to check disease status and
then for up to a year in category 3 for the challenge work, there would be a
slight saving in time, but not a significant one. Using holding pens would also
raise issues of soil contamination, risking infection of subsequent animals and
the surrounding environment.
5.4 These costings contain a number of uncertainties that require further
investigation before reliance can be placed on the figures. In particular the
standard of building required to provide containment at reasonable cost, and
the conditions under which animals should be held to ensure their welfare
both require further investigation. It is suggested that two lines of enquiry are
needed to explore the options.
6. FURTHER ENQUIRY.
6.1 Firstly, there is limited information and expertise on keeping badgers
under such conditions. A pilot study would be required to identify suitable
protocols to maximise the health and welfare of animals. This would use
uninfected badgers to obviate the need for containment. It is suggested
holding two pairs of badgers in enclosures modified from existing low
containment facilities. This pilot study should be carried out for 12 months to
develop protocols for the following.
6.1.1 Optimum space requirements for housing.
6.1.2 Routine and experimental handling.
6.1.3 Food presentation and suitable sources of food.
6.1.4 Types of bedding and nesting material required.
6.1.5 Presentation of bedding and nesting material.
6.1.6 Water presentation.
60
61
APPENDIX 9.
IMMUNOLOGICAL ASSAYS TO SUPPORT THE DEVELOPMENT AND
EVALUATION OF A VACCINE AGAINST BADGER TUBERCULOSIS.
Glyn Hewinson and Mark Chambers
Veterinary Laboratories Agency, New Haw, Addleston, Surrey KT15 3NB
1. INTRODUCTION.
1.1 One of the stumbling blocks to vaccine development for badgers is the
paucity of available immunological reagents that might be used to assess
vaccine take and to monitor M. bovis infection and vaccine efficacy in the
field. Over the past few years a number of immunological assays have been
developed for badgers. The purpose of this appendix is to review the assays
that are already available, to describe those that are in development and to
outline how each assay might be used in a vaccine development and
evaluation programme.
2. PROPOSED USES FOR IMMUNOLOGICAL ASSAYS.
2.1 Sensitive and specific detection of M. bovis infection in the target
population.
Test
Rationale
ELISA for serological response to M. The existing Brock Test ELISA detects
bovis-specific antigen(s).
IgG antibody against a single antigen,
MPB83, with a sensitivity of ca. 45%.
Adding further M. bovis specific
antigens has improved sensitivity to ca.
55% without a loss in specificity
(Kampfer et al., 2003; Greenwald et al.,
2003).
Lymphocyte
(LTA)
transformation
62
Rationale
IgA ELISA
Rationale
Recent
results
in
cattle
have
demonstrated that, following BCG
vaccination, protected animals could be
differentiated from those that were
developing disease (Vordermeier et al.,
2002) using this approach.
Rationale
Seropositive badgers are at greatest
risk of shedding M. bovis (Chambers et
al., 2002, Clifton-Hadley et al., 1995).
This assay would allow detection of
super excretors within 15 minutes of
capture.
63
64
65
performance over the Brock Test; which was originally evaluated on nearly
two thousand sera (Clifton-Hadley et al., 1995).
4. PROGRESS MADE ON TEST DEVELOPMENT: ASSAYS UNDER
DEVELOPMENT.
4.1 IFN ELISA.
4.1.1 Badger interferon-gamma (IFN) has been cloned and sequenced.
Badger IFN was found to be most similar to canine IFN, with 88% aminoacid identity. Rabbits have been immunised with DNA encoding badger IFN
and the resulting polyclonal antiserum demonstrated specificity for native
badger IFN by intracellular staining and flow cytometry analysis of badger
lymphocytes stimulated with PMA (Phorbol myristate acetate) and ionomycin.
4.1.2 At least 20 monoclonal antibodies have been generated that specifically
recognise badger IFN, as demonstrated by flow cytometry on mitogenstimulated badger lymphocytes. These antibodies are being systemically
evaluated in pair-wise combinations for their performance in the sandwich
ELISA.
4.1.3 A prototype sandwich ELISA has been produced that detects the
presence of badger IFN. However, the test requires further optimisation as
the sensitivity is currently too low to be of practical use. Blood from badgers
experimentally infected with M. bovis in the Republic of Ireland (RoI) will be
used for this purpose.
4.1.4 The IFN assay is not anticipated to be available and validated until
March 2005.
4.2 IFN ELISPOT.
4.2.1 Evaluation of a cross-reactive commercial ELISPOT kit for canine IFN
(R&D Systems) lacked the required sensitivity and reproducibility for use in
badgers. A promising prototype ELISPOT for badger IFN has been
produced using a combination of monoclonal antibodies generated against
badger IFN. However, this assay requires further optimisation.
5. USE OF M. BOVIS SPECIFIC ASSAYS TO DISCRIMINATE BETWEEN
VACCINATED, INFECTED AND VACCINATED BUT INFECTED ANIMALS.
5.1 Analysis of cellular immune responses in cattle following M. bovis
challenge has demonstrated that proliferative T cell and IFN- responses
towards the M. bovis specific antigen ESAT-6 (whose gene is absent from
BCG) were generally low in vaccinated animals, but high in all non-vaccinated
calves. Importantly, the amount of ESAT-6 specific IFN- measured by ELISA
after M. bovis challenge, but not the frequency of responding cells, correlated
positively with the degree of pathology found 18 weeks after infection.
However, diagnostic reagents based on antigens not present in BCG, like
66
67
Lyashchenko K.P., Singh M., Colangeli R., Gennaro M.L. (2000). A multiantigen print immunoassay for the development of serological diagnosis of
infectious diseases. J. Immmunol. Methods, 242, 91-100.
Southey A., Sleeman D.P., Lloyd K., Dalley D., Chambers M.A., Hewinson
R.G., Gormley E. (2001). Immunological responses of Eurasian badgers
(Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette
guerin). Vet. Immunol. Immunopathol., 79, 197-207.
Vordermeier H.M., Chambers M.A., Cockle P.J., Whelan A.O., Simmons J.,
Hewinson R.G. (2002). Correlation of ESAT-6-specific gamma interferon
production with pathology in cattle following Mycobacterium bovis BCG
vaccination against experimental bovine tuberculosis. Infect. Immun. 70,
3026-32.
68
APPENDIX 10.
REQUIREMENTS OF A FIELD TRIAL TO TEST BCG IN BADGERS.
Ivan Morrison
Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter
Bush, Roslin, Scotland EH25 9RG
1. INFORMATION REQUIRED BEFORE UNDERTAKING A TRIAL.
1.1 The following information would be highly desirable not only to justify a
field trial with BCG but also to facilitate design of the trial and interpretation of
the results. Some of this information might be available from the literature, but
much of it would need to be generated from experimental studies.
1.1.1 Optimal dose and route of administration of BCG to achieve protection.
1.1.2 A reliable method to measure vaccine uptake, if administered remotely
in bait.
1.1.3 Whether or not excretion of BCG occurs following vaccination.
1.1.4 Risk of uptake by, or transmission to, other species and potential
pathogenic effects.
1.1.5 Level of protection obtained, in terms of reduced disease and bacterial
excretion.
1.1.6 Types of immune responses induced by infected and BCG-vaccinated
badgers, including immune responses that distinguish infected from
vaccinated animals.
2. PARAMETERS THAT NEED TO BE MONITORED IN A TRIAL.
2.1 Essential parameters.
2.1.1 Badger population density and structure. This can only be estimated on
the basis of survey data. It would be needed at outset to determine where
vaccine baits should be laid and also needed during the course of a trial to
ensure that the badger population does not change radically.
2.1.2 The rate of vaccine uptake. Methods would need to be tested and
validated prior to a trial; this need only be done on a sample of badgers.
2.1.3 The incidence of cattle herd breakdowns.
2.1.4 Environmental impact. One would need to assess possible infection of
other species with BCG and any potential deleterious effects. Ideally this
69
70
3.3 For these reasons, it would be preferable to proceed directly to a largescale trial aimed primarily at examining the impact of vaccination on TB in
cattle, assuming that the experimental studies provided evidence of efficacy.
The precise design of the trial would depend on the area that would need to
be covered to include the numbers of herd breakdowns required. This might
be either a single large site or multiple sites, as in the current culling trial, with
appropriately matched control sites. Indeed, the control areas, and possibly
also the reactive areas (depending on the results), in the current culling trial
might be suitable for such a trial.
3.4 However, there may be a need for limited scale, short-term experiments
in the field to examine the feasibility of particular aspects of the trial, e.g.
assessment of environmental risks, measurement of vaccine uptake or
assessment of vaccine take.
71
APPENDIX 11.
VACCINATION OF BADGERS AGAINST BOVINE TB: THE ECOLOGICAL
CONSIDERATIONS.
Chris Cheeseman, Des Delahay & Gavin Wilson
CSL Woodchester Park, Nympsfield, Stonehouse, Glos, GL10 3UJ
1. INTRODUCTION.
1.1 Vaccination of wildlife presents particular challenges related to the
ecological characteristics of the target population. The efficacy of the vaccine
will be a product of the rates of uptake and immunisation that are achieved.
Understanding the practical constraints imposed by ecological factors is
essential for the development of an effective vaccine and a successful
strategy for its delivery.
1.2 This appendix describes the potential influence of badger social
organisation, population dynamics and the epidemiology of Mycobacterium
bovis infection on the development and execution of any future vaccination
programme, and discusses options for vaccine delivery strategies.
2. BADGER SOCIAL ORGANISATION AND POPULATION DYNAMICS.
2.1 In order to establish an effective vaccine delivery programme it is
necessary to estimate the size and distribution of the target population (which
may relate to either the number of badgers or their setts). Consequently,
vaccination of badgers would require information on population density, social
organisation and demographic structure (particularly if age or sex biased
disease transmission occurs, e.g. pseudo-vertical transmission). In addition,
information on population turnover rates (fecundity, mortality and
emigration/immigration) would be required to determine the frequency of
application that would ensure a fixed proportion of the population was always
vaccinated.
2.2 Badger density varies widely throughout the UK, from less than a single
animal / km2 in marginal habitats to more than 25 / km2 in optimal habitats
(Wilson et al., 1997). The density of badgers in the TB cattle hotspot areas of
South West England is probably medium to high, perhaps typically varying
between 6-15 adults / km2 based on the presence of 1-2 social groups of
moderate size / km2. However, it is likely that in many of these areas current
population density is below carrying capacity as a result of previous culling
operations. It will be necessary to assess the size of target populations for
vaccination, and the methodology employed will depend on the proposed
scale of operations. Current Defra funded projects are investigating the
development of methods to estimate badger abundance.
2.3 Badger social organisation varies between populations. In undisturbed
medium and high-density populations, badgers live in social groups and
72
73
2.7 Rates of immigration into stable badger populations and those that are
recovering from culling operations will influence the time scale for vaccine
deployment on all but the largest of areas (e.g. at a regional level). In high
density populations rates of movement of badgers between social groups are
relatively low (Cheeseman et al., 1988a; Rogers et al., 1998). However, rates
of movement within populations that are recovering from culling might be
higher (Cheeseman et al., 1993; Tuyttens et al., 2000b).
2.8 Consequently, the intrinsic growth rate (r) of badger populations is
relatively low; approximately 0.24 to 0.30 per year for moderate to high
density populations (Anderson & Trewhella, 1985; Smith, 2002). Rates of
population turnover need to be considered in conjunction with vaccine uptake
rates in order to determine the optimal strategy for repeated applications.
3. THE EPIDEMIOLOGY OF TB IN BADGER POPULATIONS.
3.1 The distribution of infected badgers is spatially clustered. Social groups
with endemic infection can be adjoined by groups where infection is absent
(Cheeseman et al., 1988b; Delahay et al., 2000a). Also, the prevalence of
infection might vary considerably both within and between badger populations,
and over time (Cheeseman et al., 1981; Cheeseman et al., 1985; Delahay et
al., 2000a). However, as there is currently no reliable, cost-effective and
practical technique for accurately identifying such patterns, it might not be
possible to target vaccine delivery accordingly.
3.2 Evidence from Woodchester Park suggests that the prevalence of
infection in the badger population might not bear any linear relationship with
density (Cheeseman et al., 1989; Rogers et al., 1999). However, no
concurrent data exists on both badger density and TB prevalence from other
sites. Mathematical models suggest that a threshold of about 8 badgers per
social group is required for maintenance of infection over the moderate to
long-term (i.e. up to 30 years) in a population (Smith et al., 1995).
3.3 Evidence from the Woodchester Park study suggests that the greatest
risks of infection to cattle may be posed by a relatively small proportion of the
population, consisting of persistently infectious animals (Cheeseman &
Mallinson, 1981; Delahay et al., 2000a). Infected individuals can live for
several years and breed successfully whilst excreting bacilli (Clifton-Hadley et
al., 1993; R. Delahay, unpublished data). As the distribution of infected
individuals can also be highly aggregated within populations, this argues for a
spatially broad-based strategy for vaccination, since small foci of infection
cannot be adequately identified. It is possible that a proactive campaign
involving broad scale application of a vaccine could reach a high proportion of
the target population. However, if small foci of infectious animals were missed
(perhaps reflected in the persistence of local cattle breakdowns), then smallerscale, reactive applications of vaccine could be used to target these problem
areas. Delivery of a vaccine over an extensive area might be best achieved
by deployment of baits, whereas trapping and injection could be useful in
intensive localised operations.
74
3.4 It is not yet known whether badgers can naturally mount an effective
immune response to M. bovis capable of protecting against the development
of disease and excretion of bacilli. There is some evidence from the
Woodchester Park study, of a transient sero-positivity to M. bovis in badger
cubs. However, it is unclear whether this is the result of maternally derived
antibodies or prior exposure (Newell et al., 1997; Chambers et al., in press).
Nevertheless, in the majority of badgers that exhibited transient sero-positivity
as cubs, M. bovis could not be isolated from clinical samples during later life
(R. Delahay & G. Wilson, unpublished data). Both Newell et al. (1997) and
Chambers et al. (2002) reported that Western blotting may identify serum
antibodies that are correlated with prolonged culture negativity in later life.
However, at present there is insufficient information on the true immune status
(cellular immunity in particular) of these animals to predict the likely effects of
a vaccine.
