Vol. 19, No.
2 February 1997
Continuing Education Article
FOCAL POINT
★The high-titer, low-passage
vaccines elicit a more effective
immune response in the face of
maternal antibodies.
KEY FACTS
■ Two new subtypes of canine
parvovirus 2 (CPV-2) have
emerged; these subtypes provide
complete crossprotective
immunity.
■ CPV-2a and CPV-2b have an
increased affinity for cats.
■ The highest incidence of CPV
infection continues to occur in
exposed puppies with waning
maternal antibody that interferes
with active immunization.
■ Reactions after parvovirus
vaccination are rare and should
be anticipated and treated as
soon as they arise.
Canine Parvovirus.
Part I. Pathogenesis
and Vaccination*
Auburn University
Saralyn Smith-Carr, DVM, PhD
Douglass K. Macintire, DVM, MS
Larry J. Swango, DVM, PhD
P
arvoviruses replicate only in cells synthesizing DNA (i.e., rapidly divid-
ing cells). This characteristic leads to the clinical signs of hemorrhagic
enteritis. In susceptible canine populations, parvovirus infection most of-
ten occurs as a severe systemic and even life-threatening illness.
Passive immunity from maternal antibodies blocks the immune response in
puppies but does not prevent infection. Puppies younger than 16 weeks are
therefore highly susceptible. Infection leads to hemorrhagic diarrhea and sep-
ticemia due to unrestricted viral proliferation and cell destruction in bone mar-
row, lymphoid tissue, and intestinal crypts. Newly available vaccines may stim-
ulate an adequate immune response in the face of maternal antibody.
Parvoviral disease may thus be prevented in this highly susceptible population.
Part II of this two-part presentation will discuss diagnosis and treatment of ca-
nine parvovirus infection.
PARVOVIRIDAE
Parvoviruses (Parvoviridae) are small, nonenveloped viruses. They are the
only group of mammalian viruses with single-stranded DNA. After entering
the cell, the parvovirus is carried or travels to the nucleus via endosomes to
replicate.1 Parvoviruses replicate only in cells synthesizing DNA and use the
cell’s machinery to produce viral rather than cellular proteins, thus leading to
the death of the cell. Parvoviruses are hardy, withstanding a wide range of tem-
peratures and disinfectants.2,3 However, they can be inactivated by sodium
hypochlorite, formalin, and sunlight.3,4
Parvoviruses in Dogs
Defective (adeno-associated) and nondefective (or autonomous) parvoviruses
are found in dogs. The adeno-associated parvoviruses were discovered as con-
taminants of stock cultures of canine infectious hepatitis virus. These viruses
cannot replicate or assemble mature viral particles without enzymes produced
*Part II of this presentation appears in the March 1997 (Vol. 19, No. 3) issue of Com-
pendium.
Small Animal
by adenovirus infection of cells. The autonomous par-
voviruses can replicate without the adenovirus enzymes
and are pathogenic.
The first autonomous canine parvovirus (CPV-1) was
isolated in 1967 from the feces of normal dogs.5 This
virus was first named the minute virus of canine
(MVC) because of its small size.6 This virus was diffi-
cult to grow in tissue culture. Its growth could not be
supported by other canine cell lines or cell lines from
other species. The virus could only be propagated in
vitro in one continuous cell line called Walter Reed Ca-
nine Cell (WRCC).6 This cell line was developed from
a subdermoid cyst of an irradiated dog.
Before 1985, MVC or CPV-1 was considered non-
pathogenic. Since then, however, it has been reported
to cause transient diarrhea in puppies between the ages
of 5 and 21 days. 7 Oronasal exposure of specific-
pathogen–free neonatal puppies to CPV-1 has been
observed to cause mild to severe respiratory disease,
including bronchitis, interstitial disease, and lym-
phadenitis with mild to absent small intestinal le-
sions.8
Experimental inoculation of CPV-1 into pregnant
bitches resulted in fetal death, abortion, and respiratory
distress and death of puppies born to infected bitches.
