J. Vet. Med.
B 52, 303311 (2005)

2005 Blackwell Verlag, Berlin
No claim to original US Government works
ISSN 09311793
Baker Institute for Animal Health, Cornell University, Ithaca, NY, USA.
An Annotated Historical Account of Canine Parvovirus
L. E. Carmichael
Address of author: Professor of Virology, Emeritus, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853,
USA. Tel.: +1 607 256 5600; fax: +1 607 256 5642; E-mail: lec2@cornell.edu
With 5 tables
Summary
A brief annotated history of canine parvovirus-type 2 (CPV-2)
and its variants is summarized with emphasis on the most
signicant contributions of individuals involved in the initial
recognition of CPV-2 and subsequent discoveries that have
advanced our knowledge of the nature and evolution of this
novel canine virus.
Time has obscured the observations of many veterinary
clinicians and researchers throughout the world who sensed the
presence of a new disease when CPV-2 rst made its appearance
in 1978 and then, within 12 years, spread worldwide. Since
1979, nearly 600 articles, papers, numerous text chapters and
monographs have been published on the subject of CPV-2. The
early history is well known by veterinary infectious diseases
specialists and noteworthy publications are recorded on the
National Library of Medicine (USA) website, PubMed and in
review articles. Because of the great number of publications, it is
not practicable to cite them individually; however, reference is
made to certain individuals, reviews and selected papers that I
consider particularly relevant to the history of progress in the
understanding of CPV-2 and the disease it causes.
The clinical disease caused by CPV-2 and its variants, the
immune response to infection or vaccines, host range and the
development of practical diagnostic assays are noted in
historical context. The basic biological properties and the
physical, molecular and antigenic structure of CPV-2 and its
variants are also discussed briey. Finally, key players who
have contributed to the antigenic and DNA sequence
(evolutionary) relationships between CPV-2 and the other
autonomous parvoviruses of carnivores are noted and
hypotheses regarding the origin and evolution of CPV-2 and
its variants are mentioned.
Introduction and Overview
I am honoured and pleased for the opportunity given to me by
Prof. Truyen to present a history of canine parvovirus (CPV-
2). It has now been about 30 years since CPV-2 emerged;
however, the disease caused by CPV-2 was not recognized until
serious or fatal illness aected large numbers of dogs and other
canids. From a personal perspective, it has been an exciting
and satisfying experience to view the progress of research
during the relatively short time since the virus presence was
revealed and I am challenged to do justice to those who have
made the advancement in knowledge so quickly. When one has
thrust aside the toga virilis and assumed the role of laudator
temporis acti, it is an appropriate time to talk about history
U. S. Copyright Clearance Center Code Statement: 09311793/2005/52070303$15.00/0
Received for publication July 15, 2005
Invited paper
and leave the scientic discussion to those whose intellects are
still vigorous.
In this presentation, history may be viewed as that area of
knowledge where, through time, recorded events, memory,
myths, and personal ideology all interact in an attempt to
record the contributions of many individuals who have been
involved in the recognition of CPV-2 and have made signi-
cant discoveries that advanced our knowledge of this novel
canine virus. An attempt will be made to note the most
signicant contributions. However, it is impossible to acknow-
ledge the work of all individuals who have added to the
published literature and I hope to be forgiven for the sins of
omission or serious error.
I will draw heavily on my personal experience as well as that
of my colleagues, especially Drs Max Appel and Colin Parrish
at the Baker Institute. I am mindful, however, that time has
obscured the singular observations of many veterinary clini-
cians and researchers throughout the world who sensed the
presence of a new disease when CPV-2 rst made its
appearance and spread worldwide within 12 years. Nearly
600 articles, papers, numerous text chapters and monographs
have been published on the subject of CPV-2 since 1979
(Table 1). The early history is well known by infectious disease
specialists, and noteworthy publications are recorded on
PubMeds website1 and in review articles (Carmichael and
Binn, 1981; Pollock and Parrish, 1985). Because of the great
number of publications, it is not practicable to cite them
individually; however, I will refer to certain individuals and
cite reviews and selected papers that I consider particularly
relevant to the history of progress of our understanding of
CPV-2 and the disease it causes.