3.5 It would also be important to consider what the effect of potential vaccines
would be on individuals that were already infected. If cubs are infected at an
early age by females (e.g. pre-weaning and/or pre-emergence from the sett)
then this would probably make it impossible to deliver a vaccine to them prior
to infection. However, in order for a badger vaccine to reduce the incidence of
TB in cattle it might only need to reduce the severity of disease rather than
protect against infection. It might be possible to reduce the rate of
transmission from badgers to cattle by either stopping or decreasing the
excretion of bacteria in infectious badgers. However, if the vaccine had no
effect on infected individuals, then this would suggest the necessity of
frequent follow up vaccination campaigns to prevent these animals from
causing new cases.
4. VACCINE DELIVERY.
4.1 The most likely options for successful delivery of a vaccine to wildlife are
by injection, by an aerosol spray, by ingestible bait or by an orally
administered bait with the capacity to deliver an aerosol to the respiratory
tract. The likelihood of successful immunisation resulting from each potential
delivery route will depend on the characteristics of the vaccine. For example
some vaccines might not survive passage through the gastro-intestinal tract.
The survival of the vaccine in the environment and its likely effects on nontarget species would also influence the choice of delivery vehicle. The pattern
of vaccine deployment would influence the proportion of the population that
could be reached, and this in combination with the immunisation rate would
determine the overall efficacy of the vaccine.
4.2 Delivery of a vaccine by injection would require the capture of badgers.
Cage trapping is unlikely to be more than 80% efficient and would often be
much lower (see Tuyttens et al., 1996), could be biased towards particular
age and sex classes, would be extremely labour intensive over an extended
area and would be prone to interference from objectors. In addition, capture
related stress in trapped badgers could potentially adversely affect the
immune response. However, administration by injection would eliminate the
problems associated with non-target species and survival of the vaccine in the
75
76
deployment and the local availability of natural foods might have been
influential.
4.7 The strategy might need to minimise exposure of non-target species to
baits, if the vaccine was likely to have any pathological effects, or if uptake
rates in the target population could be adversely affected. Placing baits in
badger setts would reduce exposure to non-target species, but cannot
eliminate it as some mammals (e.g. foxes, rabbits, rats, mice and, in rarer
cases, otters) might also be resident.
4.8 A bait that would be taken orally (whether or not it contains an
effervescent component) would need to be highly palatable to badgers. In
bait preference tests, a formulation consisting of plant and animal protein, fish
oil, a synthetic polymer and coated in chocolate was readily accepted by
captive badgers (OCallaghan, 1996). Scented attractants could also be used
to improve bait uptake (e.g. synthetic fermented egg in fox baits).
4.9 It is important that the vaccine had no detrimental effects if taken several
times by the same badger, as this would be extremely difficult to avoid. If
delivery of a specific dose was required, then this would seriously constrain
the options for use of an oral bait and could arguably rule it out. However, it
might be possible to use the principles of conditioned taste aversion (CTA) to
limit bait uptake by individuals. This would involve incorporating a CTA agent
in each bait, to induce nausea in any animal that consumed it. Work on foxes
and ferrets carried out by CSL suggests that this could induce a short-term
aversion to consuming further similar baits (G. Massei, unpublished data).
Trapping and injection would allow each captured animal to receive a known
dose and if these animals were marked in some way then re-dosing could be
avoided.
4.10 Monitoring rates of bait uptake during vaccination operations would be a
substantial undertaking, and would be likely to only be possible on a relatively
small sub-sample of the population. The development of a potentially
effective bait delivery strategy would require research on uptake rates with
respect to variations in season, weather, habitat and badger density.
4.11 In New Zealand, vaccine delivery trials have been undertaken using a
mechanical device that sprays an aerosol at possums visiting a bait station .
Using this approach in badgers would require the development of suitable
technology, the vaccine would need to remain viable during storage in the bait
station and suitably prepared for reliable aerosolisation. However, automated
vaccine delivery systems could be prone to mechanical failure and it might be
difficult to monitor numbers receiving the vaccine. It is likely that a large
number of such devices would be required and it is not clear how delivery of a
specific dose and avoidance of multiple dosing could be assured, but it might
be possible to substantially reduce exposure of non-target species by such a
method.
4.12 Once a vaccine candidate and delivery route were identified then firstorder estimates of its effectiveness in the badger population could be obtained
77
78
79
80
Journal of Animal
Tuyttens F.A.M., Macdonald D.W., Rogers L.M., Cheeseman C.L. & Roddam
A.W. (2000b). Comparative study on the consequences of culling badgers
(Meles meles) on biometrics, population dynamics and movement. Journal of
Animal Ecology, 69, 567-580.
White P.C.L. & Harris, S. (1995). Bovine tuberculosis in badger (Meles
meles) populations in south-west England: an assessment of past, present
and possible future control strategies using simulation modelling.
Philosophical Transactions of the Royal Society of London B, 349, 415-432.
Wilkinson D., Smith G.C., Delahay R.J., Rogers L.M., Cheeseman C.L. &
Clifton-Hadley R S. (2000).
The effects of bovine tuberculosis
(Mycobacterium bovis) on mortality in a badger (Meles meles) population in
England. Journal of Zoology, 250, 389-395.
Wilson G., Harris S. & McLaren G. (1997). Changes in the British badger
population, 1988 to 1997. Peoples Trust for Endangered Species.
Woodroffe R. & Macdonald D.W. (1995). Female/female competition in
European badgers (Meles meles): effects on breeding success. Journal of
Animal Ecology, 64, 12-20.
ANNEX TO APPENDIX 11.
STAFF TIME REQUIRED FOR A STRATEGY BASED ON DELIVERY OF
VACCINE IN BAIT.
1. This example assumes that the strategy will involve two applications of bait
each year in the proximity of all the active badger setts in the target area.
2. Initially the area would need to be surveyed for all badger setts, in the
same manner as was carried out for each treatment area in the randomised
badger culling Trial.
Between applications, follow-up surveys (directly
comparable to the re-surveys carried out in proactive treatment areas of the
Trial) would be required to identify any changes in sett use that may have
taken place. The resource requirements for survey work in Trial areas are
already known.
3. Experience at Woodchester Park suggests that one fieldworker with a
Land Rover and driving access to within several meters, can feed bait at
about 8-10 main setts each day. On average this will involve the placing of
25-30 individual baits in shallow pits covered with large stones. For the
purposes of bait-marking studies, feeding continues for 8-10 consecutive
days, although if each badger only needed to consume a single bait then this
period could probably be shortened for vaccine delivery.
81
APPENDIX 12.
VACCINATION OF CATTLE WITH BCG TO PROTECT AGAINST
INFECTION WITH MYCOBACTERIUM BOVIS.
John Pollock
Veterinary Sciences Div, DARDNI, Stormont, Belfast BT4 3SD
1. INTRODUCTION.
1.1 This appendix seeks to trace the sequence of the main events in almost a
century of attempts to develop cattle vaccines for bovine tuberculosis. Within
that broad aim, the main areas of focus have been selected to be of relevance
to the present need to assess potential strategies to address the ongoing
problem with this disease.
1.2 Considerable numbers of studies have been performed in several
countries and have been based generally on the use of Bacillus Calmette
Gurin (BCG). Some studies have been constructed as experimental
investigations, others as field trials of various magnitudes. Some have been
reported in detail as carefully designed studies with adequate controls, others
less so. This variation must be acknowledged when considering the
relevance of individual studies to the current situation and the overall potential
of vaccination. To that end, this appendix attempts to rationalise:
1.2.1 The problems the investigators were attempting to solve and the
background.
1.2.2 Any flaws now apparent which may limit the strength of the conclusions.
1.2.3 The details of the vaccination strategy which was used.
1.2.4 The protocols by which vaccine efficacy was assessed.
1.2.5 The outcome and the conclusions which were reported.
1.3 In a number of the studies which have been reviewed, particularly the
more historical ones, some of these details are difficult to ascertain. However,
with the benefit of previous reviews in this area (Francis, 1958; Zuckerman,
1980; OReilly and Daborn, 1995; Skinner et al., 2001; Buddle, 2001), it is
usually possible to fit each study into a perspective of how opinions and ideas
have changed with time.
2. IDEAL FEATURES OF A VACCINE FOR BOVINE TUBERCULOSIS.
2.1 It is apparent that the ideal features of a vaccine to combat bovine
tuberculosis depend on the prevailing conditions, including economics and
disease prevalence. For example, the requirements of a vaccine to improve
the situation in the early part of the 20th Century are likely to have been very
82
different from present requirements. Around 100 years ago, knowledge of the
pathogenesis of the disease was in its infancy. At that time, up to a third of all
cattle were infected with tuberculosis, and there had been little attempt to deal
with the situation. Currently in the U.K., however, statutory programmes for
eradication have been in place for decades and have greatly decreased
disease prevalence.
Additionally, it is become accepted that wildlife
reservoirs may play a significant rle in the maintenance of bovine
tuberculosis in particular areas (as reviewed by Krebs, 1997).
2.2 Within recent years, several authors have considered the features
required of a vaccine to effectively address bovine tuberculosis in developed
countries, like U.K. and New Zealand, where there are potential wildlife
reservoirs of infection (badgers and possums, respectively). In such a
situation, the vaccine could be targeted towards either cattle or wildlife, and
the profile of the vaccine will be different in each situation.
2.3 Within a programme to control tuberculosis in domestic animals, the aim
of a vaccine for wildlife species is, essentially, to prevent spread of infection to
cattle.
To that end, such a vaccine need not necessarily prevent
establishment of infection in the target animal, but must prevent excretion of
bacilli (Newell and Hewinson, 1995). It has been considered that a badger
vaccine should reduce the number and infectiousness of animals with active
tuberculosis, but that it is not a concern if vaccinated animals have persistent
low levels of infection (Krebs et al., 1997).
2.4 The requirements of a vaccine to be used in cattle are much more
stringent. It has been stated that such a vaccine must be capable of
protecting against establishment of persistent infection and that an outcome of
reduction in bacterial load in persistently infected animals, which may be a
good outcome for badger vaccination, would be unacceptable for cattle (Krebs
et al., 1997). Recent reviews from New Zealand (Buddle, 2001; Skinner et al.,
2001) have set out the detailed requirements for a cattle vaccine in developed
countries. As stated, the vaccine must establish a form of immunity which will
allow the animal to resist infection. The vaccine should also be safe, and be
acceptable to other countries which would be potential importers of vaccinated
cattle or cattle products. As part of that requirement, it will be necessary to be
able to differentiate vaccination from infection (Krebs et al., 1997). Skinner et
al. (2001) set the standard that the ideal cattle vaccine should allow the
animal to resist challenge without becoming positive to subsequent tuberculin
skin tests.
3. BCG.
3.1 Historical development of BCG.
3.1.1 The initial Bacillus Calmette Gurin was developed from a strain of M.
bovis, which had been isolated by Nocard from a case of tuberculous mastitis
by 230 passages through glycerinated bile potato medium between 1908 and
1919 (Oettinger et al., 1999). The initial strain was dispersed to many
countries in the 1920s and continuing maintenance in differing conditions
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85
4.1.6 Zuckerman (1980) reviewed two trials which were carried out in UK in
the 1930s and 1940s, which were stated not to have been widely published.
The first trial was conduced in 4 herds infected with tuberculosis and lasted for
11 years. 47 animals were vaccinated at 6-month intervals. Ultimately, 25% of
these were found to have tuberculosis lesions, compared with 50% of their
contacts. The second trial involved more animals, but did not last as long due
to the advent of the national test-and-slaughter programme. In that case, 30%
of the vaccinated and 50% of the non-vaccinated animals were found to have
lesions.
4.1.7 Glover and Richie (1953) report on a UK trial carried out in 2 infected
areas. In that case, vaccination reduced the number of animals with lesions,
and there was an indication that vaccination was most successful if calves
were not subjected to early challenge. In another trial which was carried out
in an infected herd, it was found that considerable numbers of vaccinated
animals developed lesions, and it was concluded that test-and-slaughter was
a more realistic option (Doyle and Stuart, 1958). In other European trials,
however, more positive outcomes were reported. In two such programmes
carried out in Germany in the 1950s, tuberculosis was successfully
eradicated from herds which were known to have been infected (Schellner
and Gaggermeier, 1955; Rolle and Wiethe, 1956).
4.1.8 Considering the variable outcomes which had been reported for the use
of BCG in cattle up until the 1950s, an Expert Committee of the WHO/FAO
(1959) stated that: generally speaking, vaccination has no place in the
eradication of tuberculosis in cattle. This conclusion was based on a lack of
proven effect and the fact that BCG vaccination compromises the tuberculin
skin test.
4.1.9 In the situations which prevail in some countries, however, tuberculin
testing followed by slaughter of reacting animals may not be an option and, in
the face of a serious zoonotic problem, further work on BCG vaccination was
performed in some African countries (Mares, 1972).
Experimental
investigations reported from Malawi in 1972 showed that BCG produced
useful resistance to challenge with M. bovis, which was more apparent in
Zebu cattle than in Zebu-cross (Waddington and Ellwood, 1972; Ellwood and
Waddington, 1972). In Madagascar, Cheneau and Blancou (1975) compared
the potential of vaccination with live BCG, killed BCG and a trypsin extract of
the Koch bacillus and found the latter to provide greatest protection. Several
field trials were carried out in Malawi in the 1970s using 2.6 x 109 cfu of BCG.
Some reports from this phase (Ellwood, 1975; Moodie, 1977) concluded that
BCG was effective in controlling spread of tuberculosis in cattle. However,
other reports (Berggren, 1977; 1981) identified little benefit of BCG in
protecting cattle from infection. Contrary to these findings, trials carried out in
infected animals in USSR indicated that BCG had the potential to clear
infected herds within a period of years (Sibgatullin, 1982).
4.2 Recent investigations.
86
87
the subunit vaccine (based on culture filtrate proteins of M. bovis and IL-2)
was seen to enhance extrathoracic spread of infection compared to nonvaccinates.
4.2.7 An alternative strategy to circumvent any adverse effect of
environmental pre-sensitisation may be to vaccinate animals while they are
very young. Recent data from experiments carried out in New Zealand
indicate that the approach of vaccinating neonatal calves with BCG holds
considerable promise in protection from challenge with M. bovis (Bryce
Buddle, personal communication).
5. CONCLUSIONS FROM FIELD STUDIES ON THE USE OF BCG IN
CATTLE.