This finding was significant. Unlike in other species,
parvoviruses had not previously been recognized as a
cause of poor reproductive performance (abortion and
fetal death) in dogs.
Parvovirus was isolated from the thymus and intesti-
nal microvilli tips of puppies infected in utero.8 The
MVC or CPV-1 differs in its in vitro host cell range,
hemagglutination, and antigenic and genomic proper-
ties from the parvovirus that causes hemorrhagic diar-
rhea.
The parvovirus causing hemorrhagic diarrhea was
originally named canine parvovirus 2 (CPV-2). It
emerged in 1978 in the United States. The earliest re-
port of a detectable titer is from Greece in 1974.9 The
first evidence of infection by CPV-2 was seen in serum
collected from dogs in Belgium in 1976, the Nether-
lands in 1977, Denmark, Australia, and United States
in 1978, and Japan in 1979.10 The CPV-2 variant is be-
lieved to have emerged from feline panleukopenia virus
(FPV) or from a parvovirus of another wildlife species
(possibly mink enteritis virus [MEV], raccoon par-
vovirus [RPV], or fox parvovirus) because it has ge-
nomic and antigenic similarities to these viruses.11,12
Between 1979 and 1982, less of the original strain of
CPV-2 was isolated from infected dogs. It was replaced
by another strain (CPV-2a), which was considered
more virulent because it replicated more efficiently in
dogs and other wild canids. 9 Later, another variant
CPV-2 ■ FPV ■ CPV-2a ■ CPV-2b
The Compendium February 1997
(CPV-2b) evolved. More than 80% of the isolates in
the United States today are CPV-2b.13
The CPV-2a and CPV-2b subtypes can be distin-
guished by their restriction endonuclease patterns and
reactivity with specific monoclonal antibodies.13 Re-
striction endonucleases are bacterial enzymes that can
be used to digest viral DNA. The size and number of
the digested DNA fragments (digests) vary according to
the particular restriction endonuclease and virus that
are used.
Digests are subjected to an electrical field (elec-
trophoresis) while placed on polyacrylamide gel that
supports and allows movement of the ensuing DNA
fragments. The viral DNA fragments migrate according
to size and separate. This is the first step in determining
sequence patterns or maps of viral genomes. The map
or sequence analysis that is generated can be used to
compare closely related organisms.
Parvoviruses in Cats
In addition to the antigenic variation, CPV-2a and
-2b are reported to differ from CPV-2 in their affinity
for host cells. Whereas CPV-2a and CPV-2b can repli-
cate and produce high titers in lymphoid and intestinal
cells of inoculated cats, CPV-2 could not. The isolation
of CPV-2a and CPV-2b from cats suggested that both
of these variants might cause clinical disease in cats as
well as dogs.
Ten percent of parvovirus isolates from cats with nat-
urally occurring disease are antigenically identical to
CPV-2a or -2b.14 Furthermore, it is postulated that the
newer isolates of CPV may further adapt to cats and
eventually replace FPV in the feline population.14 The
rapid emergence of new subtypes of CPV results from
small revisions in the viral genome in a region responsi-
ble for the virus capsid, where three protein monomers
interact.14 The capsid is responsible for the changes in
cell infectivity and the in vivo host range of the
virus.12–14
INCIDENCE AND PREDISPOSING FACTORS
Initial outbreaks of parvovirus in dogs were charac-
terized by high morbidity and mortality in all age
groups. Currently, the disease is more commonly en-
countered in puppies from 6 weeks to 6 months of age.
Most adult dogs have become immune through vacci-
nation or natural infection. This immunity is passed on
to newborn puppies via maternal antibodies.