Descriptions of the clinical disease caused by CPV-2 and its
variants, its basic pathology, pathogenesis and the immune
response to infection or vaccines, its host range and the
development of practical diagnostic assays were accomplished
rapidly. Moreover, an abundant literature is available on the
regional sero-epidemiology of CPV-2. Vaccines were quickly
made available to protect dogs, but not without controversy or
the creation of myths (Carmichael, 1999). The basic biological
properties and the physical, molecular and antigenic structure
of CPV-2 and its variants have been well described perhaps
to a greater extent than for several, more ancient, viral
infections of animals or humans (Rimmelzwaan et al., 1986;
Truyen, 1999; Steinel et al., 2001; Ikeda et al., 2002; Hueer
1
PubMed, a service of the National Library of Medicine (USA), http://
www.ncbi.nlm.nih.gov/entrez/query.fcgi
www.blackwell-synergy.com
304 L. E. Carmichael

Table 1. Number of publications* established relationship between MVC and dogs. This virus,
now called CPV-1, is distinct from CPV-2 and the parvoviruses
USA/ Australia/
Dates Canada UK New Zealand Europe Asia Other
of other species. Originally believed to be non-pathogenic, it
was shown to cause enteritis and diarrhoea in neonatal pups
19781980 20 17 5 1 0 0 (Harrison et al., 1992; Carmichael et al., 1994). CPV-1 also
19811982 25 3 5 7 1 1 was shown, experimentally, to cause the death of foetuses in
19831984 21 4 1 15 2 2 dams infected during the initial 30 days of gestation. Serolog-
19851986 20 4 1 5 5 0
19871988 16 4 1 8 6 0 ical studies indicated that CPV-1 is highly prevalent in the dog
19891990 3 0 2 9 2 1 population and it has been isolated from pups or aborted
19911992 13 2 0 7 6 0 foetuses in Europe, the USA and Asia. Unfortunately, it has
19931994 15 1 0 11 8 0 received little study for only about a dozen papers have
19951996 12 2 0 13 13 1
appeared since the initial publication of Binn et al. (1970). As
19971998 22 2 0 20 9 3
19992000 11 0 0 17 5 2 with several other viruses, more is now known about the
20012002 13 2 0 19 6 0 genomic structure of MVC than other properties of this virus,
20032004 17 1 1 11 3 1 or its disease potential. The complete genomic sequence has
Total 296 42 16 143 66 11 been accomplished on isolates from the USA and Korea and
Grand total, 574.
MVC seems more closely related to bovine parvovirus (BPV)
*PubMed, Library of Medicine (USA to 5/05). than to the other animal parvoviruses (Schwartz et al., 2002;

Mostly The Netherlands, Belgium, France and Germany. Ohshima et al., 2004). Interestingly, in early 1977, Eugster

Mostly Japan. reported a non-cultivatable parvovirus in the diarrheic stools

and Parrish, 2003). Moreover, the antigenic and DNA
sequence (evolutionary) relationships of CPV-2 to other
autonomous parvoviruses of carnivores have been well docu-
mented in the literature (Shackelton et al., 2005).
It is noteworthy to mention that the rst reported auton-
omous dog parvovirus is the Minute Virus of Canines (MVC),
which Dr Leonard Binn isolated in 1968 from the normal
faeces of US Army dogs stationed in Germany (Binn et al.,
1970). However, retrospective serological studies revealed
neutralizing antibodies to MVC in commercial canine distem-
per/hepatitis serum as early as 1956, indicating a long-
of pups that all recovered (Eugster and Nairn, 1977). It seems
likely that the virus observed by electron microscopy (EM) was
CPV-1 and not the more pathogenic CPV-2 observed until
more than a year later.
It should be acknowledged that CPV-2 was not observed
rst at The Baker Institute, as cited in some texts. Many
individuals throughout the world, especially in the USA,
Australia and Europe, almost simultaneously observed the
sudden appearance of this startling new canine disease
(Table 2). Jezyk et al. (1979) were among the rst to observe
myocarditis of probable virus origin in pups, but the cause
was not determined at the time of their report. Our laboratory

Table 2. Early reports (19781982)

Country Authors of CPV-2 enteritis and
myocarditis*
Australia Huxtable C.R. et al., Johnson B.J. and Spradbrow P.B., Kelly W.R.,
Kelly W.R. and Atwell R. B., Robinson W.F. et al., Walker S.T. et al.
Belgium Burtonboy G. et al., Schwers A. et al.
Canada Gagnon A.N. and Povey R.C., Hayes M.A. et al., Thomson G.W and Gagnon A.N.
Egypt Bucci T.J. et al.
Finland Jalanka H., Neuvonen E. et al.
France Lescure F. et al., Moraillon A. et al., Touratier L
Germany Becker G. and Becker C.H., Bergmann V. et al., Arens M. and Krauss H.,
Bohm H.O., Homan R. et al., Kraft W., et al., Niemand H.G. et al., Theil W.
Hungary Boros G. and Bartha A.
Ireland Sheahan B.J. and Grimes T.D., McNulty M.S. et al., Neill S.D. et al.
Israel Perl S. et al.
Italy Cammarata G., et al., Buonavoglia C.
Japan Azetaka M. et al., Mohri S. et al.
The Netherlands van den Ingh Th.S.G.A.M. et al., Osterhaus A.D.M.E. et al.
Madagasgar Rajaonarison J.J. and Rakotondramary E.
New Zealand Gumbrell R.C., Horner G.W. et al., Parrish C.R. et al.
Norway Krohn B. and Blakstad E.
South Africa Bastianello S.S., Van Rensburg I.B.J. et al.
Sweden Klingeborn B. and Moreno-Lopez J, Olson P-A. et al.
Thailand Tingpalapong M. et al.
UK Else R.W, Hitchcock L. M. and Scarnell J, Jeries A.R. and Blakemore W.F,
McCandlish I.A.P. et al., Thompson H. et al.
USA Appel M.J.G. et al., Black J.W. et al., Carpenter J.L et al., Fritz T.E,
Jezyk, P.F. et al., Mulvey J.J. et al., Nelson D.T. et al., Pletcher J.M. et al.,
Pollock R.V.H. and Carmichael L.E.,
Zimbabwe Blackburn N.K. and LeBlanc-Smith P.M.