5.1 It has been demonstrated that vaccination with BCG can provide a
considerable degree of protection from the development of tuberculous
lesions following experimental challenge with M. bovis. However, this outcome
has not always been reflected in field trials. Indeed, attempts to utilise BCG to
control natural tuberculosis have often given disappointing results (OReilly
and Daborn, 1995; Buddle, 2001; Skinner et al., 2001). The reasons for this
overall lack of success in field situations are not clearly understood. A
number of factors have been proposed relating to either the vaccine or the
target cattle, and include:
5.2 Factors relating to BCG.
5.2.1 Very large doses of BCG (up to 1010 cfu) were used in many field trials.
It is now considered that lower doses may induce more effective immunity
(Bretchner, 1994; Griffin et al., 1999).
5.2.2 Differing substrains of BCG were used in different trials. It has been
suggested that the lack of success in Malawi may relate to the use of BCG
Glaxo, which does not produce the dominant antigen MPB70 (C. Foster, 1992
cited by OReilly and Daborn, 1995). Interestingly, individual strains of BCG
have had very different efficacies in different trials against human tuberculosis
(Fine, 1995).
5.2.3 The viability of the BCG vaccine is difficult to ascertain. In some cattle
experiments, it has been shown that the BCG must be viable to induce
effective immunity (Haring et al., 1930). In some trials, particularly in difficult
situations, the conditions may not have been optimal for storage and
presentation of the vaccine.
5.3 Factors relating to the cattle.
5.3.1 In human tuberculosis, it is considered that host genetics are relevant to
the development of effective immunity in response to BCG (Fine, 1998). This
may also be of fundamental importance in cattle, and it was noted by Ellwood
and Waddington (1972) that Zebu cattle developed more effective immunity to
BCG than cross breeds.
88
89
6.4 One major concern about vaccinating cattle with BCG has been that the
tuberculin skin test, which is often a pre-requisite for international trade, is
compromised (WHO/FAO, 1959). However, in the post-genomic era, it is
known that the process by which BCG evolved from M. bovis resulted in
deletion of defined stretches of DNA (Behr et al., 1999). This knowledge can
be utilised in the development of tests which can differentiate BCG-vaccinates
from cattle which have been exposed to M. bovis. Thus, only cattle which
have been exposed to the virulent organism will have responses to dominant
T-cell antigens such as ESAT-6 and CFP10, which are deleted from the
genome of all substrains of BCG (Pollock and Andersen, 1997; Buddle et al.,
1999; Vordermeier et al., 2002).
6.5 However, a possible category of animals, which have been effectively
protected by BCG vaccination and subsequently exposed to M. bovis, must
still be considered. Because of post-vaccine M. bovis exposure, these
animals may develop T-cell responses to antigens such as ESAT-6 and
CFP10 in the absence of disease or tuberculous pathology. It must be
recognised that further advances will be required to allow accurate
categorisation of such animals based on immunological parameters.
7. CONCLUSIONS.
7.1 As in human tuberculosis, BCG has many potential advantages for use
against tuberculosis in cattle. It is a safe, inexpensive vaccine for which there
is evidence of protective efficacy in experimental situations. However, a
number of factors, which are not fully understood, appear to compromise field
performance. Indeed, current expectations for BCG would probably fall well
short of the 90% efficacy which was indicated as necessary to provide
benefits in a mathematical model referred to by Krebs et al. (1997). It should
also be remembered that in experimental studies, the protective benefit
derived from BCG vaccination has often referred to limitation of lesions rather
than the prevention of infection. It is now generally stated that to have an
effective impact on bovine tuberculosis, a cattle vaccine must prevent
establishment and maintenance of infection. Indeed, the previous lack of
acceptable field performance for BCG may be a vindication of this current
standard.
7.2 From the literature reviewed, it is apparent that further developments in
vaccine application and possibly in vaccine selection are required to allow
effective use against bovine tuberculosis. Such advances will require greater
understanding of protective immunity and of several confounding factors such
as pre-sensitisation with environmental mycobacteria.
7.3 Importantly, in terms of future expectations, it should be noted from
human studies that even exposure to the complete tuberculosis organism may
not guarantee total protection from subsequent challenge in all individuals
(Fine, 1995) and, as suggested even from earliest times, it may be a reality
that cattle are not capable of developing an immune response which equates
to absolute protection against M. bovis (McFadyean, 1901 cited by
Pritchard, 1988).
90
8. ACKNOWLEDGEMENT.
The input of Dr Jim McNair (VSD, Belfast) in the production of this Appendix is
gratefully acknowledged.
9. REFERENCES.
Behr M.A., Wilson M.A., Gill W.P., Salamon H., Schoolnik G.K., Rane S.,
Small P.M. (1999). Comparative genomics of BCG vaccines by wholegenome DNA microarray. Science, 284, 1520-1523
Berggren S.A. (1977). Incidence of tuberculosis in BCG vaccinated and
control cattle in relation to age distribution in Malawi. British Veterinary
Journal, 133, 490-494.
Berggren S.A. (1981). Field experiment with BCG vaccine in Malawi. British
Veterinary Journal, 137, 88-96.
Bretscher P.A. (1994). Prospects for low dose BCG vaccination against
tuberculosis. Immunobiology, 191, 548-554.
Brandt L., Feino Cunha J., Weinreich Olsen A., Chilima B., Hirsch P.,
Appelberg R., Andersen P. (2002). Failure of the Mycobacterium bovis BCG
vaccine: some species of environmental mycobacteria block multiplication of
BCG and induction of protective immunity to tuberculosis. Infection and
Immunity, 70, 672-678.
Buddle B.M., de Lisle G.W., Pfeffer A., Adwell F.E. (1995a). Immunological
responses and protection against Mycobacterium bovis in calves vaccinated
with a low dose of BCG. Vaccine, 13, 1123-1130.
Buddle B.M., Keen D., Thomson A., Jowett A.G., McCarthy A.R., Heslop J.,
de Lisle G.W., Standford J.L., Aldwell F.E. (1995b). Protection of cattle from
bovine tuberculosis by vaccination with BCG by the respiratory or
subcutaneous route, but not by vaccination with killed Mycobacterium vaccae.
Res Vet Sci., 59, 10-16.
Buddle B.M., Parlane N.A., Keen D.L., Aldwell F.E., Pollock J.M., Lightbody
K., Andersen P. (1999). Differentiation between Mycobacterium bovis BCGvaccinated and M. bovis-infected cattle by using recombinant mycobacterial
antigens. Clin Diagn Lab Immunol., 6, 1-5.
Buddle B.M. (2001). Vaccination of cattle against Mycobacterium bovis.
Tuberculosis, 81, 125-132.
Buxton J.B., Glover R.E. (1939). Experiments with calves on immunity
conferred by single and double injections of BCG in an oily excipient. Journal
of Comparative Pathology, 52, 47-56.
91
British
Novartis Foundation
Clinical
93
94
95
Country
Vaccine
M.bovis
Challenge
Assessment
Evidence for
protection
1911
France
Strain
BCG
Dose
200mg
Route
I/V1
I/V
PM4 / GP5
No lesions seen
1920
France
BCG
20mg
I/V
In-contact
PM / GP
France
Ukraine
BCG
BCG
50-100mg
S/C2
5mg I/V
0.005mg
Vallee
PM / GP
PM
Haring et al
USA
BCG
50-100mg
I/V-S/C
2mg I/V
PM
1 gm
I/V
2mg I/V
PM
USA
Killed,
virulent
BCG
S/C
Oral
PM / GP
USA
BCG
BCG
BCG
BCG
100mg
1gm
100mg
1.2-3.5 x
109 cfu8
I/V
Oral
I/D10
S/C
Oral
Oral
Oral
Oral
PM / GP
PM / GP
PM / GP
PM / GP
UK
BCG
5 and
50mg
S/C
5mg Oral
PM / GP
1930
USA
1939
96
Moderate lesions in
lungs and thoracic LN.
GP +ve. Controls died of
miliary TB
Visible lesions in 3/4
calves, 4/4 control
calves had extensive
lesions
Visible lesions, GP-ve
Visible lesions, GP+ve
Visible lesions
3/4 calves lesion
positive
Visible lesions in most
vaccinated calves, GP
Authors' Conclusion
BCG prevents lesions but bacilli
still excreted via the intestines
BCG confers protection from incontact exposure
In general, BCG confers
resistance to experimental
infection compared to nonvaccinated controls
Live bacilli are necessary to
develop a protective response.
Dead bacilli provide little
protection
Insufficient protection using
BCG
Malawi
0.1-0.5mg
PM / B
Madagascar
BCG
100mg
S/C
I/V
250mg
50mg
6 x 104
cfu
S/C
In contact
In contact
800 cfu I/T3
PM
PM
PM /H / B
6 x 106
cfu
2 x 105
cfu
S/C
S/C
2 x 103 cfu
I/T
PM / H / B
37% of vaccinated
calves were lesion and
culture positive
compared to 77% in the
M. vaccae group. 66%
of controls were
lesioned and culture
positive
USSR
Buddle et al
New
Zealand
New
Zealand
BCG
Pasteur
BCG
Pasteur
1995
PM / H / B
Buddle et al
0.1mg S/C
BCG, killed
Koch,
trypsin
extract
BCG
BK Karkov
BCG
Pasteur
1995
1972
Cheneau and Blancou 1975
Malawi
1972
97
variation
BCG appears to produce a
useful degree of resistance to
progression of TB
2 x 103
cfu
2 x 105
cfu
2 x 109
cfu
5 x 105
S/C
1 x 103 cfu
I/T
PM / H / B
Lesions found in
vaccinated and control
calves
5 x 103 cfu
I/T
PM / H / B
50% of vaccinated
calves lesion +ve. All
calves were bacteriology
positive. 100% nonvaccinates were lesion
positive
75% of calves lesion
+ve. All calves were
bacteriology positive.
Fewer lesions were
found in the vaccinated
calves compared to
controls
Buddle et al
1999
New
Zealand
BCG
Pasteur
BCG
Pasteur
M. vaccae,
killed
BCG
Pasteur
Wedlock et al
2000
New
Zealand
BCG
Pasteur
1 x 106
S/C
CFP-IL29
200g1mg
S/C
S/C
I/T
I/D
Superscripts:
1
Intra-venous
2
Sub-cutaneous
3
Intra-tracheal
4
Post Mortem
5
Guinea-Pig
6
Histopathology
7
Bacteriology
8
Colony forming unit
9
Culture filtrate protein-Interleukin-2
10
Intra-dermal
98
Country
Vaccine
Dose
20mg
M.bovis
Challenge
Assessment
1920
France
Strain
BCG
Gurin et al
1927
France
BCG
Watson et al
1928
Canada
BCG
1929
USA
BCG
100mg
S/C2
0.5g
S/C
USA
Killed bacilli
No vaccine
BCG
Haring et al
1930
USA
BCG
50mg
S/C
Infected
herd
PM / GP4
1953
UK
BCG
50mg
I/V1
2 areas
with
infected
herd
PM / GP
1958
UK
BCG
100mg
S/C
Infected
PM / B5
Evidence for
protection
Authors' Conclusion
Route
In-contact
Infected
herd
Infected
herd
PM3
PM
In-contact
PM
4/7 had TB
PM
PM
PM
2/8 had TB
2/6 had TB
Some degree of
resistance from
localisation and
generalisation of TB
No macroscopic lesions
seen but some LN were
bacilli positive
Infected
animals
99
8+27% of vaccinated
calves were lesioned.
Some LN were bacilli
positive. 52% of control
animals were affected
by TB
10 / 25 vaccinated cattle
herd
Schellner & Gaggermeier
Germany
Strain P
1955
1956
Bavaria
BCG
50mg
S/C
Ellwood
1975
Malawi
BCG
Galaxo
2.6 x 109
cfu6
S/C
Moodie
1977
Malawi
BCG
S/C
Berggren
1977
Malawi
BCG
Galaxo
2.6 x 109
cfu
2.6 x 109
cfu
Berggren
1981
Malawi
BCG
Galaxo
2.6 x 109
cfu
S/C
USSR
BCG
Sibgatullin
1982
S/C
28 infected
herds
Infected
herd
Infected
herd
Meat
inspection
Infected
herd
Infected
herd
Meat
inspection
Meat
inspection
Infected
herd
PM / B
Infected
herd
Superscripts:
1. Intra-venous
2. Sub-cutaneous
3. Post Mortem
4. Guinea-Pig
5. Bacteriology
6. Colony forming unit
100
11.9% of vaccinated
calves were lesioned,
17.8% non-vaccinated
were lesion positive
Reduced numbers of
reactor cattle
With age matched
vaccine and control
groups there was no
difference in the levels
of protection
Similar levels of lesion
positive cattle were
found in vaccine and
non-vaccine groups
APPENDIX 13.
CHAIRMANS DISCUSSION PAPER ON FORMAT OF FINAL REPORT.
John Bourne
ISG, Location 105, 1A Page Street, London SW1P 4PQ
1. INTRODUCTION.
1.1 The use of vaccines in either cattle or wildlife remains a potential policy
option, although this option offers prospects only in the medium to longer
term. A vaccine development programme is already in place. This involves a
number of international collaborations which harness a global resource which
includes a significant effort to develop a vaccine against the human form of
TB.
1.2 For the future while success cannot be guaranteed, if a vaccine policy is
to be pursued for either cattle or wildlife, it must be recognised that a
demanding research programme would have to be put in place to provide
proof principle that a vaccine is likely to be effective. But more importantly its
value in the field must be validated before the Sub-Committee can
appropriately advise.
1.3 There are I believe a number of important questions that need further
discussion. The purpose of this Appendix is to revisit some of the major
questions.
2. WHAT IS AN EFFECTIVE CATTLE VACCINE?
2.1 Introduction.
2.1.1 We need to discuss under what circumstances could a cattle vaccine be
used and would BCG fit the bill?
2.1.2 The demands of an acceptable cattle vaccine are particularly severe
since it would be expected to both prevent the establishment of infection and
to eliminate transmission. Additionally it should not give a positive reading in
the tuberculin test (or any other immunological-based test) since this would
confuse the regular herd testing procedure and create serious regulatory
problems. However an additional concern about the use of cattle vaccination
in GB relates to the strong likelihood that a wildlife reservoir of TB infection
would persist in the countryside environment and exposure of cattle, protected
by a successful vaccine to this source of infection, would result in
immunological responses which might compromise the skin test.
