Journal of General Virology (2016), 97, 2043–2057 DOI 10.1099/jgv.0.

000540

Review Canine parvovirus: the worldwide occurrence of

Correspondence
Gertrude Thompson
gat1@mail.icav.up.pt
antigenic variants
Carla Miranda1,2 and Gertrude Thompson1,2
1
Department of Veterinary Clinics, Instituto de Ci^
encias Biom
edicas de Abel Salazar (ICBAS),
Universidade do Porto, 4050-313 Porto, Portugal
2
Centro de Investigaç~
ao em Biodiversidade e Recursos Geneticos (CIBIO), InBio, Laboratório
Associado, Universidade do Porto, 4485-661 Vair~
ao, Portugal

The most important enteric virus infecting canids is canine parvovirus type 2 (CPV-2). CPV is the
aetiologic agent of a contagious disease, mainly characterized by clinical gastroenteritis signs in
younger dogs. CPV-2 emerged as a new virus in the late 1970s, which could infect domestic
dogs, and became distributed in the global dog population within 2 years. A few years later, the
virus’s original type was replaced by a new genetic and antigenic variant, called CPV-2a. Around
1984 and 2000, virus variants with the single change to Asp or Glu in the VP2 residue 426 were
detected (sometimes termed CPV-2b and -2c). The genetic and antigenic changes in the
variants have also been correlated with changes in their host range; in particular, in the ability to
replicate in cats and also host range differences in canine and other tissue culture cells. CPV-2
variants have been circulating among wild carnivores and have been well-documented in several
countries around the world. Here, we have reviewed and summarized the current information
about the worldwide distribution and evolution of CPV-2 variants since they emerged, as well as
the host ranges they are associated with.