*Modied from Pollock and Parrish (1985, p. 147).

To nd specic references on PubMeds website, go to: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi and
type: author name, canine parvovirus (Note: Articles and some journals not cited on PubMed).
An Annotated Historical Account of Canine Parvovirus
rst became aware of unusual outbreaks of vomiting and
diarrhoea in dogs when an excited Dr Max Appel telephoned
while I was on vacation. He alerted me that the Baker Institute
was becoming inundated with faecal samples from the mid-
West and Eastern USA and that I had better hurry back to the
laboratory. By the time I returned, a large number of people
had called the Institute and Appel and his assistant were
attempting to cope with packages of dog faeces that had
arrived some poorly packed and leaking oensive uid that
may have contributed to viral dissemination via the mail.
Appel quickly observed, by EM, a virus similar to feline
panleukopenia virus (FPV) in several of the faecal samples;
within a few days, a cytopathogenic virus was isolated in feline
cell cultures. Dr Fred Scott at Cornells Feline Health Center
provided antiserum prepared against FPV in specic patho-
gen-free (SPF) cats and the dog virus was shown to react
strongly in an indirect immunouorescence (IFA) test (Appel
et al., 1978).
The thought at that time was that a mutation had taken
place in FPV that allowed it to infect dogs and, eventually,
enter the dog population. This impression still persists, despite
later studies that claried the relationships between the
members of the felid parvoviruses. At the time of the initial
outbreaks of CPV-2, we had been studying an outbreak of
coronaviral enteritis in dogs at a show in Kentucky and were,
therefore, in a position to deal with the new outbreaks of
enteric disease that appeared toward the end of August 1978.
Our initial studies focussed on the development of a practical
diagnostic test and vaccination strategies.
Meanwhile, pathologists quickly recognized that a new
canine disease had appeared and a plethora of reports followed
at numerous meetings, in brief reports in veterinary journals
and in the news media. During the period between 1979 and
1983 the basic pathogenesis was determined (Carpenter et al.,
1980; Robinson et al., 1980; Pollock, 1982; Macartney et al.,
1984; Carman and Povey, 1985; Meunier et al., 1985) and the
immune response of dogs to the natural infection and various
candidate vaccines was described (Chappuis and Duret, 1980;
Pollock and Carmichael, 1982; Carmichael et al., 1983).
Fortunately, the Baker Institute had available for study a
kennel of SPF Beagles maintained in strict isolation.
In 1980, we were fortunate to attract Colin Parrish as a
graduate student. He rst become acquainted with CPV-2 in
his home country, New Zealand, and had developed an
interest in this novel virus (Parrish et al., 1980). Upon his
arrival, Colin gazed about the laboratory and saw mainly
dogs, serological equipment, and dog faeces. He quickly
declared: This is not what I came here to study I want to
know about the virus, the relationships between genetic and
structural properties and the mechanism how CPV-2 evolved
to infect dogs and cause disease!. This required taking up the
methods of modern molecular virology, which neither my
laboratory nor I was equipped to do. It is evident that Colin,
together with his students and colleagues, has achieved a major
portion of his original goal and is now, without a doubt, The
Leader of the Pack. He understood that only the lead sled
dog enjoys the change in scenery.
This commentary will call to mind the uncommon experi-
ence of being on the threshold of discovery when a new
pandemic viral disease came into view, and the sense of
satisfaction in achieving a general understanding of its nature
and accomplishing the means for its control within a period of
305
about 5 years. It also is hoped that recalling some of the
principal events in history of CPV-2, and its variants, will
illustrate that modern virology, as well as the collegial spirit
that prevailed, allowed exceptionally rapid progress in recog-
nizing the nature of the causal virus, the development of rapid
diagnostic tests, elucidation of the basic mode of pathogenesis
and the development and commercialization of eective
vaccines. Moreover, within a period of <5 years, the essential
nature of CPV-2 and its relationship to the other parvoviruses
of carnivores was established in large part through the
research eorts of Colin Parrish and his students and
colleagues worldwide with who he has worked in close
partnership. Of course, important work was carried out
independently in several dierent laboratories.
The following account of CPV-2 will not be strictly
chronological but, to some extent, topical since discovery does
not follow an uninterrupted path.
The Canine Disease Recognition and Control
As noted earlier, CPV-2 was rst recognized in the late summer
of 1978. The disease was rst reported from the USA (Appel
et al., 1978), but Australian and European scientists had
recognized it almost simultaneously. Serological studies (Schw-
ers et al., 1979) indicated that the virus was present in Europe
in 1976; however, Koptopoulos et al. (1986) reported that
antibodies which inhibited haemagglutination and neutralized
CPV-2 were found in dog sera from Greece in 1974. However,
the authors remarked that their results were most likely non-
specic and possibly because of infection with a related
parvovirus from another species perhaps an evolving
antecedent to CPV?
As already noted, within a few weeks following the initial
isolation of CPV-2 it was found by conventional serology that
the novel dog parvovirus was very similar to FPV and other
parvoviruses that cause enteritis in mink, raccoons, as well as
certain other carnivore species.