2.1.3 Any diagnostic test based upon detecting an immune response would
need therefore to distinguish immune responses generated following infection
from those elicited following challenge of a protected vaccinated animal. This
would be difficult to achieve. In addition to being highly sensitive such a test
101
102
103
104
4.9 The outcome of the culling trial will have a profound influence on the
expected success of any vaccination programme. Unless perturbation effects
are massive, vaccination is likely to be less effective than culling. The trial will
provide data that are essential if we are to provide informed scientific opinion.
5. NEXT STEPS.
5.1 Establishing the protective activity of candidate vaccines, including BCG.
An immune effect and some protection has been demonstrated following
intradermal vaccination of badgers with BCG, but the effects of bacterial
excretion and transmission have not been studied in detail and duration of
immunity has not been determined.
5.2 Protection studies are needed. Facilities in GB are not available; can we
rely solely on studies that will take place in RoI which will encompass:
5.2.1 Establishing an experimental colony of badgers.
5.2.2 Establishing an experimental challenge model.
5.2.3 Using this model to reach point of proof principle of vaccine candidate.
5.3 If we are satisfied about the relevance of the RoI studies to the GB
situation we could move on to consider field experimental trials and field
validation.
5.4 If our advice is that further experimental studies should be conducted in
GB, what additional information do we need?
5.4.1 Legal position.
5.4.2 Re-procurement and use of badgers as an experimental animal, given
that, it will be argued, this work will provide little if any benefits to the badger
population.
105
CHAPTER 14.
VACCINATION OF CATTLE AGAINST TB
Ivan Morrison
Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter
Bush, Roslin, Scotland EH25 9RG
1. INTRODUCTION.
1.1 Vaccination of cattle against TB would require either a vaccine that is
compatible with the diagnostic assay currently used for herd testing, or
changes in the way surveillance for TB is conducted to permit the use of
alternative vaccines. Any new control strategies incorporating vaccination
would not only need to be cost-effective, with respect to control of the disease
in cattle, but also would be required to maintain protection of human health.
2. PROSPECTS FOR VACCINATION IN THE SHORT TERM.
2.1 As discussed elsewhere, the only vaccine that is likely to be available for
use in the field over the next few years is BCG. Although vaccination of cattle
with BCG has been shown to reduce the severity of pathology following
challenge with virulent M. bovis, a significant proportion of the vaccinated
animals continue to harbour bacteria. Moreover, animals vaccinated with
BCG give a positive reaction in the tuberculin skin test, and hence cannot be
distinguished from infected animals. For these reasons, vaccination of cattle
with BCG is not a viable option at present.
3. POTENTIAL USE OF VACCINATION IN THE LONGER TERM.
3.1 For the last 50 years control of bovine TB in the UK and the rest of
Europe has relied on herd testing to identify and remove infected animals.
This strategy was originally adopted with the aim of eradicating the disease.
The only available vaccine, BCG, was not sufficiently effective for vaccination
to be considered as a primary strategy to achieve eradication, and BCG could
not be used in conjunction with herd testing because of interference with
interpretation of the skin test. Looking to the future, development of new
diagnostics and vaccines might allow alternative control strategies
incorporating vaccination to be considered:
3.2 Vaccination in conjunction with an alternative diagnostic test. Leaving
aside the issue of vaccination, there is a need to improve the sensitivity of the
diagnostic assay used in herd testing. Substantial research effort (funded by
DEFRA) is currently being devoted to development of TB-specific gamma
interferon assays incorporating defined M. bovis antigens. In the short term, it
is envisaged that such assays could be used in conjunction with the skin test
106
107
APPENDIX 15
1.1 The Terms of Reference for the Sub-Committee were: to assist the ISG
in advising Defra Ministers on the feasibility for pursuing a TB vaccination
strategy for either cattle or wildlife. This should also include consideration of
future research requirements in addition to those already in place.
2.1 The Composition of the Sub-Committee was:
Meetings
attended: no /
max possible
Chairman:
Professor F J Bourne
Members:
Dr C L Cheeseman
Dr M J Colston
Professor C A Donnelly
Miss S M Eades
Professor P Fine
Dr B Grenfell
Dr R G Hewinson
Mr S Houghton
Professor W I Morrison
Dr J Pollock
Mr A G Simmons
ISG
7/7
6/7
Dr R Woodroffe
Professor D B Young
Adviser:
Miss F A Stuart
Defra Science Directorate
Visiting Speakers:
Dr L Corner
Massey University, New Zealand
Dr E Gormley
University College, Dublin, Eire
Mr W Nash
Consultant
Secretariat:
Dr A L Patey
Defra Animal Disease Control Division
Mr J W Pitchford
Defra Animal Disease Control Division
Mr T K Matthewsa
Defra Animal Disease Control Division
Ms S Shahb
Defra Animal Disease Control Division
a = meetings 1 & 2; b = meetings 3-7
108
7/7
5/7
6/7
1/7
1/7
7/7
4/7
6/7
4/7
6/7
4/7
6/7
6/7
1/1
1/1
1/1
7/7
6/7
2/2
4/5
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4.Different strains of M.tuberculosis. New molecular techniques have demonstrated that there are a large
number of different strains of the bacterium. It is possible that different areas of the world have different
strains, which may vary in virulence.
5.Genetic differences in population. There is variation in individual susceptibility to tuberculosis. This could
have caused disparity in results.
6.Intensity of infecting dose. Infection and susceptibility to disease may be affected by the quantity of
bacteria inhaled.
7.Nutritional differences. It is known that different nutritional states can vary susceptibility to disease. The
poorly fed individual is more susceptible.
8.Protection of controls by environmental mycobacteria. These free living mycobacteria which resemble
M.tuberculosis sometimes cause disease. They may be responsible for infecting individuals therefore
providing partial immunity to M.tuberculosis.
In addition to the national policy for all teenagers, BCG is given at birth to those at
high risk of disease; those with a family history of tuberculosis and those from
minority ethnic groups.(see below)
Is the policy of BCG vaccination the same throughout the world?
No, mainly because of variation in trial results. Most countries give BCG at birth to
provide protection in the early years when infection can often lead to devastating
widespread disease such as miliary tuberculosis or tuberculous meningitis. This is
particularly important in high prevalence countries where the chance of being
infected in very early life is high. Some countries such as the USA have chosen not
to use it because most trials there have not shown any protective effect.
Why is there not international agreement on how to use BCG?
Again because of variation in trial results across the world.
In 1994 a metanalysis of all the trials was published. (2)This looked at a total of 1264 articles, 70 in depth,
14 prospective trials and 12 case-control studies. The authors found that seven trials show a protective effect
from death of 71%, five trials showed protection from meningitis of 64%, three, protection from disseminated
disease of 78% and three, protection from laboratory-confirmed disease of 83%.
The authors concluded that geographical site of study explained 66% of variability.
They also found that on average BCG reduces risk of infection leading to disease
by 50%.
This is probably an erroneous conclusion, as the efficacy of BCG cannot be averaged. Trials show it to be
80% protective in one place and 20% in another. Average efficacy should not be taken.
In contrast sequential studies form the UK show that the 75% efficacy has been
http://www.priory.com/cmol/bcg.htm (3 of 8) [04/01/06 23:21:44]
maintained (4,5)
Does giving BCG prevent the use of the tuberculin test in determining the
presence of infection with M. tuberculosis?
This is another area of controversy . BCG converts the tuberculin test from negative
to positive. Workers are split as to whether it is possible to tell the difference
between a positive test due to BCG alone and a positive test due to infection with
M.tuberculosis whether the individual has had previous BCG or not.
In the UK we believe it is possible to do this on the basis of the degree of
positivity.(6) The USA do not use BCG partly for the reason that they do not believe
it is possible to make the distinction.
The importance of this is the decision to give preventive therapy for Latent Tuberculosis Infection (LTBI).
The USA has relied on prevention by determining whether infection (without disease) is present on the basis
of regular tuberculin testing for those at risk of infection such as health workers. BCG is not given as it is
believed to interfere with the interpretation of the tuberculin test. Other countries, such as the UK, do
give BCG but in cases where infection has occurred in addition to BCG and where
the risk of disease is appreciable, such as in co-householders of Sputum Smear
positive patients, preventive therapy can be given if the tuberculin test is strongly
positive.(7)
Doea BCG protect against drug resistant tuberculosis
The probable answer to this is yes though evidence for this is necessarily sketchy. It
is probably more effective in preventing disease than providing preventive therapy to
those infected; a procedure for which there is no evidence of any efficacy at all. For
health care workers who may be exposed to drug resistant tuberculosis, even a low
protective efficacy of BCG would make vaccination worthwhile.
In a recent study of a mathematical model, BCG was preferred by small margin over
post-infection chemoprophylaxis. Threshold for protective efficacy was 26%.
BCG should be considered for health care workers with risk of MDRTB
exposure.(8,9)
http://www.priory.com/cmol/bcg.htm (4 of 8) [04/01/06 23:21:44]
Conditions necessary to stop giving BCG include a good control programme, good
reporting especially of TB meningitis and the prevalence HIV and its possible impact
on TB increase must be evaluated.(11)
For example in 1975 mass vaccination in Sweden was replaced by selective
vaccination. As a result BCG coverage fell from95% to 1.8%. It then increased to
13.7% (12)
The result on TB cases is shown in the table below which shows rates of disease in
the Swedish and foreign born children at different percentage BCG cover.
BCG coverage
%
95
13
1.8
0.8
2.9
3.9
Foreign
2.6
13.2
39.4
From these figures it can be calculated that the protective effect was 82%.
In the present climate of rapidly increasing cases of disease world wide and mass
travel, the decision is probably not whether to stop BCG but whether to increase its
use.(13)
Arguments against use of BCG vaccine in a mass programme are not about efficacy but cost
effectiveness. (14)
In conclusion
Im glad I had my BCG
PDODavies.
References
1.Hart PD. Efficacy and applicability of mass BCG vaccination in tuberculosis control
BMJ 19677;1:587-592.
2.Colditz GA et al.Efficacy of BCG Vaccine in the prevention of TuberculosisJAMA
1994;271:698-
and prevention of
tuberculosis in the United Kingdom:Code of practice 2000 Thorax Thorax
2000;55:887-901.
7.Rathus EM. The Heaf multiple puncture test compared with the Mantoux test in
epidemiological surveys.Med J. Aust 1956;1:696-8.
8.Greenberg PD et al.Tuberculosis in House StaffA decision analysis comparing the
Tuberculin Screening Strategy with the BCG vaccination.Am Rev Respir Dis 1991;143:490495.
9.Stevens JP Daniel TMBCG immunization of health care workers exposed to MDRTB: a decision
analysisTubercle & Lung Dis. 1996;77:293-4.
10.Tala EO et al. Pros and Cons of BCG Vaccination in Countries with Low
Incidence of Tuberculosis.Infection Control and Hospital Epidemiology 1994;15:497499.
11.Trnka L Dankova D Svandova E.Six years experience with the discontinuation of
BCG vaccinationTubercle & Lung Disease 1993;74:167-72.
12.Romanus et al.The impact of changing BCG coverage on tuberculosis incidence
in Swedish-born childrenn between 1969 and 1989.Tubercle and Lung disease
1992;73:150-161.
13.Cobelens GJ, van Deutekom H, Draayer-Jansen WE et al: Risk of infection with M.tuberculosis in
travellers to areas of high tuberculosis endemicity. Lancet 2000;356:461-65.
PGSmith and PEMFine BCG vaccination in Clinical Tuberculosis 2nd Editn Edit PDODavies, Chapman and
Hall, London 1998 pp417-434.
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Registre de Tuberculosi
1. cas amb malaltia confirmada per cultiu provocada pel complex M. tuberculosis.
2. cas amb frotis positiu per bacils acidoresistents (AFP) si no es disposa de
laboratoris de nivell II (que puguin processar mostres per al cultiu) o quan no es
pot esperar el cultiu rutinari d'espcies extretes de tots els casos.
Tamb s'han de notificar els casos "no definits", els quals han de complir les dues
condicions segents:
1. quan un clnic cregui que els signes i/o els smptomes clnics i/o radiolgics del
pacient sn compatibles amb la tuberculosi, i
2. quan un clnic decideixi tractar el pacient amb una terpia completa contra la
tuberculosi.
Els casos "definits" (i, quan sigui aplicable, els "no definits") de tuberculosi pulmonar
s'han de dividir en funci del resultat del frotis provocat o espontani en:
Registre de Tuberculosi
Variables essencials
Les variables essencials sn: informaci que descrigui el cas, incloent-hi el temps, el lloc i la
persona, com tamb els detalls de la localitzaci de la malaltia, l'estat bacteriolgic i el fet si el
pacient ha estat tractat anteriorment.
1. Persona afectada
Edat i sexe: La data de naixement, que permet calcular l'edat en el moment en qu es va iniciar
el tractament, i el sexe sn variables que s'han de saber de cada pacient.
Pas de naixement. A les societats de cultura heterognia, la incidncia de la tuberculosi pot
variar d'una manera important en diferents grups tnics. En vista de la importncia creixent de la
tuberculosi als pasos europeus entre els immigrants i altres estrangers, el Grup de Treball sobre
el Control de la Tuberculosi i Migraci Internacional va identificar el pas de naixement com una
variable addicional que s'hauria de recollir rutinriament [5]. En alguns pasos, l'origen tnic, la
ciutadania o la ciutadania dels pares pot ser ms important que el pas de naixement a l'hora de
descriure la demografia dels pacients de tuberculosi.
El lloc de residncia. El lloc de residncia d'un pacient de tuberculosi s essencial per a l'acci
de la salut pblica. El lloc de residncia ha de ser el lloc on el pacient estava vivint en el moment
en qu es va iniciar el tractament. En el cas de persones sense llar, migrants, detinguts.., es pot
donar el lloc de residncia dins del pas durant els 3 mesos anteriors, o es pot buscar qualsevol
altra soluci que els pasos individualment considerin apropiada.
Localitzaci de la malaltia.
2. Localitzaci principal
3. Localitzaci menor
La localitzaci de la malaltia s'ha de recollir en tots els pacients. Ats que els pacients poden
tenir diverses localitzacions de malaltia, es recomana que es recullin com a mnim dues
localitzacions, una de principal i una de secundria (o menor), quan sigui aplicable. Ja que la
classificaci de la localitzaci de la malaltia pot variar a diferents pasos, es recomana que es
facin servir les localitzacions segents, perqu permetran fer les agregacions que siguin
necessries en un pas concret:
Tuberculosi pulmonar: tuberculosi del parnquima del pulm i de l'arbre
trqueobronquial. La tuberculosi pulmonar, si hi s present, sempre s'ha d'inscriure com
a localitzaci principal, sigui quin sigui l'altre lloc que pugui estar afectat.