Introduction
Canine parvovirus type 2 (CPV-2) is one of the most
important enteric pathogens of dogs. This virus is extremely
contagious, causing high morbidity with increased inci-
dence in shelters, pet stores and breeding kennels. The dis-
ease is characterized by a rapid clinical course with death
that can often occur 2–3 days after onset of signs in non-
protected hosts (Carman & Povey, 1985; Parrish, 1995). It
can affect dogs at any age, but severe infection is most com-
mon in puppies between 6 weeks and 6 months of age
(Houston et al., 1996). All breeds are susceptible to the dis-
ease, although the mixed breeds are described to be less sus-
ceptible than many pure-breds. Rottweilers, Doberman
Pinschers, English Springer Spaniels, American Pit Bull Ter-
riers and German Shepherd are the pure-breds that have
been reported with higher risk for CPV enteritis (Glickman
et al., 1985; Houston et al., 1996).
The infection is generally acquired by the faecal-oral route
through the contact with faeces from infected dogs or con-
taminated surfaces. Upon entering the body, the virus affects
mainly mitotically active tissues, such as the lymphoid tissues,
intestinal epithelium and bone marrow, as well as the heart
in neonatal pups. Following an incubation period of 3–
7 days, the disease can be characterized by two clinical forms,
the enteric form that comprises vomiting, haemorrhagic diar-
rhoea, depression, loss of appetite, fever and dehydration in
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younger dogs (Nelson et al., 1979; Carman & Povey, 1985;
Parrish, 1995; Hoelzer et al., 2008a). Myocarditis may be seen
after infection of neonatal puppies, where the clinical signs
are seen a number of weeks after infection (Meunier et al.,
1984; Sime et al., 2015). Canine parvoviral infection is also
characterized by a drop in the white blood cell counts as a
result of the infection of the bone marrow infection and other
lymphoid tissues (Kelly, 1978; Appel et al., 1979).
The main method for controlling the disease in domestic
animals is by vaccination. After the emergence of the dis-
ease, modified live virus vaccines were soon developed,
being the first CPV vaccine available in 1979. The vaccines
appear to be safe and to confer protective immunity allow-
ing much of the disease to be controlled. However, the virus
is still widely distributed in nature, and if pups are not vac-
cinated, and or when maternal antibodies interfere with
their vaccination, they generally become naturally infected
(Parrish, 1999). The evolution of the virus raises questions
about the efficacy of some vaccines, so that an understand-
ing of the variation is required (Truyen, 2006).
Aetiology of CPV-2
Taxonomy
The CPV-2 belongs to the genus Protoparvovirus, member
of the Parvoviridae family, that has been included within the
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C. Miranda and G. Thompson
species Carnivore protoparvovirus 1, together with Feline
panleukopenia virus (FPV), Mink enteritis virus (MEV)
and Raccoon parvovirus (RPV), according to the Interna-
tional Committee on Taxonomy of Viruses (Tijssen et al.,
2011).
Virus structure
Parvoviruses have small (~25 nm diameter), non-enveloped
icosahedral capsids. The three-dimensional structure of
CPV-2, FPV and CPV-2a particles has been determined at
atomic resolution using X-ray crystallography (Tsao et al.,
1991; Agbandje et al., 1993; Xie & Chapman, 1996). The
virus has a linear, single-stranded and negative-sense DNA
genome of ~5200 nucleotides, containing two major open
reading frames (ORFs). One of which encodes the non-
structural proteins NS1 and NS2, and the other two struc-
tural proteins VP1 and VP2. At either end of the genome,
palindromic hairpins of about 150 bases are used in the rep-
lication of the viral DNA (Reed et al., 1988; Parrish, 1999).
The parvoviral capsid contains 60 protein subunits of VP1
(5–6 copies) and VP2 (54–55 copies), and those share a
common structure. The coding regions for the VP1 (727
residues) and VP2 (584 residues) proteins overlap, apart
from a 143 amino acid N-terminal region unique to VP1
(Tsao et al., 1991; Agbandje et al., 1993). The two structural
proteins are produced by alternative splicing of viral
mRNAs (Reed et al., 1988; Wang et al., 1998; Parrish &
Kawaoka, 2005). The VP2 protein can be cleaved near its
N-terminus by host proteases to produce another structural
protein, VP3. The capsid proteins have a highly conserved
central core composed of an eight-stranded, anti-parallel b-
barrel with flexible loops between the b-strands that inter-
act to form most of the capsid surface. The surface features
of the capsid includes a 22 Å long raised region (spike) on
the threefold axes, a 15 Å deep depression (canyon) sur-
rounding cylindrical structures at the fivefold axes, and a
15 Å deep depression (dimple) at the twofold axes. In addi-
tion, the threefold axes are the most antigenic region of the
capsid and serve as a target for neutralizing antibodies
(Tsao et al., 1991; Agbandje et al., 1993).
Virus emergence
In the 1970 s, CPV-2 emerged as a new virus in domestic
dogs. It caused a pandemic disease and spread through
Asia, Australia, New Zealand, the Americas and Europe in
early 1978 (Parrish et al., 1988, 1999). This virus was identi-
fied as CPV-2 to distinguish it from the distantly related
minute virus of canine (MVC) or also known as CPV type 1
(CPV-1) (Carmichael et al., 1994). Molecular clock esti-
mates and phylogenetic studies indicated that CPV-2 likely
emerged a number of years before spreading globally in
dogs in 1978 and 1979 (Parrish et al., 1988; Shackelton
et al., 2005; Hoelzer et al., 2008b). Testing for antibodies in
dog sera showed that the first positive titres in dogs in
Greece and Belgium were reported between 1974 and 1976
(Schwers et al., 1979; Koptopoulos et al., 1986), while the
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first positive sera in the USA, Japan and Australia were
reported early in 1978 (Parrish, 1999). Since that year, the
virus has been ubiquitous in dogs throughout the world
(Parrish, 1999). During 1979, wild coyotes in the USA also
became widely infected (Thomas et al., 1984).
Origin
The phylogenetic relationships between CPV-2 isolates from
dogs and the viruses from cats (FPV), mink (MEV), raccoon
(RPV), raccoon dog (Raccoon dog parvovirus, RDPV) and
blue fox (Blue fox parvovirus, BFPV) showed that all CPVs
derived from a single common ancestor, and that the strains
were mostly similar to viruses from different wildlife animals
including raccoons and foxes (Allison et al., 2012, 2013).
CPV was shown to be related to a virus similar to the long
recognized FPV, but likely not from cats (Truyen et al.,
1995). CPV-2 likely arose when it acquired mutations that
allowed binding to the canine transferrin receptor (TfR)
type-1 (Truyen et al., 1996a; Shackelton et al., 2005; Allison
et al., 2012). Several studies have demonstrated that the TfR
plays a key role in the susceptibility of cells to infection by
these viruses (Hueffer et al., 2003; Palermo et al., 2006).
CPV and FPV are over 98 % identical in DNA sequence,
but have specific host ranges, antigenic and haemagglutina-
tion (HA) properties which are controlled by the capsid
protein gene (Chang et al., 1992; Truyen et al., 1995; Shack-
elton et al., 2005). The successful cross-species viral transfer
and adaptation to the new canine host involved few amino
acid changes in and around the threefold spike (Truyen
et al., 1995). These six genomic changes were sufficient for
CPV-2 to acquire the canine host range, but lost the ability
to replicate in feline host (Chang et al., 1992; Truyen & Par-
rish, 1992). Three differences at VP2 residues 93 (Lys to
Asn), 103 (Val to Ala) and 323 (Asp to Asn) between FPV
and CPV-2 could introduce the canine host range (Chang
et al., 1992; Truyen et al., 1995). The changes of VP2 resi-
dues 80 (Lys to Arg), 564 (Asn to Ser) and 568 (Ala to Gly)
were associated to the loss of ability to replicate in cats
(Truyen et al., 1994) and are shown in Figs 1 and 2. How-
ever, residues 232 (Val to Ile) and 375 (Asp to Asn) also
changed between FPV and CPV-2 sequences. The residue
375 variation was found only in some isolates of the original
strain of CPV-2, and in later CPV variants that residue
reverted to an Asp, suggesting that 375Asn is not critical to
the success of CPV in nature. However, VP2 residue 375
that is located on the side of the threefold spike, this amino
acid together with 323 determines the pH dependence of
HA (Parrish, 1991a, b; Chang et al., 1992).
Emergence of antigenic CPV-2 variants
Antigenic variant CPV-2a
After the detection of CPV-2, in many countries that virus
was replaced around 1980 in the USA by an antigenically
and genetically variant virus, designated CPV-2a. While the
CPV-2 strain was present in the USA, Japan, Belgium and
Journal of General Virology 97
 CPV: the worldwide occurrence of antigenic variants