Initial cases were characterized by myocarditis in pups and a
mucoid, sometimes bloody, diarrhoea. Although untold
thousands (millions?) of dogs were aected worldwide, the
overall mortality appears to have been relatively low, except in
pups <34 months old. Unfortunately, little broadly based
epidemiological data are available; if the overall mortality in
the USA had been 2%, then over 1 million dead dogs would
have been observed. I do not believe that this was the case. We
shall never know.
By 1980, the disease had spread worldwide because of the
movement of dogs, or their owners, in transit by air, land or
sea. The principal source, other than dogs, was faecal material
on shoes and clothes parvoviruses are highly contagious and
stable. National and international mail also may have served
as a vector.
Pandemonium prevailed for about 2 years among dog
owners and veterinarians until the nature of the canine disease
and its pathogenesis became claried. Baker Institute scientists
answered more than 10 000 telephone calls from veterinarians
and dog owners between August 1978 and the end of 1980.
Also, the news media had a eld day reporting outbreaks,
reports that often created extreme apprehension because of
sensational coverage and fabricated myths.
Many investigators made important contributions to the
basic pathology and pathogenesis of CPV-2 within a short time
306 L. E. Carmichael

Table 3. Contributions to
Disease form Authors* CPV-2 pathology and pathogenesis
I. Pathology
Enteric Atwell A.B, and Kelly W, Carman P.S. and Povey R.C,
Cooper B.J. et al., Harcourt R.A. et al., Kelly W.R, Lenghaus C.
and Studdert M.J, McAdaragh J.P, et al., Muenier P.C. et al.,
Nelson D.T. et al., OSullivan G. et al., Parrish C.R. et al.,
Pletcher J.M. et al., Potgeiter L.N.D. et al., Robinson W.F. et al.,
Walker S.T. et al., Yasoshima A. et al., and others.
Myocardial Bastianello S.S, Burren V.S, Cammarata G. et al.,
Carpenter J.L. et al., Robinson W.F, Ingh Th..SGAM
van den et al., Harcourt R.A. et al., Hayes M.A. et al.,
Huxtable C.R. and Pass D.A, Lenghaus C. et al., Mason K.V.
and Mason S.M, Meunier P.C. et al., Mulvey J..J. et al.,
Rensburg I.B.J. et al.
Other (e.g. bone marrow, brain) Agungpriyono D.R. et al., Boosinger T.R. et al., Brock K.V. et al.,
Johnson B.J. and Castro A.E, Otto C.M. et al., Cohn L.A. et al.
II. Pathogenesis (general)
Route of infection and Appel M.J.G. et al., Atwell R.B. and Kelly W.R, Carman P.S.
viral shedding and Povey R.C., Carmichael L.E, Joubert J.J. and Pollock R.H.V,
McAdaragh L.P. et al., McCartney L. et al., OSullivan G. et al.,
Pollock R.H.V, Potgeiter L.N.D. et al., Robinson W.F. et al.,
Studdert M.J. et al., Wilcox G.E. and Flower R.L.P, and others
Sites of viral replication in dogs Ahrens M. and Krauss H, Appel M.J.G. Scott F.W.
and Carmichael L.E, Vlemmas I. et al., Carman P.S.
and Povey R.C, Azeteka M. et al., Cooper B.J. et al.,
McCartney L. et al., Muenier, P.C. (thesis, 1983),
Muenier P.C. et al., Nho W.G. Sur J.H. and Kim SB,
Robinson W.F. et al., Teramoto Y.A. et al.,

*References may be found by author search in PubMed (National Library of Medicine, PHS, NIH, USA).

following recognition of the disease (Table 3). Principal sites of
viral growth in the dog were identied and transmission
studies revealed the faeces as the principal mode of transmis-
sion. Later, sequential in situ hybridization studies (Peters,
1996) demonstrated that the initiation of CPV infection in
dogs occurs primarily in pharyngeal lymphoid cells and not in
intestinal M cells, as suggested earlier (Carman and Povey,
1985).
The control of CPV by vaccination proceeded through a
series of strategies heterologous inactivated or live FPV/mink
enteritis virus (MEV), inactivated CPV-2, modied live CPV-2
or CPV-2a, -b. During the rst 3 years after CPV came into
view, attempts to control the disease with vaccines were
uncertain and chaos prevailed. Initially, some vaccines provi-
ded variable degrees of protection; however, others, such as
commercial MEV vaccines, were generally ineective, but they
made large prots for some veterinarians. There was a lack of
immune response data, and the availability of vaccines that
would protect and interrupt viral transmission. Myths
ourished and recommendations were based mainly on
intuition until the principal factors that interfere with success-
ful vaccination were understood especially, the role of
maternal antibodies and the capacity of CPV to mutate during
passage in cell cultures.
With the early recognition of the close relationship between
CPV-2 and FPV, heterologous (FPV/MEV) vaccines were
rapidly deployed; but the commercial FPV or MEV vaccines
(inactivated or live virus) then used provided unreliable
protection to pups. Studies between 1979 and 1981 revealed
substantial variation in the ecacy of commercial FPV
vaccines for dogs and cats (Pollock and Carmichael, 1983).