Puppies become susceptible to viral infection as the
maternal antibody titer declines to nonprotective levels;
and adequate immunization to parvovirus does not oc-
cur during the first year of life. There seems to be a
window of time during which the maternal antibodies
The Compendium February 1997 Small Animal

TABLE I dence that any vaccine can com-

Antibody Titers Capable of Interfering with Active Immunization pletely override interference from
maternal antibody (Table I). The
Serum use of serial vaccinations or vacci-
Interference by Neutralization Hemagglutination nation schedules therefore remains
Maternal Antibody Titer Inhibition Titer a practical approach for maximizing
the probability that puppies will be
Interferes with low-titer attenuated ≥1:2 ≥1:10 immunized during the normal peri-
and inactivated vaccines
od of maternal antibody interfer-
Interferes with high-titer attenuated ≥1:16 ≥1:64 ence.
vaccines The predisposing factors for par-
vovirus infection in puppies are
Interferes with all vaccines but 1:20 1:80
provides protective immunity lack of protective immunity; inter-
nal parasites; and overcrowded, un-
sanitary, and stressful environmen-
block the immune response to CPV vaccine but cannot tal conditions.21 In adult dogs, parvovirus infection is
prevent CPV infection.15,16 usually inapparent, acute, or subacute. Many infections
Maternal antibody titer in puppies varies with are subclinical. Immunity to canine parvovirus caused
amount of colostrum ingested, the serum titer of the by infection or attenuated vaccine is reported to be
mother at whelping, and litter size.15 The CPV-2 titer long lived (>20 months) and perhaps lifelong.22
provided by absorbed colostral antibody is 50% to 60% Certain breeds are reported to be more susceptible to
of the mother’s.15,16 This maternal antibody has a half- the development of parvovirus disease despite antibody
life of about 10 days.15,16 titers considered protective in other breeds21 (see Risk
How long maternal antibody continues to interfere Factors for Canine Parvovirus Infection). Rottweilers,
with CPV vaccines depends on the type of CPV vac- Doberman pinschers, and Labrador retrievers are report-
cine the puppy receives. Less maternal antibody is ed to be more severely affected by parvoviral infection.21
needed to suppress an immune response to an inacti- In one study, signalments associated with increased
vated vaccine than to new-generation, low-passage, risk were immature male Doberman pinschers and rott-
high-titer, modified-live virus (MLV) vaccines. These weilers and mature female springer spaniels.23 Data
vaccines are also better at stimulating an immune re- from the nationwide Veterinary Medical Data Program
sponse during the period of maternal antibody interfer- indicated that Doberman pinschers and rottweilers
ence than are the low-titer MLV vaccines. were at significantly increased risk of CPV enteritis.23
The antibody titer that interferes with immunization The prevalence of von Willebrand’s disease has been
by vaccination varies depending on the serologic suggested to be a predisposing factor in the develop-
method used to measure the titer.15–18 Serum neutraliza- ment of severe bloody diarrhea in some breeds, particu-
tion (SN) titers from 1:2 to 1:16 have been reported to larly Doberman pinschers and rottweilers.20
interfere with vaccination, depending on the type of In a West German study, the breeds at increased risk
vaccine used.15,17,19 High-titer MLV vaccines will gener- were German shepherds and Yorkshire terriers. In this
ate an immune response in most puppies with
SN titers of 1:8 and in some with SN titers of
1:16. A protective SN titer over 1:20 will inter-
Risk Factors for Canine Parvovirus Infection
fere with essentially all CPV vaccines.17,19
Hemagglutination inhibition (HI) titers of Predisposed Breeds Breeds at Decreased Risk
1:80 are usually protective and also interfere Rottweilers Cocker spaniels
with vaccinations.18 However, HI titers of 1:10 Doberman pinschers Toy poodles
have also been reported to interfere with inacti- Labrador retrievers
vated vaccines as well as with low-titer attenuat- German shepherds Months with High Incidence
ed vaccines. 16 The new-generation high-titer
Springer spaniels November, December, and
MLV vaccines induce immune responses in
pups with HI titers equal to or slightly less than American pit bull terriers January (in Germany)
1:80. 20 Yorkshire terriers July, August, and September
Serologic titers are not routinely measured be- (in Canada)
fore vaccination. Furthermore, there is no evi-

SERUM NEUTRALIZATION TITER ■ HEMAGGLUTINATION INHIBITION TITER ■ PARASITES

Small Animal
study, incidence peaked in November, December, and
January and was at a minimum in June, July, and
September.24
In a retrospective study from Canada, rottweilers,
American pit bull terriers, Doberman pinschers, and
German shepherds were at increased risk whereas toy
poodles and cocker spaniels were at decreased risk.25 In
that study, incidence peaked in July, August, and
September. Among dogs older than 6 months, sexually
intact males were twice as likely as sexually intact fe-
males to develop CPV enteritis.25 In all studies, the
population at highest risk was puppies younger than 6
months.