Tuberculosi extrapulmonar: Tuberculosi que afecta qualsevol altre lloc diferent dels que
afecta la pulmonar.
- Tuberculosi pleural. Tuberculosi extrapulmonar que noms s una pleuresia
tuberculosa, amb efusi o sense.
Registre de Tuberculosi
1. tuberculosi espinal i
2. altres tuberculosis osteoarticulars que no siguin l'espinal.
- Tuberculosi del sistema nervis central (CNS). La tuberculosi del sistema
nervis central se subdivideix en:
1. meningitis tuberculosa i
2. una altra tuberculosi del sistema nervis central que no sigui la meningitis.
- Tuberculosi genitourinria. La tuberculosi del sistema gnitourinari, inclou la
tuberculosi renal, ureteral, de la bufeta i del tracte genital mascul i femen.
- Tuberculosi del tracte peritoneal/digestiu. Aquesta tuberculosi inclou la
tuberculosi del peritoneu, amb ascitis o sense, i la tuberculosi del tracte digestiu.
- Altres. Altres localitzacions extrapulmonars, incloent-hi la tuberculosi larngia, i
per a l'anlisi de pasos concrets es poden anomenar especficament.
- Tuberculosi disseminada. La tuberculosi disseminada inclou tuberculosis en
ms de dos rgans o la tuberculosi miliar. Si un d'aquests llocs afectat s el
parnquima del pulm, el cas s'hauria de classificar com a tuberculosi pulmonar o
com a tuberculosi disseminada. Per tant, la tuberculosi miliar, per exemple, es pot
classificar com a pulmonar i com a disseminada. Quan el complex M. tuberculosis
ha estat allat de la sang, la localitzaci de la malaltia s'ha de designar com a
"disseminada".
4. Estat bacteriolgic
La informaci sobre l'estat bacteriolgic s'ha d'incloure sempre. El metge ha d'enregistrar:
- La mostra i data de recollida de la localitzaci principal o, si s negativa o sense
http://www.col-legidemetges.ad/docs/fulltb.html (3 of 5) [05/01/06 2:08:03]
Registre de Tuberculosi
resposta, la de la localitzaci secundria que hagi donat un resultat positiu (ex.: frotis
d'esput positiu, tuberculosi pulmonar confirmada per cultiu o frotis de bipsia negatiu,
tuberculosi limftica confirmada per cultiu).
- el resultat i la data:
- de l'examen microscpic directe (negatiu o positiu respecte dels bacils
acidoresistents, o examen no realitzat).
- del cultiu (negatiu o positiu respecte del complex M. tuberculosis, o examen no
realitzat).
- l'espcia identificada: M. Tuberculosis (MT), Mycobacterium bovis (MB), o
Mycobacterium africanum (MA),.
- L'examen histolgic amb evidncia de bacils acidoresistents hauria de
considerar-se com un examen microscpic positiu i, per tant, s'hauria de registrar
tamb aix.
5. Cas recurrent o nou cas
Abans de comenar el tractament per a la tuberculosi, s important establir el segent: 1) que el
pacient t tuberculosi activa; 2) si el pacient ha patit de tuberculosi anteriorment; i, si s aix, 3)
quin tractament se li va donar anteriorment. Les dues primeres preguntes sn de carcter tant
epidemiolgic com clnic, i la tercera t una importncia clnica ja que la resposta determinar el
tractament ms apropiat per a l'episodi de tuberculosi en qesti.
Per als efectes de la salut pblica s essencial informar sobre tots els casos de tuberculosi que
hagin estat diagnosticats per metges. Per a l'epidemiologia, on les tendncies en la incidncia
sn d'especial inters, s molt important conixer si un cas notificat ha tingut o no tuberculosi
prviament. S'ha d'anar amb compte a l'hora d'assegurar-se que no es repeteixen els informes
dels casos crnics i dels pacients que van i vnen de forma intermitent. La resposta a les
preguntes d'aquest apartat hauria d'aclarir aquestes qestions:
- la primera pregunta demana si al pacient se li havia diagnosticat tuberculosi
anteriorment. Si la resposta s afirmativa, la segona pregunta respon l'any de l'episodi
anterior i, si pot ser, el mes. La tercera pregunta estableix si al pacient se li va fer un
tractament amb quimioterpia i, si la resposta s afirmativa, si es va considerar
satisfactori o no. Aix permetr classificar aquests casos en recaiguda i recurrncia amb
quimioterpia prvia o sense i, per tant, millorar la definici dels casos.
6. El temps
La data d'inici del tractament:
L'ideal, per obtenir estimacions acurades de la incidncia de la malaltia, seria conixer la data
del seu comenament, per aix no acostuma a ser factible; tamb la data del diagnstic pot ser
difcil de fixar en el temps, per aix es recomana que la "data d'inici del tractament" ,
considerada una dada proxy se registri en tots els casos.
La data d'inici del tractament es defineix com la data en la qual el metge est prou
segur de la seva diagnosi i inicia el tractament adequat per a la tuberculosi. Per a la
tuberculosi pulmonar, aquesta acostuma a ser quan s'obt del laboratori un resultat de
Registre de Tuberculosi
frotis d'esput positiu o, en els casos de frotis d'esput negatiu, quan el metge ha reunit
proves clniques i/o radiolgiques suficients per a la diagnosi que justifiquen l'inici del
tractament. Quan no es pot disposar de la data d'inici del tractament, aquesta es pot
substituir per la data de notificaci del cas. I per als casos que no han rebut mai cap
tractament, com ara la diagnosi postmortem, aquesta ha de substituir la data del
diagnstic.
TB Publications
E
Database : Abstracts of
@@@@@@
World TB Day
@@@@
Cured TB patient stories
Updated 05/12/07
morphological and particularly molecular studies on gliding bacteria were impossible due to the
lack of a suitable technique for the genetic manipulation of this group of bacteria including
Flexibacter chinensis. Our study has focused on the physiological and morphological changes in
molecular level in this organism during the transition from the exponential to stationary phase of
growth, and during long -term stress condition. Our data demonstrate that there is a dramatic
change in respiration activity and enzymes during the stationary phase which can not be seen in the
exponential phase. Parallel to this bacterial morphology changes with a particularly noticeable size
reduction in this usually filamentous bacterium. With the collaboration of Wisconsin University in
USA we have developed a method for the molecular study of this group of bacteria. We have
constructed two mutants for the genes which produce two novel sigma factors, KatF(sS) and
RpoH(s32), and have investigated the effect of these mutants with respect to cell size changes
during the transition from growth to starvation conditions and under heat stress. The mutants
were unable to change from the filamentous to coccoidal form and consequently were unable to
survive stress as effectively as the parental strain which could undergo morphological changes. Our
data have demonstrated the importance of cell division in Flexibacter chinensis for the survival of
this bacterium under stress conditions. 4- Research work. The Microbial sulfur-specific
transformation which selectively desulfurize organic sulfur compounds in fossil fuels, has been
identified. We have cloned a 4kb gene locus from Rhodococcus erytheropolis IGTS8 (4S pathway)
on a broad host range plasmid with integration ability in chromosome of gram negative bacteria.
This organized as one operon with three genes (dszA, dszB and dszC)under the control of single
promoter. The dsz gene has been cloned under control of tac promoter in different pseudomonas
solvent tolerant species. We have applied an industrial microorganism , with the ability in
biological desulfurization. In this way, using molecular and microbiological techniques we
successfully constructed a manipulated bacterium with two relevant industrial application, that is
biosurfactant production and desulfurization of fossil fuel. Further researches is in progress to find
out the influence of the biosurfactants on DBT desulfurization. This is the new alternatives to
commercialize the biodesulfurization of crude oil processes. 5- Work experiences I have at least
four years experiences in laboratory work in microbiology and molecular microbiology in full time
basis. I have learnt many techniques in this time including molecular cloning, DNA sequencing,
southern hybridisation, northern hybridisation, two dimentional gel electrophoresis, DNA
separation techniques, DNA cloning methods using different vectors including several suicide and
other vectors, general microbiology and relevant computer skills. 6- Skills I have had more than
four years laboratory experience and have used various techniques involved in the detection,
isolation and manipulation of nucleic acids and feel that I could make a significant contribution to
your program. I have made contributions to the field of molecular biology of bacteria, due to
working with a particularly difficult bacterial strain, Flexibacter, to manipulate using conventional
molecular biology techniques. I have learned many techniques in Warwick University in United
Kingdom and National Research Center for Genetic Engineering and Biotechnology, including
molecular cloning, polymerase chain reaction, DNA sequencing, southern hybridization, northern
hybridization, western blots, DNA separation techniques, two-dimensional gel electrophoresis,
general microbiology, DNA library, Over-expression of proteins, and computer skills. 7-Resarch
interests. Molecular Biology and Microbiology Research. 8- Publication and record Currently three
works for publication on the molecular biology and physiology of Flexibacter are being prepared
http://www.stanford.edu/group/molepi/guestbook.html (4 of 58) [05/01/06 2:27:10]
have any information. At present i'm working with a reputed pharmaceutical co. in my own city as
a sr. microbiologist.my future plans are to go for research.
PINKAL DIWAN <pinnacle@netwala.com>
ahmedabad, gujarat india - Sun Oct 15 13:47:20 2000
information on Muti-drug resistant Tuberculosis.(Especially India,and to be more specific
Karnataka,India)
vidya <vidyasundareshan@yahoo.com>
- Sun Oct 15 01:45:15 2000
I am interested in speaking with anyone who has information about the former Mt. Kipp
sanitorium located in Glen Gardner, New Jersey. I am writing a research paper on the institution
and how its role has changed.
Karin Gruss <nirakg@yahoo.com>
- Sat Oct 14 21:37:43 2000
Film research: writer needs accounts of patients, doctors, nurses, admin. workers associated with
tb sanitoriums in 1940s-50s. Also those involved with tb screening of US public schools. Many
thanks, patriciaroberts@home.com
patricia roberts <patriciaroberts@home.com>
toronto, ontario canada - Wed Oct 11 15:45:55 2000
Interested in it 2 much !
savita chauhan <chausavi@rediffmail.com>
Indore, MP INDIA - Tue Oct 10 17:42:14 2000
My department is advising the Swiss government on various international health issues. A recent
topic of concern and interest is the tuberculosis in penitentiary centers in countries of the former
Eastern Block and possibilities to control it. Nicolaus Lorenz MD, MSc Head of Department Swiss
Tropical Institute Swiss Centre for International Health Socinstrasse 57 P.O. Box CH-4002
Basel/Switzerland Tel. +41 61 284 8 125 Fax + 41 61 271 86 54
http://www.sti.unibas.ch/scih/scih.htm
Dr. Nicolaus Lorenz <nicolaus.lorenz@unibas.ch>
Basel, Switzerland - Wed Oct 4 12:23:00 2000
My theory is proven correct. One of my relatives complained of back pain. We thought maybe it
was muscle strain. We went to the doctor for a check up. After the check up she was given a
medicine which is for TB. Aha! So I asked my relative. Have you been lacking sleep. She said yes.
She said she was working a lot. Could not get much sleep because of a lot of worries. She does get
enough rest and sleep she says. But there is a difference between a genuine rest and sleep and just
closing your eyes and pretending to be asleep. When you worry don't do it while you are resting.
Start worrying once you wake up. When you rest, just free your mind of worries. And just
concentrate on sleeping. They said she was coughing and her back really hurts.She even skipped
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one day of work because of it. So I told her that her lungs are strained. And that she should let it
expand. I told her about the "Ulcer Theory". And the next day she was working already. Had I not
told her about the "Ulcer Theory" she would be in a hospital coughing blood already. And now
she's fine.
Norman Greg <Pehpot@yahoo.com>
CA U.S.A. - Wed Sep 27 23:20:04 2000
Hello everybody, I shall highly appreciate if you send me detailed information on PCR based
diagnosis of TB and MDR-TB.I shall be happy to receive the details about the PCR protocols,
primer designs and information regarding detection kits and their reference. Thank you
Dr Nilanjan Das <dasnilanjan@hotmail.com>
Calcutta, West Bengal India - Wed Sep 27 18:47:45 2000
I have been working in the medical research center in Russia (Novosibirsk State medical
University).We are developing the project about dependence with hypertermia (temperature
increase) and pulmonary tuberculosis. I would highly appreciate if somebody could provide me the
information about it.(do you have an experience to treat a people with this type of treatment, what
kind of results were achieved) Or may be you know where can i find this information. I hope that
there is the possibility of fruitful cooperation. seeler@mail.ru
Elena <seeler@mail.ru>
Novosibirsk, RU Russia - Sat Sep 16 13:44:28 2000
I am presently researching on the history and statistics of tuberculosis. Hope you'll help me to
accomlish this research through giving addresss that are relevant to my research. Thanks
bernard <blue_svo@yahoo.com>
manila, philippines - Wed Sep 13 02:18:44 2000
Mycobacterium bovis ADN isolation in milk. PCR
Cristian Leiva <mfleiva@yahoo.com>
Santa Fe, Santa Fe Argentina - Fri Sep 8 21:07:03 2000
Tuberculosis-Diagnosis-serology
Tsigeweini Asgedom <Tsigeweini.Asgedom@cih.uib.no>
Bergen, Bergen Norway - Fri Sep 8 13:46:20 2000
Seeking for Co-operation and Support -----a specific remedy for tuberculosis Now, a specific
tuberculosis remedy, which belongs to Traditional Chinese Medicine has been discovered. It's
named " Jiupin Baoling Pellet". According to the results of observation from more than 1,000
cases, this remedy has outstanding result in treating pulmonary tuberculosis, tuberculosis of lymph
nodes and bone tuberculosis. The curative rate may reach over 85%. This completely natural
remedy is adapted to pharmacopeia compatibility clo9sely. The intranasal usage enables the
effectiveconstituents exchange with qi and blood in lungs. According to Traditional Chinese
Medicine theory, tuberculosis is caused by infection of " certain worm ". People are attacked by
http://www.stanford.edu/group/molepi/guestbook.html (7 of 58) [05/01/06 2:27:10]
this worm at the state of deficiency of vital- qi and blood. Pulmonary tuberculosis occurred when
the worm existed in lungs. If the worm reached bone marrow from the blood circulation, bone
tuberculosis and tuberculosis of lymph node would form. Among the constituents of this pellet,
secretio bufonis has the functions of detoxification, analgesis, inducing insuscitationa and treating
the toxifying disease with poisonous agents: Unbelliferae can promote blood circulation to stop pain
and tonify the blood. If the course lasted too long, this chronic disease may demage qi and blood,
even cause stagnancy of qi and blood stasis. Deficiency of qi may prevent the folw of blood, and
deficiency of blood may do harm to channedl and collaterals. The symptoms of blood stasis and
stagnation of qi can be relieved by the use of umbelliferae in the remedy. Another component --horner nest can be used for eliminating wind and toxic material, stopping pain and even killing the
worm. Because of the cause of disease mentioned above, the use of hornet nest can achieve expected
results. With the rich clinical practice and hard research, the use of the components is efficient, and
the results are satisfied. According to outside body experience, the tuberculomyces which have
drug resistance to anti- tuberculosis drugs are sensitive to the remedy. In clinical use obvilus results
of treatment have been achieved especially for the patients with long lasting tuberculosis. All right
reserved by ZhaoDong. Any co-operations in research, development, investment and sale are
welcome.