Inactivated vaccines were only marginally eective and,
importantly, they failed to interrupt transmission of the virus.
Pollock also veried restricted replication of FPV in dogs by
the parenteral, but not the oral route of inoculation and he
demonstrated a strong immune response to an experimental
FPV vaccine (105.7 TCD50), as well as to certain (but not all)
commercial products tested. It was then determined that
eective immunization of dogs with live FPV vaccines required
at least 1000 times the cat minimum infectious dose; strain
dierences also seemed important. Notwithstanding, an
experimental basis was established for the use of FPV while
homologous (CPV-2) vaccines were under development.
Extensive studies during the 19791980 period showed that
FPV was safe for dogs and was not shed.
The use of live FPV vaccines was not without controversy
since several individuals were strongly opposed to their use for
a variety of reasons. A few were opposed on the general
principal that live virus vaccines were inherently dangerous;
others alleged that CPV-2 had evolved from FPV vaccines and
that their irresponsible use in dogs might create additional
undesirable consequences. One distinguished investigator
asserted that FPV given to dogs might mutate further,
implying that humans might ultimately suer infection. This
placed substantial pressure on those engaged in the develop-
ment of safe and ecacious vaccines. A great deal of work was
done to address those concerns, but uncertainty continued to
persist. Fortunately, in the fullness of time, those concerns
proved unfounded since Truyen, later, unambiguously dem-
onstrated that CPV-2 did not arise directly from FPV or from
a FPV vaccine (Truyen et al., 1998).
CPV-2 cases declined during the 19801981 period as a
consequence of the herd immunity resulting from natural
infection and the widespread use of vaccines. It should be
noted that the principal virus circulating in the dog population
at that time was CPV-2. Vaccination of dogs was extensive
during that period and, doubtless, had a benecial eect. Live
vaccines were recommended by most specialists since they had
An Annotated Historical Account of Canine Parvovirus
proved safe in laboratory and eld trials, and immunized pups
at an earlier age than did inactivated vaccines. Importantly,
live virus vaccines interrupted the transmission of virulent
virus. Notwithstanding, several commercial, live (CPV-2)
vaccines were shown to have poor ecacy in dogs. The
principal reason was then discovered rapid mutation of CPV
occurred during the passage of seed virus in cell cultures (feline
cells were commonly used) with the subsequent accumulation
of mutants that failed to replicate eciently in dogs and
provoke an adequate immune response (Carmichael, 1999).
Some homologous vaccines with exceptionally high titres (in
feline cells) had minimum immunizing doses greater than 105
within a year of their licensing for use in dogs. Thus, the viral
titre of a vaccine, per se, had little meaning with respect to the
capacity to immunize. Fortunately, vaccines have greatly
improved and veterinarians have become aware of the critical
role of maternal antibodies that interfere with natural infec-
tion, and vaccination.
During the 19811982 period veterinarians in the USA, and
other countries, reported outbreaks of exceptionally severe
disease in both vaccinated and unvaccinated dogs. Pups often
collapsed suddenly in a shock-like state and died, with or
without enteric signs. Many pups also developed an acute,
rapidly progressing illness with exceptionally severe haemor-
rhagic enteritis that was not commonly seen in the initial
outbreaks. In addition, veterinarians reported poor responses
of sick dogs to treatment with intravenous uids, a very
eective treatment during the period 19791980. Moreover,
SPF dogs in the laboratory became severely ill after oralnasal
exposure to a virus isolated by Dr Ron Schultz (University of
Wisconsin) from a 1981 outbreak. That virus was subsequently
identied as CPV-2a. A signicant problem encountered by
those who studied vaccines was the great diculty in produ-
cing clinical disease in SPF pups with the original virus for
they developed relatively mild or no illness after inoculation
with the original 19781979 isolates. In contrast, the disease
caused by the 1981 virus, and subsequent isolates, was
signicantly dierent in other ways from that produced by
the original virus. Pups commonly died in a shock-like state tides were described (Paradiso et al., 1982), but the NS-2
after an exceptionally brief (45 day) incubation period.
Surprisingly, faecal infectivity titres (TCD50) of sick dogs
infected with the 1981 isolates were much lower than titres in
the faeces of dogs infected with the original virus; however,
faecal haemagglutinin (HA) titres were much higher. Faecal
HA titres of the original CPV-2 were rarely higher than
1 : 5000. In contrast, faecal HA titres of dogs infected with the
19811982 viruses were commonly 1 million at the peak of
viral shedding.
It was about that time that the rst mutation of CPV-
2 CPV-2a occurred a change that was conrmed in 1984,
after a panel of monoclonal antibodies (Mabs) had been
developed (Parrish and Carmichael, 1983). Subsequently, those
Mabs served scientists throughout the world to identify the
CPV types that emerged around 1980; they also have been
invaluable in determining the antigenic structure of CPV and its
variants, as well as to chart the evolutionary history of CPV.