TRANSMISSION
Direct transmission occurs by the fecal–oral route.
Indirect transmission occurs orally through articles con-
taminated by feces. The transport of virus by people or
fomites also contributes to the spread. The virus is
ubiquitous and hardy, withstanding a wide range of
temperatures and environmental conditions. At low
temperatures (<–7°C [<20°F]), virus within feces may
remain infective for months.2,3 Persistence of the virus
in the environment is attributed to the hardiness of the
virus and shedding of virus by subclinically infected
dogs.
Most common disinfectants fail to inactivate canine
parvovirus.2,3 In experiments, the virus is shed in high
titers for 2 weeks after viremia in subclinical and clini-
cal infections.26–29 The months of the year in which the
incidence of clinical disease related to parvovirus is
highest seems to vary geographically. For individual
dogs, the highest risk of parvovirus infection coincides
with the loss of maternal antibody titers in susceptible
puppies and exposure to active virus shedding. Experi-
mental infections have been produced by several routes
(oral, intranasal, and subcutaneous).16,26,27 The incuba-
tion period has been reported to vary from 2 to 14 days
but in most cases is 4 to 7 days after infection.26,27
PATHOGENESIS AND IMMUNE RESPONSE
Experiments have shown that after fecal–oral expo-
sure, the virus replicates in the local lymphoid tissue of
the oropharynx. Viremia ensues, and the virus is trans-
ported to tissues of rapid cell turnover, where it prolif-
erates (days 3 to 5 after experimental infection).
The main factor that determines the severity of dis-
ease appears to be the rate of lymphoid and intestinal
cell turnover. Higher rates of turnover are directly cor-
related with virus replication and cell destruction. In-
creased pathogenicity should therefore correlate with
concurrent intestinal parasitic or viral infection.
Parvovirus exhibits tropism toward tissue with viral
VIRAL SHEDDING ■ INCUBATION ■ TROPISM ■ VIRAL RECEPTORS
The Compendium February 1997
receptors. Therefore, not all rapidly proliferating cell
populations are equally infected. The cells infected in
neonatal puppies are bone marrow, lymphoid tissue, in-
testinal epithelium, and heart. The clinical syndrome in
puppies infected in utero or shortly afterward was char-
acterized by hemorrhagic diarrhea and/or myocarditis
causing sudden death. The myocarditis is rarely seen
today because most neonates are protected by maternal
antibodies.
The cells most often infected in adolescents and
adult dogs are in bone marrow, lymphoid tissue, and
intestinal epithelium. The resulting syndrome seen in
adult dogs is hemorrhagic diarrhea. Feline parvovirus
(panleukopenia virus) exhibits tropism toward the cere-
bellum. However, the cerebellum is not affected in
neonatal puppies with canine parvovirus infection.30
Canine parvovirus replicates within the crypt cells of
the small intestinal villi, thus causing collapse of the in-
testinal epithelium and leading to the characteristic
pathologic lesion of shortening and atrophy of the villi.
During this period of villous atrophy, the small intes-
tine loses its absorptive capacity because the germinal
epithelium that normally replaces the mature epitheli-
um has been destroyed. Because cell turnover is rapid
(1 to 3 days), this loss is usually short-lived. Disease
may be more rapid and severe in animals in which the
intestinal barrier is already compromised by enteric
parasites or viruses.