ZhaoDong <dhc0@21cn.com>
- Fri Sep 8 13:08:53 2000
i'm reserching for the case of ashtma it's a disease that can kill and no one has found a cure for it
yet i have ben reserchen about it for over 18 years and still have not found the closes to it i have the
disease my self and believe me i have allmost died of it alot of times i would like to find something
that is close to it so i my self can have a good life to just like other people too. so if any one out there
can give me some pointers i would sped it where everyone will know that you have gave me infor.
and you will be in that book that i write about this killer disease and god will thatnk you too. i
know i would; thank you again; ms. june;;
june lopez <lopezjune@hotmail.com>
houston, tex. 77020 usa - Fri Sep 1 17:26:32 2000
Dine in or take out?
Shang-hai Chef <shrmpflavor@mailcity.net>
- Tue Aug 29 08:11:09 2000
lady doctors are invited to have sex with andhra doctor
suresh <mysexmail@rediffmail.com>
- Thu Aug 17 19:23:09 2000
Hi there!. I would like to know about tuberculosis diagnosis and antigen immunogenicity
evaluation, collaboration programs between institutions and MSc and PhD schollarships.
Jorge Luis Gonzalez Quintana <jlgonzalez@finlay.edu.cu>
Havana, Cuba - Thu Aug 17 18:45:44 2000
Deteriorating liver.
Tom Crowley <TomCrowley13@aol.com>
Shelby Twerp, MI USA - Wed Aug 16 04:56:44 2000
i am originally from bangladesh.i,Dr.md.nazmul haque, doing ph.d in microbiology from dhaka
university.i have strong interest in doing reseach in microbiology.for that iwantjoin in ph.d
programme in usa.are there any scholorship or assistanceship for me.pleasesend me the response as
soon as possible.
dr.md nazmul haque <rokeya@technohaven.com>
dhaka, bangladesh bangladesh - Sun Aug 13 06:45:50 2000
I am interested in the application of bioinformatics on studying the virulence genes of M.
tuberculosis. My mailing address: School of Graduate Studies Mapua Institute of Technology
Intramuros, Manila 1002 Philippines
Bonifacio T. Doma,Jr. <bonidoma@hotmail.com>
- Sat Aug 12 16:20:14 2000
cool!
Jango <Jango@office.com>
- Fri Aug 11 10:49:52 2000
am a respiratory therapist..i have a case study report this tuesday about pleural effusion and
pulmonary edema and am having a hard time finding patient data,history etc.. please HELP! JAE
RRT
jae <jae718@yahoo.com>
manila, manila phillipnes - Sat Aug 5 06:27:36 2000
I have a sister who is a doctor, in her practice with patients with Tuberculosis she got the Potts
disease; I want to known a Medical Center in the Conus of U.S. which can help us to treat her as
aid for foreign patient with this disease; any help is welcome.
Enrique A. Posada <fam.posada@navegante.com.sv>
N.Cuscatlan, La Libertad El Salavdor - Tue Aug 1 04:32:09 2000
I am doing research in production and quatitative techniques in india and Looking for any
additional scholarships/sponserships by organisations to carry out studies.If U know any of the
organisations pls inform me.Thanks
jha T.K <tarun_kumar_jha@hotmail.com>
Ahmedabad, Gujrat india - Mon Jul 31 18:41:34 2000
I am doing research in production and quatitative techniques in india and Looking for any
additional scholarships/sponserships by organisations to carry out studies.If U know any of the
organisations pls inform me.Thanks
jha T.K <tarun_kumar_jha>
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We are interested in molecular characterization and drug sensitivity of Mtb strains. Also,
serodiagnosis of infection by Mtb is of our interest.
Angel Gustavo GUEVARA PhD <labinves@hcjb.org.ec>
Quito, Pichincha Ecuador - Wed Dec 22 16:05:23 1999
TB.Microbiology $ Epidemiology
Mir.Mohammad Ziaei <mmziaei@hotmail.com>
Tabriz, East Azerbaijan Iran - Mon Dec 13 19:54:18 1999
HIV-TB, cytokines in TB, controlled clinical trials in tuberculosis
Soumya Swaminathan <mahadevi90@yahoo.com>
Chennai, Tamilnadu India - Sun Dec 12 16:30:30 1999
effects on body, treatments, symptoms
Rachel Wilford <peaches31484@yahoo.com>
Millsboro, DE USA - Tue Dec 7 22:59:35 1999
effects on body, treatments, symptoms
Rachel Wilford <peaches31484@yahoo.com>
Millsboro, DE USA - Tue Dec 7 22:59:21 1999
effects on body treatments symptoms
Rachel Wilford <peaches31484@yahoo.com>
Millsboro, DE USA - Tue Dec 7 22:58:06 1999
Too big of words. I don't understand it. Please use smaller words, or maybe hyperlinks to the
definations of big words. Thank you. tammi
Tammy <sporkypunk@aol.com>
Bremerton, WA USA - Sat Nov 27 21:44:55 1999
I am a student completely fascinated with molecular biology and genetics. I have performed
research on transgenic mice in embryonic develpoment at the EIB/NCI/NIH, the most incredible
experience I have gained yet. My interests mainly include the following: the human genome
research project, cancer research, and anything affiliated with genetics.
Leana Movsessian <HyeLeana@aol.com>
Germantown, Maryland USA - Mon Nov 22 20:26:03 1999
I am a student completely fascinated with molecular biology and genetics. I have performed
research on transgenic mice to decode all genes coding for embryonic develpoment and the
EIB/NCI/NIH. My interests mainly include the following: the human genome research project,
cancer research, and anything affiliated with genetics.
Leana Movsessian <HyeLeana@aol.com>
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extrapulmonary tb.
Jose Roy Z. Gregorio, M.D. <joeygmaninistis@yahoo.com>
Quezon City, Philippines - Sat Jul 3 01:00:28 PDT 1999
I have a bachelor's degree (honors) in Molecular, Cellular, and Developmental Biology and will be
studying infectious diseases as a graduate student. I would like to volunteer either in clinical or
laboratory environments - I have experience in both areas. Please contact me if you would like
assistance and are located in the SF area.
Kiersten Israel-Ballard <kiersten_ballard@hotmail.com>
Santa Cruz, CA USA - Tue Jun 29 21:28:37 PDT 1999
I want to volunteer in your research project. I am a medical doctor and already had one year
clinical experience (internship in Internal medicine at New York Hospital ).Want to volunteer
while waiting for residency.I hope to hear from you soon.
Roeliza Ebbah-Pascua <roelizapascua@hotmail.com>
San Jose, California - Tue Jun 29 09:58:07 PDT 1999
Tuberculosis and Patient's Compliance/Treatment Partners (DOTS)
DR. DOMILYN VILLARREIZ <domz@main.dmsf.edu.ph>
Davao, Philippines - Tue Jun 15 03:32:34 PDT 1999
Spatial epidemiology of TB
Phil Atkinson <p.atkinson@cdsc.nthames.nhs.uk>
London, UK - Tue Jun 8 09:10:42 PDT 1999
Bovine TB, molecular epidemiology, RFLP, spoligotyping, PFGE, VNTR, AFLP, virulence,
transmissibility, stability, genomics, direct detection, PCR
Robin Skuce <skucer@dani.gov.uk>
Belfast, Northern Ireland - Tue Jun 8 06:42:57 PDT 1999
tuberculosis diagnosis, prevention, treatment We will be interested to know whether a case where
M.tb. has been isolated twice on two different days by Bactec and confirmed by use of TMA of
Gene Probe should be treated or not. General consesus is not people who are infected as the above
case should not be treated. Why. Are they not in danger to themselved in future ? How does one get
extrapulmonary tuberculosis such as renal, bone or meningitis, or lymphadenitis. Are these
infected people also dangerous to other. Would appreciate to form and be part of discussion group
on this type of matter. I am new web learner and would appreciate reply by e-mail.
Dr.Suresh Amin <suamin@pi.zaverchand.com>
Baroda, Gujarat India - Sun Jun 6 19:02:22 PDT 1999
RFC and ELISA in Paratuberculosis
Dr. Valeriu Crangus <vally@k.ro>
Bucharest, Romania - Thu Jun 3 07:01:57 PDT 1999
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I am interested to conduct an evaluation study on the TB Program of our local government. Are
there available research literature in this area?
Dr. Jocelyn C. Kintanar, <joycorki@iname.com>
Cebu, Cebu Philippines - Mon May 31 05:56:10 PDT 1999
I am researching the effects and damage caused by bacterial infections following surgical
procedures within major hospitals. I am interested in hearing from anyone who following infection
has tested positive for Tuberculosis, Mycomplasma, Toxomplasma, Luekemia, Cytomegolivirus.
My research interest is in particular to women who have had caesarian section.
Liani Simpson <liani@powerup.com.au>
Brisbane, Queensland Australia - Thu May 20 21:07:49 PDT 1999
I'm a graphic designer and i've been assigned a project to create a stamp collection related to
Tuberculosis and its history. I need all the visual information i can get about subjects, people linked
to this disease and pictures of the bacteria itself. Websites with good pictures related with TB will
help very much. This work will help ANTDR (Associacao Nacional de Tuberculose e Doencas
Respiratorias) in its fight against this plague. Any help i could get would be very important.
Thanks in advance.
Antonio Manuel Silva <antonio@mrnet.pt>
Lisbon, Portugal - Thu May 20 13:31:50 PDT 1999
DNA based methods for diagnosis of tubersulosis and molecular epidemiology. Interested in
collaborations.
Dr Madhu Goyal <m.goyal@herts.ac.uk>
Hatfield, U.K - Mon May 17 06:13:41 PDT 1999
I'm doing a science report on tuberculosis and I really, Really,REALLY need pictures of the
tuberculosis microbe. Katrina
Katrina Howe <thowe@ideafamilies.org>
Fairbanks, AK USA - Fri Apr 30 13:22:55 PDT 1999
I am currently conducting some research on the increasing occurance of antibiotic immunity of TB
and would appreciate any info. that could be given. Thank you.
Matt Nelson <Wolfrton@aol.com>
Tacoma, WA USA - Tue Apr 20 23:28:50 PDT 1999
interested in vaccine development for tuberculosis. by using molecular techniques and
bacteriophage.
M.S.Ranjith mehendarkar <msranjith@hotmail.com>
chennai, tamil nadu india - Fri Apr 9 10:46:26 PDT 1999
i am a post graduate student doing my thesis work on mycodot LAM test efficacy in diagnosing TB
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would suffer first. "I myself," he wrote, "have seen primary tuberculosis of the intestines only
twice. ...at Charity Hospital in Berline, only ten cases in five years. Primary TB of intestine w/o
lungs and bronchia never occured, in 933 cases. Biedart found only 16 cases in 3104 postmortems
on tubercuar children. So how then can we accunt for the inter-transmissibility of human and
bovine tuberculosis?" (Koch) The solution? The very tiny dark particles within each of the diseased
cells are actually plasmids. They are far too small to be clearly identified with an ordinary
microscope. Note also, plasmids are the microorganisms that transfer genes between various stains
of bacteria. it is not only tuberculosis that produces plasmids. The same microorganism(s) also
transfer genes, DNA, or drug resistant modlues between drug resistant bacteria. Hence, the very
dark, tiny particles within each cancer cell, turn out to be the same thing - plasmids. The plasmid
transfers into a weakened cell, and it resets the genes. Some plasmid are self-transferable. All are
self replicating. Hence, this well-hidden genetic altering mechanism is what produces tuberculosis,
as well as all kinds of cancers and tumors. Onces the new gene(s) are transplanted, the newly
completed genetic material functions completely FROM INSIDE THE IMMUNE
SURVEILLANCE SYSTEM OF THE HOST. Hence, this explains the subtle inheritance patterns
found in many disease, such as TB, MS, MD, Diabetes, Leprosy - and any of these, as well as
cancers and tumors are only PSEUDO-GENETIC in the orgin. Would you agree with these
statements, or not? Please let me know.
Bruce D McKay, Bio Epistemologist <jeferson@gte.net>
Tampa, FL USA - Fri Mar 5 00:23:09 PST 1999
Studying Mycobacterium paratuberculosis. Interested in tuberculosis virulence factors, antibiotic
resistance mechanisms, cell wall components, identification/location of these genes(plasmid?).
Jason Azat <azat@mindspring.com>
Santa Barbara, CA USA - Sat Feb 27 22:52:39 PST 1999
I am conducting a study on the toxic elements in hair analysis of both patients diagnosed with TB
and family members that don't have the disease. I need information or research done on the effects
or lack of of nutrients and toxic elements in TB. I work in Hospital Santa Clara, the most
important hospital for TB in South America and we are in great need for help and support.
John E. Bastidas M.D. <fmoser@cable.net.co>
Bogot, Colombia - Fri Feb 12 04:16:37 PST 1999
I am a PhD student and my research involves in vitro screening of antimycobacterial (both
sensitive and MDR strains) activity by South African medicinal plants. Any relevant information in
this respect will be greatly appreciated.