Several diagnostic tests have been developed during the
period 1978 through the present time for detecting virus and
for serology. They are too numerous to discuss here, but the
ones most commonly used are haemagglutination, commercial
membrane ELISA kits and, for specialized laboratories, the
polymerase chain reaction (PCR) (Table 4). The haemagglu-
307
Table 4. Diagnostic assays for canine parvovirus
Virus Antibodies
Electron microscopy (1978 ) Haemagglutination-inhibition (1979)
Immunouorescence (1978 ) Virus neutralization (1979)
Virus isolation (1978 ) Indirect immunouorescence (1981)
Stool haemagglutination Single radial haemolysis (1981)
(1980 )
Latex agglutination (1980 ) ELISA (1985 )
ELISA (1983 ) ELISA BioGal kit (1996)
Membrane ELISA (1994 )
PCR (1995 )
Coagglutination (1998)
Nested-PCR (2004)
tination-inhibition (HI) and IFA tests are commonly used by
clinicians for serology; however, the IFA test is less sensitive
and has not been correlated with immunity. An ELISA test for
use in clinics to determine antibody titres (Galed Labs,
Kibbutz Galed, Israel; Synbiotics, San Diego, CA, USA) has
had some application since test results correlated with the HI
test. However, many consider the quantitative ELISA test for
antibodies (BioGaled, Kibbutz Galed, Israel) time-consuming,
at least for individual samples. The TiterChek (Synbiotics)
ELISA is rapid and simple to perform, but gives only positive
or negative results.
Basic Properties of CPV
In 1978, most investigators were quick to realize that a
parvovirus was the cause of the widespread outbreaks in dogs.
Parvoviruses were well known at the time and the novel-dog
virus, like Humpty Dumpty, was recognized initially by its
size and shape.
Soon afterward, studies of the basic properties of CPV-2 and
its relationship to FPV/MEV were initiated in a series of
papers published between 1981 and 1985. In that series of
reports, CPV-2 DNA and the three major structural polypep-
transcripts were not characterized until 10 years later (Wang
et al., 1998). Solon Rhode 3d rst determined the complete
nucleotide sequence of the major capsid protein gene (Rhode,
1985), which was later conrmed and amended by others
(Reed et al., 1988; Parrish et al., 1991). Initial restriction site
mapping also demonstrated a close relationship between CPV-
2, FPV and MEV; however, analysis of the restriction maps
and serological comparisons indicated that CPV diered from
those viruses (McMaster et al., 1981; Tratschin et al., 1982).
At that time, it appeared to several individuals that a closer
relationship existed between CPV-2 and vaccinal FPV. Great
controversy then arose over whether CPV-2 had evolved as a
direct mutant of FPV, or from an FPV vaccine. As mentioned
before, this was not resolved until papers, published between
1995 and 1998, proved that CPV-2 did not emerge as a direct
variant of FPV or a FPV vaccine virus (Truyen et al., 1998).
Important and rapid developments occurred after 1984.
Parrish had developed a large number of Mabs to CPV-2, FPV
and MEV that revealed unique and shared epitopes between
those viruses (Parrish et al., 1984). Using genomic recombi-
nation in concert with epitope mapping, and then comparing
biological properties and the host-cell range of the recombi-
nants, the restriction sites that indicated dierences between
308
Table 5. Major contributors to canine parvovirology
Institution
Baker Institute, College of Veter-
inary Medicine, Cornell University
USA
Baker Institute, College of Veter-
inary Medicine, Cornell University
USA
Baker Institute, College of Veter-
inary Medicine, Cornell University
USA
L. Maxmillians University/Univer-
sity of Leipzig, Germany
Department of Biological Sciences,
Purdue University, USA
Ingenasa, Madrid, Spain
Kyoritsu Corporation, University
of Tokyo, Japan
Faculty of Veterinary Medicine,
University of Bari, Italy
NIPHIP, Bildhoven, The Nether-
lands
ID-DLO, Lilystad, The Nether-
lands
University of Tokyo, Japan
Department of Biological Sciences,
University of Jyvaskyla, Finland
Obihiro University, Hokkaido,
Japan
National Veterinary Institute,
Helsinki, Finland
University of Guelph, Guelph,
Canada
University of Alabama, USA
Swedish University of Agricultual
Sciences, Uppsala, Sweden
University of Wisconsin, Veterin-
ary Pathobiology, USA
School of Veterinary Science, Uni-
versity of Melbourne, Vicoria,
Australia
University of Bern, Switzerland
James Cook University, Queens-
land, Australia
Laboratory principals
Parrish C.R. et al.: Tresnan DP, Chang
SF, Yuan W, Parker J, Palermo L, Gru-
enberg A, Truyen U, Huer, K, Strass-
heim M.L, Weichert W
Carmichael L.E, et al.: Pollock R.H.V,
Joubert J..J. Peters, D
Appel, M.J.G Meunier P, Greisen, H
Truyen U, et al.
Rossmann M.G, Chapman M.S, Ag-
bandje-McKenna M, Tsao L.M, Luo M,
et al.
Casal J.I, et al., with Lilystad, The Neth-
erlands
Mochizuki M, Nakamura M, Ikeda Y,
et al.
Buonavoglia C, Pratelli A, Decaro A,
Cavelli A, Martella V, Tempesta M et al.
Rimmelzwann G.F, et al.
