Академический Документы
Профессиональный Документы
Культура Документы
IDM213
Software used
Microsoft Word
Word count
2444
101163710
No
IMPORTANT:
Only one assignment can be uploaded with each Assignment Cover Sheet.
You will need to read and accept the online plagiarism declaration on your initial login before
being able to upload your assignment(s).
Ensure that you have read and adhered to the guidance on referencing provided in the
Student Handbook.
Epidemiological evidence
Assessing natural immunity compared to vaccine-mediated immunity is by no
means simple. Aside from challenge experiments, which are an ethical quagmire, the
next best estimates would come from epidemiological surveys. True estimates would
require large samples including adequate unvaccinated cases, problematic for diseases
with widespread vaccine coverage, in order to pick up rare cases of actual infection.
Further, detailed lifelong histories together with laboratory confirmed status of past
infection (including ideally molecular typing and serological correlates) would be
necessary to compare against vaccination histories, if possible along with exposure
histories. For many diseases, based on limited evidence, there is a widespread
understanding that natural immunity is better than vaccine-mediated immunity (1,2).
Unfortunately this is dependent on surveillance for repeat infections, which is of a
different quality in the pre-vaccination era compared to the present.
Tetanus may provide the strongest example for the possibility of better
vaccine-mediated immunity than natural immunity using epidemiological evidence,
while comparing to a well-described example of where natural immunity is usually
said to be better than vaccine-mediated immunity, namely varicella. For tetanus,
received wisdom is that infection does not confer immunity (3) . Series of repeated
infections have been reported (4). Irreversible binding and rapid sequestration of the
tetanus toxin tetanospasmin into neurons may be responsible for the short exposure
of the toxin to the immune system and thus minimizing time for generation of an
adaptive immune response. Together with the small doses required for a severe, often
fatal clinical course, few people develop antibodies, as serosurveys in non-immunized
populations have shown (5). In contrast, the formaldehyde treated tetanus toxoid has a
virtually 100% seroconversion rate, and while [e]fficacy of the toxoid has never been
studied in a vaccine trial. It can be inferred from protective antitoxin levels that a
complete tetanus toxoid series has a clinical efficacy of virtually 100%(6) . Reasons for
higher vaccine-mediated than natural immunity in this case may include a higher dose
of antigen in the vaccine and a longer period of time in the bloodstream for generation
of an adaptive immune response.
In contrast, taking varicella as typical of many other diseases where natural
immunity is taken to be superior to vaccine-mediated immunity, clinical chickenpox
after reinfection is considered extremely rare. There are only a handful of case reports
with serological correlates (7,8). Considering the historically widespread risk, this,
together with an upper estimate of a 7% attack rate in an outbreak setting for children
with a clinical history of previous varicella (9), itself prone to misreporting,
demonstrates the very high rate of natural immunity. In contrast, clinical efficacy of
the varicella vaccine has been reported in a meta-analysis at 84.5% (95% CI 44-100%)
and vaccine failures are constantly reported (10).
As these contrasting examples may show, evaluating natural vs vaccinemediated immunity from epidemiologic evidence alone is not without problems.
However, they also demonstrate that there does exist the possibility that vaccines can
lead to better immunity than natural infection.
VLPs are able to elicit high titres of neutralizing antibodies (two orders of magnitude
more than natural infection), and antigen dose exceeds that in natural infection (11).
Antigen variation
Influenza virus uses antigenic shift and antigenic drift to evade host immune
response, allowing for repeated infections(13). To avoid lack of immune memory, or
confounding effects of original antigenic sin, one strategy is to use conserved epitopes
of the influenza virus to generate a universal vaccine (14).
Immune privilege
In chronic infections, and those with a period of latency, pathogens may enter
immune-privileged sites to reduce host immune response. Varicella zoster virus (VZV)
after primary infection as varicella enters dorsal nerve root ganglia and is latent,
reactivating sporadically as herpes zoster. During the period of central nervous
system (CNS) latency, minimal protective immunity is elicited due to immune
privilege. By introducing high antigen loads into the bloodstream with zoster
vaccination, the immune system is stimulated above the level of natural infection to
generate protective immunity against the latent VSV (15). Another example of relative
immune privilege is the liver (16) . Plasmodia have a liver stage where they are
relatively protected from the immune system. Vaccine strategies have included using
liver stage antigen 1 (LSA-1), the only P. falciparum antigen expressed exclusively by
hepatocytes in vaccination strategies by presenting it outside the tolerogenic
environment of the liver in order to stimulate the immune system into acting against
liver-stage parasites, over and above the level of protective immunity generated by
natural infection (17).