Namrita Lall <mailto:Namrita@scientia.up.ac.za>
Pretoria, Gauteng South Africa - Thu Feb 11 00:09:20 PST 1999
I have an interesting case on tuberculosis of gall bladder. I need some references regarding the
tuberculosis of Gall Bladder
Dr. O. P. Sudrania <opsudrania@usa.net>
Siliguri, West Bengal India - Wed Feb 10 03:28:40 PST 1999
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I'm doing and investigation about tuberculosis, Immunology, Genetics, diagnostic in LCR I would
like to have some information about this, if you please by able to send me these information
victor Minera <oscargal@mail.concyt.gob.gt>
Guatemala, Guatemala Guatemala - Tue Feb 9 10:16:03 PST 1999
radiology tuberculosis diagnostic
Olga Malyscheva <ok_mal@usa.net>
Moscow, mo Russia - Sun Feb 7 23:59:28 PST 1999
tuberculosis
Olga Malyscheva <ok_mal@usa.net>
moscow, mo RF - Sun Feb 7 07:33:12 PST 1999
I am the student of medicine faculty of Cerrahpaa and 1 year left to be a doctor.I just want to
learn more about every patience and especially about tuberculosis because of the fact that
tuberculosis is a very important patience in my country.
Ozan Karata <okaratag@hotmail.com>
stanbul, Trkiye - Sat Feb 6 08:00:34 PST 1999
Me: TB epidemiologist at the World Health Organization (but applying to medical school, hoping
to be able to go back to California!). In the meantime, my research interests include TB and
gender, particularly gender-based differences in the delivery of TB care (a common problem in the
developing world), among other things...
Suzanne K. Scheele <ScheeleS@who.ch>
Geneva, Switzerland - Tue Feb 2 07:00:02 PST 1999
Ihave a 5 month old patient with tuberculous meningitis&cavitary lesions.How frequent we see
cavitary tuberculosis in children?
Soner Sarmask <mehmetsoner@.superonline.com>
Istanbul, Turkiye - Wed Jan 27 11:51:43 PST 1999
Doing some research work related to tuberculosis, Immunology, Genetics
MengZhang <meng.zhang@263.net>
Beijing, PRChina - Tue Jan 26 03:14:00 PST 1999
Looking for more info about the guidelines on testing positive on the Manatoux test when the BCG
was given over 22 years ago.
Shelagh Taylor <Oscaig@aol.com>
Great Lakes, IL USA - Fri Jan 22 07:28:41 PST 1999
I am a doctor specializing in the spheres of immunology, allergies, infectious diseases, pediatrics,
gastro-intestinology, endocrinology and also cancer diseases in the recent past. In 1985 I started to
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develop this method of diagnosis for different diseases, the foundation being in immunological
reactions, registered with the help of the immuno-bio-chemo-luminescence naturally present in the
body, and stimulated in the acidic agent hydrogen peroxide. With the use of standard methods of
testing as a control I compared them for many years with this method of analysis and it has proved
extremely accurate.
Yakuba Nataliya <frolke@ibm.net>
Toronto, Ontario Canada - Thu Jan 21 02:43:01 PST 1999
Any research findings on TB in immigrants to developing countries. Are they responsible for
transmission to the indeginous peoples or is the reverse true?
Kenneth <kennethm@epid.lan.mcgill.ca>
Montreal, Quebec Canada - Mon Jan 18 15:07:02 PST 1999
Any research findings on TB in immigrants in developing countries. Are they responsible for
transmission to the indeginous peoples or is the reverse true?
Kenneth <kennethm@epid.lan.mcgill.ca>
Montreal, Quebec Canada - Mon Jan 18 15:05:23 PST 1999
I want to know about multiresistant tuberculosis, any information or link will be useful. Thank
Katherine Hernandez <bartleyjames@hotmail.com>
Lima, Lima Per - Mon Jan 18 14:51:49 PST 1999
Research on Active TB in adults who have had no sympotoms, negative skin tests and negative
chest Xrays negative smears, but does have positive culture of liquid from a washing of the lungs
due to a broncochope as result of a chronic non-productive cough for years..
Kay <kdddalga@ocsonline.com>
Dalton, GA USA - Sun Jan 10 22:54:04 PST 1999
Genetics, MHC, T cell receptors, thymic education.
PITCHAPPAN <immunology@vsnl.com>
MADURAI, Tamil Nadu INDIA - Thu Jan 7 07:54:56 PST 1999
Tuberculosis in children and adolescent, profilaxis, epidemiology, treatment.
Datchev <datchev@rousse.bitex.com>
Rousse, Bulgaria - Wed Jan 6 14:12:51 PST 1999
Portable TB Isolation Systems For Healthcare and other needs eliminates most respirator use
Ted Arts <isosys@localnet.com>
Buffalo, NY USA - Wed Jan 6 06:48:34 PST 1999
We want to express several recombinant proteins from M.tuberculosis. Where can we get the
corrseponding DNA or cDNA?
Werner Schmitz <wschmitz@biozentrum.uni-wuerzburg.de>
http://www.stanford.edu/group/molepi/guestbook.html (27 of 58) [05/01/06 2:27:10]
I am interested in all aspects related to molecular drug resistant mechanisms employed by TB.
Eric T. Y. Leung <eric@hkusua.hku.hk>
- Wed Nov 4 21:58:54 PST 1998
I am interested in any reported case dealing with Mycobacterium tuberculosis infection leading to
Interstitial lung disease or pulmonary fibrosis or any new treatment modalities for tuberculosis
infection or disease.
Emilina Montero-Luz <vinlyn@compass.com.ph>
Manila , Philippines - Mon Nov 2 21:47:43 PST 1998
I need information about resistance to Tuberculosis in Per
HENRI PEREA <henriperea@hotmail>
AREQUIPA, AREQUIPA PERU - Sun Nov 1 21:00:11 PST 1998
I am interested in research about susceptibility genetic and TB or others topics about Molecular
Genetic in this disease
Paula Andrea Granda Carvajal <agranda@mailexcite.com>
Medelln, Antioquia Colombia - Wed Oct 14 14:42:59 PDT 1998
I'd really apreciate if anyone could send me any file rellated with tuberculosis treatment. Chemical
aspects of the drugs, farmacology, etc. Any kind of information would be usefull. Thanks!
Julian Catalan <julian@crb.org.br>
Blumenau, SC Brasil - Tue Oct 13 15:52:29 PDT 1998
Please include infor regarding epidimiology of TB within the Asian population in America.
Christine Nguyen <christine112.hotmail.com>
san jose, california U.S.A - Tue Oct 13 12:54:44 PDT 1998
I'm a biologist working at the hygiene institut in Morocco I'm unteresting in huomoral response to
mycobateium tuberculosis,SDS PAGE.
LARBI BAASSI <baassilarbi@mailcity.com>
Rabat, Morocco - Fri Oct 9 08:57:21 PDT 1998
Please forward all information/latest research papers on TUBERCULOSIS regarding D.O.T.
[direct observation treatment].
Khalid <jt3d@super.net.pk>
Karachi, Karachi Pakistan - Tue Oct 6 07:54:09 PDT 1998
Interest in PCR of gene probe. The local distributer claims that we can do sensitivity by PCR. Is it
true ?
Dr Suresh Amin <suamin@pi.zaverchand.com>
Baroda, Gujarat india - Sun Oct 4 17:09:13 PDT 1998
Lizzie
- Sun Jul 19 07:15:16 PDT 1998
I would appreciate any information about all forms of TB throughout history in New York state
especially sanitoriums>Thank-you
Rebecca Guthrie <Beks1@aol.com>
- Wed Jul 1 20:56:10 PDT 1998
Clinical Tuberculosis, Chapman and Hall London, 1998. Why is the AIDS conference in Geneva
not telling the world that the commonest cause of death in AIDS patients is tuberculosis?
Peter Davies <p.d.o.davies@liverpool.ac.uk>
Liverpool, UK - Mon Jun 29 04:01:49 PDT 1998
I am in need of information about TB to be used as a teaching tool for children and parents in a
pediatric hospital in Boston
Ed Gilbert <ejg51@yahoo.com>
Evertt , MA. U.S.A. - Wed Jun 24 16:34:26 PDT 1998
Rapid mycobacterial identification by PCR-Restriction Enzme Analysis (hsp65 gene) How to make
it more practical for use in heavy burden clinical laboratories?
O. Kaya Koksalan <koksalan@escortnet.com>
Istanbul, Turkey - Mon Jun 22 11:35:22 PDT 1998
MDR tuberculosis,molecular methods of rapid identification of drug resistance,molecular
mechanisms drug resistance
Edward Generozov <Edward.Generozov@ripcm.org.ru>
Moscow, Moscow Russian Federation - Fri Jun 19 04:47:14 PDT 1998
Medical Air Technology Corporation provides leading edge Air Purification systems for hospital,
correctional and long term care facilities. We work closely with infection control personnel,facility
management,safety officers, engineers and architects to provide individually designed rooms that
are GUARANTEED and CERTIFIED in writing to meet or exceed all present CDC guidelines and
OSHA regulations. For more information on TUBERCULOSIS / AIRBORNE INFECTION
CONTROL for the 21st century visit our website www.medair.com Thank you
Jeff Olarte <medairjeff@aol.com>
mission viejo, ca usa - Thu May 28 09:32:11 PDT 1998
Medical Air Technology Corporation provides leading edge Air Purification systems for hospital,
correctional and long term care facilities. We work closely with infection control personnel,facility
management,safety officers, engineers and architects to provide individually designed rooms that
are GUARANTEED and CERTIFIED in writing to meet or exceed all present CDC guidelines and
OSHA regulations. For more information on TUBERCULOSIS / AIRBORNE INFECTION
CONTROL for the 21st century visit our website www.medair.com Thank you
http://www.stanford.edu/group/molepi/guestbook.html (32 of 58) [05/01/06 2:27:10]
complex " interested molecular mechanisms granuloma formation, mycobacterial virulence and
impaired macrophage function. other interest include Rheumatoid arthriris, Stroke and cancer. Dr
Vinayak D Kanade, Dept of Microbiology and Cell Biology, Indian Institute of Science, Bangalore
560012, Karnataka State, INDIA.
Dr Vinayak D Kanade <vinay@mcbl.iisc.ernet.in>
Bangalore , Karnataka INDIA - Sun May 3 09:57:15 PDT 1998
tb anything
Jeff Bauer <jeff_bauer1@hotmail.com>
New york, New york U.S.A - Fri May 1 18:18:36 PDT 1998
I am doing a term paper for Anatomy. I am a junior in high school. I am very interested in the
study of this disease. if applicable, please send me any info. Thanks.
H. Khan <h-man@thegrid.net>
- Tue Apr 28 19:15:15 PDT 1998
Isoniazid, Serodiagnosis, Newer drugs, Culture methods, Slow release preparations of antiTB
drugs
Dr.Rajesh M.Ballal <clintech@mailexcite.com>
Nagpur, Maharashtra India - Tue Apr 28 04:01:16 PDT 1998
This is a really helpful web page.
Jasmine Lopez
Bellevue, IA U.S.A - Fri Apr 24 12:40:35 PDT 1998
(M. bovis)Tuberculin production, quality assurance, potency assay Animal (domestic and
exotic)tuberculosis diagnosis
Dr. Elizabeth Rohonczy <Rohonczyl@em.agr.ca>
Nepean, Ontario Canada - Fri Apr 24 09:53:44 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
Wolverhampton, UK - Wed Apr 22 01:25:05 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
Wolverhampton, UK - Wed Apr 22 01:24:34 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
http://www.stanford.edu/group/molepi/guestbook.html (34 of 58) [05/01/06 2:27:10]
Molecular interactions between MTB and human macrophage. MTB gene expression pattern
Francesca Mariani <mariani@utovrm.it>
Rome, Italy - Thu Feb 19 01:58:30 PST 1998
I went to the gulf in 90/91. In March of 1997, I found out I was TB Positive after a positive skin test.
I completed the regimen of six months isoniazid. If you need someone for post treatment study, I'd
like to volunteer, and I'm in the area. Jonathan L. Hopwood
Jonathan L. Hopwood <hopwood@hoover.stanford.edu>
Menlo Park, CA US - Sat Feb 14 14:54:14 PST 1998
TUBERCULOSIS CUTANEAS
PRESEDO JULIO <JULPRE@CIUDAD.COM.AR>
BUENOS AIRES, ARGENTINA - Sun Feb 8 20:50:28 PST 1998
I am a graduate student at the University of Georgia. I am currently working on an intervention
proposal for a Strategies of Health Promotion course. My interest is in examining TB in the South
African children population.
Preston Clark <pclarkjr@coe.uga.edu>
Athens , GA United States - Thu Feb 5 18:17:06 PST 1998
I am a graduate student at the University of Georgia. I am working on an intervention proposal for
a Strategies of Health Promotion course. My interest in examining TB in the South African
children population.
Preston Clark <pclarkjr@coe.uga.edu>
Athens , GA United States - Thu Feb 5 18:14:25 PST 1998
Tratamiento de Tuberculosis drogoresistente. Drugresistant Tuberculosis Treatment
Felix Canal <fcanal@acer.com.pe>
Lima, Peru - Wed Feb 4 13:52:39 PST 1998
Data concerning incidence of suspect/confirmed infectious Tb in the long-term health care setting
(e.g. skilled nursing and assited living facilities).
Chris Davis <chris_davis@manorcare.com>
Gaithersburg, MD - Wed Feb 4 08:53:19 PST 1998
TB clinic Follow-up of patients on anti-TB medication Treatment of MRTB
Dr. Gilles Blanchette <blanchg@ere.umontreal.ca>
Montreal, Quebec Canada - Tue Feb 3 18:48:53 PST 1998
I'm in the 8th grade and doing a Science Fair Prject on TB. Please provide me with any
information possible by the end of the week.
1998
Lena Gutberlet <lgutberl@mail.vt.edu>
Blacksburg, VA usa - Mon Jan 12 09:17:46 PST 1998
international opportunities- I would like to help with research abroad during the summer months
of 1998
Lena Gutberlet <lgutberl@mail.vt.edu>
Blacksburg, VA usa - Mon Jan 12 09:05:57 PST 1998
I would be grateful for any information relating to the instance of TB in Ireland, past and present,
general information on TB would be likewise valuable. Thanking you, in anticipation....
Edel <Ge94323861@ailm.may.ie>
Co.Kildare, Ireland - Mon Jan 12 05:31:13 PST 1998
Hey, cool page here. Yah, well THAT'S ALL hahahahahahaha yelling's DUMB!!!