Langeveld J.P, et al.
Hirasawa T, et al.
Vihinen-Ranta M, Suikkanen S., et al.
Horiuchi M, Goto H, et al.
Veijalainen P, Neuvonen E, et al.
Carman P.S, Povey R.C
Basak A.S, et al.
Klingeborn B, Olson P, Hedhammar P-A,
et al.
Schultz R.D, et al.
Lenghaus C, Studdert M.J, Martyn J.C,
et al.
Siegl G, McMaster GK, Tratschin J.D,
Kronauer G., et al.)
Smith J.R, Johnson R.H, Campbell R.S,
et al.
L. E. Carmichael
Papers 10 Research (time span)
58 Evolution, monoclonal antibodies; host range
determinants; antigenic structure; virus-cell
interactions; sequence variants, etc. 1982
2005
27 Vaccine development (MLV; FPV), immune
response; clinical disease (exptl); pathogene-
sis; diagnostic tests (HA-HI); seroprevalence.
19792002
10 Pathogenesis/pathology; wildlife host range;
inactivated vaccine development 19791997
20 Characterization feline host range; evolution;
PCRembedded tissues; antigenic analysis;
CPV-2a,b cats; types wild carnivores, etc.
19922005
12 Fine structure of CPV three-dimensional
structure; X-ray crystallography, surface
mapping 19882003
19 Chimeric plant viruses; peptide vaccines/host
responses; neutralizing epitopes; CPV types/
Spain; recombinant vaccine 19912002
17 Antigenic/genomic variants; epidemiology;
CPV-2a in cats; evolution; novel variants;
monoclonal abs; feline host range 19842004
19 Immune response, vaccine evaluation, mater-
nal antibody interference, clinical studies,
intranasal vaccination, diagnostic methods
(PCR), sequence analysis CPV variants (It.)
19832005
10 Diagnostic methods; monoclonal abs, anti-
idiotype abs; synthetic peptides, B-cell epi-
topes 19912001
10 New generation vaccines: synthetic peptide,
plant-derived edible, B-cell epitopes, protec-
tion studies 19912002
8 Viral detection; n-PCR; genomic analysis;
seroprevalence (Jap); clinical studies. 1981
1996
8 Virus-cell interactions, mechanism entrance,
cytoplasmic tracking, release; role recycling
endosomes 19962003
7 Inf. DNA clone, host specicity, host range
determinant mapping, epitope mapping 1991
1994
8 Diagnostic tests; characterization isolates
from bluefoxes, raccoon dogs. Detection CPV
antigens with antibodies to synthetic peptides
19962003
5 Pathogenesis in dogs, vaccine response
(MEV/FPV/CPV), Comparisons viral pro-
tein. 19801985
4 Polarized cell entry pathways, attachment
peptide. 19881994
5 Diagnostic tests; vaccine responses/evaluation
19822000
6 Serosurveys, vaccine evaluation 19872000
5 Clinical, pathology myocarditis-generalized
disease, diagnosis, epidemiology (Aust), NT
sequence FPV; relationships FPV/CPV 1980
1990
4 Relationship CPV to FPV/MEV, wild and
vaccinal FPV, R-enzyme analysis. (major re-
views of CPV and other parvoviruses) 1981
1991
3 Inactivated vaccine development; diagnosis
(ELISA) Commentaries on vaccination
(Johnson) 19811986
An Annotated Historical Account of Canine Parvovirus
CPV and FPV/MEV were determined (Parrish and Carmi-
chael, 1983). In subsequent studies most changes were found
on, or within one amino acid of the capsid surface. This
methodology also was used, in concert with escape mutants, to
map important functional sites on the viral capsid, e.g. host-
cell determinants, red-cell binding (haemagglutination) and
host-cell tropism, which provided insight into the mechanism
of the evolution of CPV-2.
Colin Parrish had a serendipitous encounter with Michael
Rossmann at the 1986 Meeting of the American Society for
Virology; from then on Parrishs two-dimensional approach
took on a third dimension, for changes could be mapped on
the viral three-dimensional structure. It took about a year until
a method was perfected to crystallize CPV in order to obtain
X-ray crystallographic images (Luo et al., 1988). The condi-
tions that yielded crystals were very exact and it took about
2 weeks to grow them. In 1991, the three-dimensional atomic
structure of CPV and the structural motif of the major capsid
protein (VP-2) was described in a classical paper by Jun
Tsao and her colleagues (Tsao et al., 1991). The canyons,
dimples and spikes that form the surface topography were
illustrated and a two-dimensional road map of the amino acid
residues that comprise the viruss surface within a single
icosahedral unit was constructed. The roadmap, illustrated by
Jean-Yves Sgro (Institute of Molecular Virology, University of
Wisconsin, Madison, WI, USA) became the logo for Parrishs
laboratory and it embellished T-shirts worn by the technicians
and students. The roadmap was critical in relating genomic
changes to changes in the amino acid structure of the viral
capsid and identifying the surface epitopes. Subsequently,
several other investigators utilized the roadmap to study CPV-
2 and its variants. The roadmap also was an important tool
that facilitated construction of the evolutionary pathway taken
by CPV-2 CPV-2a and the other variants that emerged
subsequently.