In experimental infections, virus appears in the feces
by day 3 or 4 after exposure; it may appear later in nat-
ural infections. The virus is then shed in the feces for 1
to 2 weeks. In experiments, virus is not recovered from
feces in tissue culture for more than 2 weeks after oral
exposure.26–29
Electron microscopy shows that virus–antibody com-
plexes occur late in the course of disease and are fre-
quently observed in large clumps. Local intestinal anti-
body response is important in terminating the fecal
excretion of parvovirus.31 Systemic antibody in blood
that passes from the capillaries into the disrupted in-
testinal lumen may terminate viral excretion into feces
and cause false-negative parvovirus antigen test results
in the face of acute infection.
After infection, parvovirus is found mainly in small
intestinal and lymphoid tissue. It has also been recov-
ered from lungs, spleen, liver, kidney, and myocardium.
Immunity to parvovirus develops rapidly. There seems
to be a local and systemic humoral immune response to
parvoviral infection. However, the systemic response is
responsible for protection because the virus invades the
intestinal tract from the bloodstream rather than from
the luminal epithelium.29 Local antibody, although de-
tectable, is considered nonprotective. Circulating anti-
Small Animal
bodies are usually detectable by the time clinical signs
appear.
The systemic antibody response limits viremia and
viral spread. This limitation of viral spread also limits
disease caused by the virus. A rapid immune response
may therefore limit the magnitude and duration of
viremia and result in milder disease and rapid recovery.
PREVENTION AND VACCINATION
A broad group of vaccines is available today for par-
vovirus vaccination. When CPV-2 emerged, only feline
and mink vaccines were available. These have largely
been replaced with attenuated or inactivated canine-
origin products. Canine-origin attenuated vaccines
containing high-titer, low-passage CPV are currently
the vaccines of choice. The term high-titer refers to the
amount of virus in a dose of vaccine.
The amount of virus used in the vaccine is based on
studies that determine virus infectivity, dose range, and
ability to generate an immune response (antigenicity).
These vaccines have a higher amount of virus than pre-
vious vaccines. The term low passage refers to the num-
ber of times that the virus was grown in various tissue
cultures. Passage or growth in tissue culture is used to
decrease the virulence of attenuated vaccines. Virus
grown by fewer passages retains some of its ability to
infect cells but does not cause disease. This quality
makes the vaccine virus more antigenic.
The high-titer, low-passage vaccines cause a more ef-
fective immune response in the face of interfering ma-
ternal antibodies. Some of these vaccines result in
shedding of vaccine virus in the feces and can cause false-
positive fecal antigen results, usually by 5 to 6 days
after vaccination.
Postvaccination reactions (primarily characterized by
facial swelling or local inflammation but occasionally as
severe as anaphylaxis) within 1 to 3 hours after vaccina-
tion have been reported. The reported incidence, ac-
cording to vaccine manufacturers, is less than 1%—de-
pending on the vaccine.
At our clinic, we occasionally observe systemic ana-
phylaxis or facial edema and local inflammation with
wheal formation within 20 minutes to an hour after
vaccination with combination attenuated products. We
have not seen a higher incidence of these reactions with
the newer high-titer, low-passage CPV vaccine products
than with the low-titer combination vaccines used pre-
viously. Nevertheless, the owner should be informed of
the possibility of a reaction when any vaccine is used so
that the puppy or dog will be closely monitored for 1
to 3 hours after vaccination.
Inactivated CPV vaccines induce an immune re-
sponse that is inferior to that generated by attenuated
HIGH TITER ■ ANTIGENICITY ■ LOW PASSAGE ■ POSTVACCINATION REACTIONS
The Compendium February 1997
vaccines. Still, there are instances in which an inactivat-
ed CPV vaccine may be advantageous (e.g. vaccination
of a pregnant dog, a dog with generalized demodicosis,
or a dog in an immunocompromised state) because the
virus in inactivated CPV vaccines does not replicate.