Ben Jones <banjones@hotmail.com>
Pitwomen, New Jersey USA - Sun Jan 11 14:55:46 PST 1998
social impact of tuberculosis in urban areas
Amy Harrington <aharrin1@swarthmore.edu>
- Sat Jan 10 22:56:34 PST 1998
MDR Tuberculosis
Dr. S. Martnez-Selmo <martnez.selmo@codetel.net.do>
Santo Domingo, Distrito Nacional Dominican Republic - Sat Jan 10 18:47:49 PST 1998
Interests: Tuberculosis in Colorado throughout history We need some information, please!!!!
jessica Perino <perino_jim@fortlewis.edu>
Durango, Co USA - Sat Jan 10 15:02:46 PST 1998
Antimocrobial Susceptibility Testing
Ron Dudek <ron_dudek@bio-rad.com>
Hercules, CA USA - Thu Jan 8 18:56:13 PST 1998
TB in other organs than lungs.
Loriane Frewing <Loriane_Frewing@bc.sympatico.ca>
Langley, B.C. Canada - Thu Jan 8 13:30:29 PST 1998
Dear Sirs: Be very pleased of directing me you with motive of requesting informacion on the
disease called granuloma tuberculosis or tumor endumedular, the request is due to that I have to a
relative with that disease and wanted to know of the fact that is tried and which isyour cure. From
already I thank your time, and I wait prompt response.
study. We need more information about local experiencies with 6 months/four drugs/short course
TB treatment
Oswaldo Jave Castillo <gjave@rcp.net.pe>
Lima, Lima Peru - Tue Nov 18 13:33:25 PST 1997
HIV/TB Multidrug-resistant TB Short course treatment Molecular epidemiology Third World
TB/HIV research
Oswaldo Jave Castillo <gjave@rcp.net.pe>
Lima, Lima Peru - Tue Nov 18 12:35:57 PST 1997
Looking for info about how M.Tuberculosis escapes the immune system and develops into TB
disease
Margarida Monteiro <mmam@students.si.fct..unl.pt>
Almada, Portugal - Sat Nov 15 11:09:02 PST 1997
I don't have any comments at this time.
Corey Zadlo <Vike00@hotmail.com>
Chicago, IL USA - Fri Nov 14 12:38:05 PST 1997
Personal experience of having TB
Diane Morris <dmorris@e-tex.com>
Mt. Vernon, Tx USA - Wed Nov 12 08:14:55 PST 1997
tuberculosis, drug resistance, transmission, and treatment.
Scott Richardson <sorrento@eatel.net>
sorrento, la usa - Sat Nov 8 09:33:13 PST 1997
I am interested in any materials on tuberculosis.
Jill Sanders <jsand019@uwsp.edu>
Stevens Point, WI USA - Tue Nov 4 12:10:36 PST 1997
INFORMATION REGARDING TUBERCULOSIS RESEARCH
Dr.V.VISHWANATH <FRD@IFEUNIV.UNIFE.IT>
FERRARA, ITALY - Tue Nov 4 07:01:12 PST 1997
I'm doing my BSc Genetics and biochemistry at the university of Wales, Aberystwyth. I am
interested in the treatment to TB and in its future research into new treatments for MDR-TB.
Karen Barker <kab5@aber.ac.uk>
Ceredigion, Wales UK - Fri Oct 31 08:42:37 PST 1997
I have an uncle who is diabetic and was diagnosed lately to have potts disease. Is potts disease
curable in this case? Or is it more likely to spread through the rest of the body? Thanks in advance.
Mostafa Afifi <the_afifis@hotmail.com>
http://www.stanford.edu/group/molepi/guestbook.html (46 of 58) [05/01/06 2:27:11]
growing mycobacteria
Jaime Esteban <fjdmicro@microb.net>
Madrid, Spain - Thu Jun 26 05:45:13 PDT 1997
I am a MS student and want to pursue a PhD degree in TB research. My research
interests.(1)RFLP analysis of M.tuberculosis.(2)Multi-drug resistance of
M.tuberculosis.(3)Detection of M.tuberculosis by PCR (4)Molecular epidemiology of TB. ***The email user's name is not Chuntao Wu,but Qi-lun Sun. Thank you.
Chuntao Wu <qsqq@bltda.com.bta.net.cn>
Beijing, P.R.China - Sun Jun 22 03:57:03 PDT 1997
Diagnosis and treatment
Maria Luigia Lamona <m1970@telcel.net.ve>
Caracas, Distrito Federal Venezuela - Mon Jun 16 18:24:23 PDT 1997
tuberculosis:resistance BK (primary and secondary) cancer bronchopulmonary (brachytherapy)
dr. Ciobanu Doru Traian <ciobanut@unitbv.ro>
Brasov, ROMANIA - Sat Jun 14 01:31:29 PDT 1997
BCG; Tuberculosis innoculations;
Gerri Hynes <ghynes@ican.net>
Burlington, Ontario Canada - Fri Jun 6 20:27:01 PDT 1997
Sensitivity of tuberculosis agent to UV-A exposure.
Derek Griffith <dgriffit@csir.co.za>
Pretoria, Gauteng South Africa - Wed Jun 4 14:04:33 PDT 1997
More zero band strains of M.tb exists in South India. DR probe has been found to be the ideal
probe for molecular typing of M.tb. Key words: Mycobacterial virulence genes, promoters,
intracellular survival.
Dr. R. Sahadevan <sahadevan@hotmail.com>
Madras, Tamil Nadu India - Sat May 31 04:43:56 PDT 1997
Study Results of UV Light Technologies, Management of DOT & DOPT, Community Healthcare
Epidemiology Issues
Kevin A. Gritzke <jjmce@ixnetcom.com>
St. Louis, MO USA - Tue May 27 17:35:25 PDT 1997
EthnoBios S.R.L. is a small biotech company located in Bolivia working with medicinal plants that
have a history of traditional usage. At this time we are working with the sap of a plant that has a
history in treating TB, rheumatoid arthritis annd verruges. Studies have suggest that this product
induces differnt effects on sveral phases of the immune response which may be compatible with the
reported capacity to resolve the TB process. In addition, these effects (stimulation of splenocytes
http://www.stanford.edu/group/molepi/guestbook.html (53 of 58) [05/01/06 2:27:11]
and modulation of the marcrophages activity) lead to consider this substance as a promising
candidate to further studies and application as an immunomodulatory product. We have another
that is just as interesting but I have already writen more than a "few lines." Sorry. If anyone is
interested please contact me at lipena@wara.bolnet.bo We lack funding to continue our studies so
any info. would be apprecialted. Thanks, Joseph C. Traini
Lic. Joseph C. Traini <lipena@wara.bolnet.bo>
La Paz, La Paz Bolivia - Tue May 27 12:10:02 PDT 1997
38-kDa antigen, 16-kDa antigen, Diagnosis, Vaccine, TB molecular bilogy
Zengyi Chang, Ph.D. <changzy@mail.tsinghua.edu.cn>
Beijing, P.R.China - Thu May 22 16:05:41 PDT 1997
Louisiana Office of Public Health employee in Tuberculosis Control Program interested in learning
more about TB diagnosis and treatment.
Richard Adams <RWadams@msn.con>
New Orleans, LA USA - Sun May 18 20:35:21 PDT 1997
INH therapy and longivity further testing once treated
Dawn Bisenius
Peoria, Illinois USA - Sun May 18 20:05:57 PDT 1997
I'm a graduate student who is prepareing a paper on the resurgence of TB and it's effects on the
community. Any information that can be obtained would be very much appreciated
Leslie F. Dowers <Sansouci22>
Rosedale, New York U.S.A. - Sun May 18 19:19:33 PDT 1997
Synthetic organic chemistry. Preparation of tuberculostatic agents having enhanced lipophilicity.
Preparation of antimicrobials having multiple tuberculostatic moieties in one chemical structure.
Near infrared spectroscopy for the analysis of tuberculosis antimicrobials.
M. J. Hearn <MHearn@Lucy.Wellesley.edu>
Wellesley, MA USA - Sun May 18 07:22:01 PDT 1997
I would like to receive the lattest news about tuberculosis and the co-infection with AIDS. Im a
brasilian pulmonologist that work with TB/AIDS. Thank you for your help
Enio Pires Studart <enio@openlink.com.br>
rio de janeiro, RJ Brasil - Sat May 17 15:33:18 PDT 1997
Mycobacterial genetics and pathogenesis
Ed Swords <wds0@cdc.gov>
Atlanta, GA USA - Fri May 16 11:42:53 PDT 1997
Use of HPLC for species identification of mycobacteria, susceptibility testing and epidemiology.
David Fett <keon@prof.slh.wisc.edu>
http://www.stanford.edu/group/molepi/guestbook.html (54 of 58) [05/01/06 2:27:11]
Stanford University and individuals maintaining this page are not to be held responsible for any
consequences whatsoever resulting from any and all words or other information on this page, or any
actions taken as a result of contacting individuals listed herein.
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Furthermore, the size of a tuberculin skin-test reaction in a BCGvaccinated person is not a factor in determining whether the reaction
is caused by M. tuberculosis infection or the prior BCG vaccination.
Tuberculin skin testing is not contraindicated for persons who have
been vaccinated with BCG, and the skin-test results of such persons
are used to support or exclude the diagnosis of M. tuberculosis
infection.
A diagnosis of M. tuberculosis infection and the use of treatment of
latent TB infection should be considered for any BCG-vaccinated
person who has a tuberculin skin-test reaction of >=10 mm of
induration, especially if any of the following circumstances are
present:
The vaccinated person is a contact of another person who has
infectious TB, particularly if the infectious person has transmitted M.
tuberculosis to others;
The vaccinated person was born or has resided in a country in which
the prevalence of TB is high; or
The vaccinated person (e.g., some health care workers, employees
and volunteers at homeless shelters, and workers at drug-treatment
centers) is exposed continually to populations in which the
prevalence of TB is high.
Treatment of latent TB infection should be considered for BCG-
vaccinated persons who are infected with HIV and who are at risk for
M. tuberculosis infection if they have a tuberculin skin-test reaction
of >= 5 mm induration.
BCG-vaccinated persons who have a positive reaction to the
tuberculin skin test, but who do not have TB disease, should be
evaluated for treatment of latent TB infection. The possibility of TB
disease should be considered for BCG-vaccinated persons who have
symptoms suggestive of TB.
Tinplate Hospital
P.O.Golmuri, Jamshedpur
Phone: +91-0657-2340512, EPABX: 2340713-720
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Turberculosis
"TB"
"MDR-TB" (multi-drug resistant TB)
This is part of a series on Opportunistic Infections ("OIs"). Please note that -1. This Page Is Just A Starting Point: GIS is a great place for you to find overview
information about HIV and opportunistic infections, but it is not a substitute for getting
medical advice from a doctor who specializes in treating HIV.
2. Finding The Latest Information: Advances in treating opportunistic infections can
happen at any time, so the material on this page may be outdated. Some links in the see
also section at the bottom of this page are actually special database links. They may
contain information published after this page was written.
Classification
Infection with Mycobacterium tuburculosis
Description
Multi-drug Resistant TB: Of particular concern for people with AIDS is multi-drugresistant TB (MDR-TB). MDR-TB occurs when patients fail to take their TB medicine for
the prolonged periods necessary to destroy all parts of the TB organism and it becomes
resistant to the drugs. These resistant organisms can be spread to other people. Even with
treatment, for individuals coinfected with HIV and MDR-TB, the death rate may be as high
as 80 percent, as opposed to 40 to 60 percent for people with MDR-TB alone. The time
from diagnosis to death for some patients with HIV and MDR-TB may be only months as
they are sometimes left with no treatment options. (NIH)
In about half of the HIV+ people with TB, the infection involves more than just the lungs.
Other targets include the lymphatic system.
Symptoms include: cough, fever, night sweats, weight loss, fatigue.
Diagnosis is usually made with a skin test.
The US Centers For Disease Control considers TB an AIDS-defining condition.
Danger Zone
TB is more frequent for those with CD4+ cells less than 200/mm but can occur at any
CD4+ count.
NOTE: If you are undergoing treatment that has increased your CD4+ levels, see the important
note on Naive T-Cells. There is some evidence that you should use the lowest CD4+
level you ever had when considering your risk for some opportunistic infections.
Prevention
The US CDC recommends treatment for any HIV+ person with latent (inactive, no
symptoms) M. tuberculosis. That diagnosis is made using skin tests.
Prophylaxis (prevention) is usually isoniazid.
Outside the US, BCG vaccination has been used for the prevention of TB.
NOTE: Many HIV experts stress that it is important that anyone newly diagnosed as being HIVpositive be given a "TB with anergy" test. That is a test for TB, mumps, and candida. Those with
severely damaged immune systems can show false negative results on the TB test.
1. If you test positive for TB, you are infected with TB.
2. If you test negative for TB but positive for mumps or candida, you do not have TB. This is
the result you want! Those with functioning immune systems will test positive for mumps,
candida, or both ... so a positive result on these tests means the negative TB test can be
http://www.aegis.com/topics/oi/oi-tb.html (2 of 3) [05/01/06 2:52:55]
trusted.
3. If you test negative for all three, then you have anergy, which means your immune system
is to damaged to respond to common antigens.
Treatment
See Also...
This information is designed to support, not replace, the relationship that exists between you and your doctor.
1998. AEGIS.
HOLIDAY SEALS
PROGRAMS
HISTORY
TB FACTS
LOCATION
CONTACT
LINKS
TB is at the lowest rate of increase since it's emergence in the 1980's according to the CDC.
The Tuberculosis Association of Ohio County is a nonprofit organization located in Wheeling, West Virginia. The association
has been providing programs and services for the residents of Ohio
County since 1909.
Unlike many organizations which funnel contributions to a national headquarters, we use our funds
locally, to benefit Ohio County residents. The money is not used for high administrative salaries and
bureaucratic costs; it is used almost exclusively to fund preventive medical programs, scholarships and
community service projects in Ohio County.
Generous local donors can see the good things their contributions accomplish.
Home Page
TBC India
WHO-recommended
Directly Observed
Treatment, Short Course
(DOTS) strategy was
launched formally as
Revised National TB Control
programme in India in
1997 after pilot testing
from 1993-1996. Since
then DOTS has been widely
advocated and successfully
applied.
Indian TB
Programme officers