Evolutionary Changes in CPV-2 and Their Signicance
With the exception of Aleutian Mink Disease virus and the
MVC, the parvoviruses that infect and cause disease in
carnivores are approximately 99% homologous in their
genomic sequences and they are all closely related antigeni-
cally. The principal dierence is in their in vitro and in vivo host
ranges. Those viruses have been informally grouped within
the feline parvovirus subgroup, probably because FPV was
the rst member recognized. Although the viruses within the
subgroup may infect more than one species, they are named
for the host in which natural disease occurs. When a
phylogenetic tree that encompasses all the viruses within the
subgroup is eventually completed, a more suitable name might
be the carnivore parvovirus subgroup.
The antigenic variant (CPV-2a) that emerged about 1979
diered from the original CPV-2 in three informative AA
changes in the capsid protein (VP2) which resulted in antigenic
change (Parrish et al., 1988a,b). The biological eects of the
genomic changes were extraordinary, as mentioned earlier.
Not only was the pathogenesis and mode of viral growth in
dogs aected, but CPV-2, which did not originally infect cats,
mutated to CPV-a and, around 1984, to CPV-2b by a
nucleotide substitution that resulted in a further antigenic
change (Parrish et al., 1991; reviewed in Steinel et al., 2001).
These two viruses are now the predominant types, but their
309
geographical locations dier. The original CPV-2 disappeared
around 1981. It should be noted that there are no known
consequences as regards immunization new vaccines were
not required to protect dogs because of the antigenic changes.
(Carmichael, 1999) Nevertheless, certain commercial produc-
ers of CPV vaccines spuriously utilized the evolutionary data
to account for poor vaccine ecacy.
Thus, within about 8 years after it had emerged, CPV-2 had
undergone evolutionary change, including an extended host
range it acquired the ability to infect cats. CPVs with
additional single nucleotide substitutions have been reported
in Asia and Europe (Mochizuki et al., 1996; Horiuchi et al.,
1998; Ikeda et al., 2000; Truyen et al., 2000; Battilani et al.,
2001; Martella et al., 2004) The new antigenic types also have
been found in certain wild carnivores (Steinel et al., 2001).
In a recent, and signicant, paper Shackelton et al. (2005),
analysed a large number of isolates collected from several
countries over the period since CPV-2 rst emerged. Her data
suggests that CPV emerged at least 10 years before the clinical
disease was recognized. It was deduced that benecial muta-
tions (to the virus) had accumulated during that period until a
virus emerged from an unknown source that infected a new
host (the dog) and acquired the ability to spread. After a
period of adaptation, the virus became highly infectious for
dogs, resulting in the pandemic that became evident in 1978
1979. Recombination did not appear to play an evolutionary
role; instead, the slower evolutionary process involved a high
rate of accumulation of critical amino acid substitutions
through mutations in the major capsid gene, some which were
benecial to virus survival. In addition, Shackeltons study
illustrated the rapid rate at which parvoviruses accumulate
mutations in vivo-similar to observations made in studies on
CPV-2 vaccinal virus, where mutations were found to accu-
mulate rapidly during passage in tissue culture (Badgett et al.,
2002). Nucleotide substitutions in CPV continue to be
observed, but their biological signicance is not known. It
seems clear, however, that the major impact on dogs was the
ve or six amino acid changes that occurred during the
evolution of CPV-2 to CPV-2a.
Finally, in a series of important papers, John Parker, Colin
Parrish, Karsten Hueer and, more recently, Laura Palermo
demonstrated that the transferrin receptor (TfR) plays a
decisive role in the determination whether an animal becomes
infected, or not (Parker et al., 2001; Hueer et al., 2003;
Hueer and Parrish, 2003; Palermo et al., 2003).
In Conclusion
This brief review of the history of CPV-2 has been an
annotated account of the development of knowledge of the
most recently emerged canine virus, CPV-2. Because of time
constraints, I have avoided extensive discussion of vaccines, the
area in which I had been most active, and omitted discussion of
epidemiology and the impact of CPV-2 on wildlife species.
Instead, I have attempted to point out some of the major
discoveries and events that have led to our general knowledge
of CPV-2, the disease it causes and its evolution. As stated in
the beginning of this account, many scientists and veterinarians
who have not been cited have made signicant contributions;
yet, no individual has provided as extensive and consequential
knowledge to our understanding of the virus and its evolution
as has Dr Colin Parrish and his students and colleagues.
310
Colin has followed a teaching of Schiller, who lived briey in
Leipzig (1785). Shiller believed that Science should be a useful
cow, which provides some butter, not just a holy cow:
Dem einem ist sie die hochste, die alles beherrsc-
hendende Gottin, dem anderen eine tuchtige Kuh, die
ihn mit Butter versorgt
I think that the parvovirus story illustrates what can be
accomplished in a brief period by the concerted eorts of both
applied and basic scientists whose common goals are to
understand a disease, devise means for its control, characterize
the nature of the causal agent and chart the mechanism of its
evolution.
Finally, I wish to acknowledge those colleagues who have
made major contributions to the biology of CPV-2, the disease
it causes and to its control (Table 5).
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