Subunit vaccines that are being developed may generate
a better immune response than inactivated vaccines but
not as good as that elicited by attenuated vaccines.32
These subunit vaccines may not solve the problem of
maternal antibody interference but may offer an alter-
native to inactivated vaccine.32
The subtypes CPV-2, CPV-2a, and CPV-2b vary so
little antigenically that immunity induced by infection
or vaccination with any of the subtypes provides com-
plete crossprotection. Therefore, a vaccine containing a
given subtype of CPV is neither better nor worse than
another vaccine simply because of the subtype. The
CPV vaccine is available in combination or as an indi-
vidual viral vaccination. Many combinations are avail-
able; but canine distemper, parainfluenza, and adeno-
virus 1 and 2 is the usual grouping. Leptospira bacterin
and attenuated or inactivated coronavirus vaccine are
also available in combination vaccines with parvovirus
and the other viruses mentioned above.
Although only one or two doses of vaccine are re-
quired to immunize an immunizable puppy, vaccina-
tion protocols usually recommend that puppies be giv-
en a combination parvovirus vaccine every 2 to 3 weeks
from 6 to 8 weeks of age up until 16 to 18 weeks of age
and then annually. For breeds at high risk, it was rec-
ommended that the vaccination protocol be continued
to 20 weeks or that parvovirus titers be evaluated 2
weeks after the last vaccination.19,21 Further vaccination
protocols for these high-risk groups recommended re-
vaccination twice a year and/or 2 to 3 weeks prior to
presentation to environments of high parvovirus expo-
sure (e.g., dog shows or boarding kennels).
The new-generation, high-titer, low-passage CPV
vaccines may give grounds for reconsidering vaccina-
tion schedules for dogs. Data generated by manufactur-
ers of the new vaccines and by independent investiga-
tors reveal that three doses of vaccine given at 6, 9, and
12 weeks of age are as effective at immunizing puppies
as were the earlier vaccines given at 3-week intervals
through 18 to 20 weeks of age.20,33
Whether annual boosters are needed is controversial.
Serologic testing for level of immunity is not routinely
performed before the annual booster, and there is grow-
ing concern about the possible increase in immune-
mediated disease caused by overvaccination.
There is no scientific justification for giving boosters
more often than annually unless serologic testing shows
lack of protection. In our experience, most boosters fail
Small Animal
to increase the level of immunity. Therefore, the practi-
tioner may opt to perform serologic testing 2 to 3
weeks after the last vaccination of a series, 2 weeks be-
fore presentation to an area of high CPV exposure, or
at the time of annual boosters in order to detect vaccine
failures and prevent disease in animals considered im-
munized (particularly in high-risk breeds).
There is some controversy over the interference of
parvovirus vaccination with canine distemper vaccina-
tion or vice versa. Most canine distemper vaccines tran-
siently decrease the in vitro lymphocyte blastogenic re-
sponse for 10 to 12 days after vaccination. The normal
immune response to parvovirus vaccine occurs 4 to 5
days after vaccination of an immunizable, susceptible
dog.
If a canine distemper virus vaccine is given 7 days be-
fore the parvovirus vaccine, then theoretically it could
interfere with the immune response to the canine par-
vovirus vaccine.19,21 However, previous reports of canine
distemper neuritis caused by simultaneous vaccination
with parvovirus have not been repeatable. Therefore,
combination and/or simultaneous (at two different
sites) canine distemper virus and CPV vaccination
should avoid the theoretical interference with immune
response to vaccination.
There is currently a lack of data comparing the effec-
tiveness of weekly, biweekly, and once-a-month (or ev-
ery 3 weeks) vaccination protocols for immunizable
young dogs. The main cause of vaccine failure with
parvovirus is interference by maternal antibody. The
age of a puppy when maternal antibody has declined to
a noninterfering level and the puppy is immunizable is
hard to predict unless antibody titers are evaluated be-
fore vaccination. Puppy owners should be advised to
avoid environments with possible high parvovirus ex-
posure or in which adult dogs are present until effective
immunization has been achieved.
About the Authors
Drs. Smith-Carr, Macintire, and Swango are affiliated with
the Department of Small Animal Medicine and Surgery,
College of Veterinary Medicine, Auburn University, Alaba-
ma. Dr. Macintire is a Diplomate of the American College
of Veterinary Internal Medicine and the American College
of Veterinary Emergency and Critical Care.
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