Granuloma formation
Organisms may subvert natural protective immunity through stimulating
immunopathologic responses that serve to evade host defences. Granuloma formation
by pathogens in the Mycobacterium tuberculosis (Mtb) complex demonstrates this. Upon
initial infection, inflammatory reaction often leads to a granuloma containing
dormant mycobacteria that are inaccessible to elimination by the immune system (18).
It can be conceived that vaccines leading to sterile eradication of Mtb can be designed,
that overcome the suboptimal natural immunity leading to latent infection. Kaufmann
suggests a vaccine strategy of stimulating different T cell populations that can in
concert eliminate latent Mtb: chemoattractant Th17 cells, Th1 cells that activate
macrophages, cytotoxic CD8 T cells that attack intracellular Mtb, and antibodies to
opsonize released Mtb(19).
Immunosenescence
Immunosenescence constitutes a major deficiency of natural protective
immunity against infectious disease. In the older adult, a whole array of changes to
innate and adaptive immune mechanisms contribute to a poorer protective response
than in younger adults. Work on this phenomenon in the context of influenza has been
active, with demonstrable poor cellular immunity to natural infection in the elderly
(23). While current influenza vaccination strategies in the elderly remain suboptimal
(24), there is the potential to improve these potentially over the response to natural
infection by modulating the immunosenescent phenotype: Cell-intrinsic changes
that impair the activation and differentiation of T cells and B cells are rather subtle
and may be overcome by temporally limited interventions at the time of vaccination.
(25).
Tissue-specific life-stages
Schistosomes infect humans via the skin as cercarial larvae, transiting through
the skin as schistosomlae before maturing to adult worms with associated
immunopathology. Repeated infections are common, which indicates that adaptive
immunity against larval forms is not effective. One mechanism by which cercariae
avoid stimulating the immune system is by secretion of immune modulators including
prostaglandins which inhibit antigen-presentation by Langerhans cells in the skin (29).
The increased efficacy of irradiated cercariae in inducing protective immune in mouse
models(30) demonstrates how artificial vaccine formulations focusing on particular
parasite life-stages may improve on natural immunity.
Conclusion
This essays aims to demonstrate that not only is it theoretically possible but,
given definitional constraints, that vaccine-mediated immunity has already surpassed
natural immunity in a few cases by epidemiologic and immunologic criteria. Both
clinical endpoints and immune correlates such as seroconversion have been used in
the discussion. Further theoretical extensions to the principle have been proposed
within a typology of compromised natural immune responses and suggestions of
potential vaccine strategies made.
References
1.
Frequently Asked Questions - Vaccination - Ministre de la Sant et des Services sociaux [Internet]. [cited
2014 Mar 30]. Available from: https://www.msss.gouv.qc.ca/sujets/santepub/vaccination/index.php?
foire_aux_questions_en#q14
2.
General Vaccine Safety Concerns | The Childrens Hospital of Philadelphia [Internet]. [cited 2014 Mar
30]. Available from: http://www.chop.edu/service/vaccine-education-center/vaccine-safety/general-safetyconcerns.html#natural-infection
3.
Cook TM, Protheroe RT, Handel JM. Tetanus: a review of the literature. Br J Anaesth. 2001 Sep
1;87(3):47787.
4.
Lindley-Jones M, Lewis D, Southgate J. Recurrent tetanus. The Lancet. 2004 Jun 19;363(9426):2048.
5.
Matzkin H, Regev S. Naturally acquired immunity to tetanus toxin in an isolated community. Infect
Immun. 1985 Apr;48(1):2678.
6.
Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable
Diseases. 12th ed. Atkinson W, Wolfe S, Hamborsky J, editors. Washington DC: Public Health
Foundation; 2012.
7.
Johnson JA, Bloch KC, Dang BN. Varicella Reinfection in a Seropositive Physician Following
Occupational Exposure to Localized Zoster. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011 Apr
1;52(7):9079.
8.
Gershon AA, Steinberg SP, Gelb L. Clinical Reinfection with Varicella-Zoster Virus. J Infect Dis. 1984
Feb 1;149(2):13742.
9.
Ross AH. Modification of chicken pox in family contacts by administration of gamma globulin. N Engl J
Med. 1962 Aug 23;267:36976.
10.
Seward JF, Marin M, Vzquez M. Varicella Vaccine Effectiveness in the US Vaccination Program: A
Review. J Infect Dis. 2008 Mar;197(s2):S82S89.
11.
Mariani L, Venuti A. HPV vaccine: an overview of immune response, clinical protection, and new
approaches for the future. J Transl Med. 2010 Oct 27;8(1):105.
12.
Ravindran R, Bhowmick S, Das A, Ali N. Comparison of BCG, MPL and cationic liposome adjuvant
systems in leishmanial antigen vaccine formulations against murine visceral leishmaniasis. BMC
Microbiol. 2010 Jun 24;10(1):181.
13.
Smith DJ, Lapedes AS, Jong JC de, Bestebroer TM, Rimmelzwaan GF, Osterhaus ADME, et al. Mapping
the Antigenic and Genetic Evolution of Influenza Virus. Science. 2004 Jul 16;305(5682):3716.
14.
Stanekov Z, Varekov E. Conserved epitopes of influenza A virus inducing protective immunity and
their prospects for universal vaccine development. Virol J. 2010;7:351.
15.
Abendroth A, Arvin AM. Immune evasion as a pathogenic mechanism of varicella zoster virus. Semin
Immunol. 2001 Feb;13(1):2739.
16.
Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S. Cellular and molecular mechanisms
of liver tolerance. Immunol Rev. 2006 Oct 1;213(1):10118.
17.
Taylor-Robinson DAW. Immunity to liver stage malaria. Immunol Res. 2003 Feb 1;27(1):5369.
18.
Ramakrishnan L. Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol. 2012
May;12(5):35266.
19.
Kaufmann SHE. Future Vaccination Strategies against Tuberculosis: Thinking outside the Box. Immunity.
2010 Oct 29;33(4):56777.
20.
Rijkers GT, Sanders EAM, Breukels MA, Zegers BJM. Infant B cell responses to polysaccharide
determinants. Vaccine. 1998 Aug;16(1415):1396400.
21.
Shapiro ED, Ward JI. The Epidemiology and Prevention of Disease Caused by Haemophilus influenzae
Type b. Epidemiol Rev. 1991 Jan 1;13(1):11342.
22.
Klein Klouwenberg P, Bont L. Neonatal and Infantile Immune Responses to Encapsulated Bacteria and
Conjugate Vaccines. J Immunol Res [Internet]. 2008 Sep 23 [cited 2014 Mar 31];2008. Available from:
http://www.hindawi.com/journals/jir/2008/628963/abs/
23.
Jia N, Li C, Liu Y-X, Richardus JH, Feng D, Yang H, et al. Lower cellular immune responses to influenza
A (H3N2) in the elderly. J Med Virol. 2009 Aug 1;81(8):14716.
24.
Lambert ND, Ovsyannikova IG, Pankratz VS, Jacobson RM, Poland GA. Understanding the immune
response to seasonal influenza vaccination in older adults: a systems biology approach. Expert Rev
Vaccines. 2012 Aug;11(8):98594.
25.
Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat
Immunol. 2013 May;14(5):42836.
26.
Titus RG, Ribeiro JM. Salivary gland lysates from the sand fly Lutzomyia longipalpis enhance
Leishmania infectivity. Science. 1988 Mar 11;239(4845):13068.
27.
Gomes R, Oliveira F. The immune response to sand fly salivary proteins and its influence on Leishmania
immunity. Microb Immunol. 2012;3:110.
28.
Kedzierski L. Leishmaniasis Vaccine: Where are We Today? J Glob Infect Dis. 2010;2(2):17785.
29.
Jenkins SJ, Hewitson JP, Jenkins GR, Mountford AP. Modulation of the hosts immune response by
schistosome larvae. Parasite Immunol. 2005;27(10-11):38593.
30.
Richter D, Harn DA, Matuschka F-R. The irradiated cercariae vaccine model: Looking on the bright side
of radiation. Parasitol Today. 1995 Aug;11(8):28893.