Australia prior to 1980, it was replaced by the CPV-2a vari-
ant in all of those countries between 1979 and 1982, as well
as, in France and Denmark (Parrish et al., 1988). The exam-
ination of sera collected from wild coyotes (Canis latrans)
between 1979 and 1984 in the USA also indicated that these
were originally infected by CPV-2 (Thomas et al., 1984),
but that after 1980 the juvenile coyotes were being infected
with CPV-2a, as well as by the 426Asp variant (also known
as CPV-2b) (Parrish et al., 1988).
The natural global replacement of CPV-2 by CPV-2a over a
period of 2–3 years indicates that CPV-2a has a strong epide-
miological advantage over CPV-2 (Parrish et al., 1988). It was
also seen that the CPV-2a and its derivatives had regained the
ability to infect cats, and it also became the most common
virus in many other carnivores (Truyen et al., 1996a). CPV-
2a became the new dominant lineage and underwent further
evolution, gaining several common point mutations in vari-
ous lineages. Some of these mutations changed the antigenic
properties of the capsid and reached high frequencies in viral
populations (Maya et al., 2013). The CPV-2a strain that
emerged in 1979 differs in only five or six amino acids from
CPV-2 isolates (Parrish et al., 1991b). The changes of the res-
idues 87 (Met to Leu), 300 (Ala to Gly) and 305 (Asp to Tyr)
allowed the replication in cats (Figs. 1 and 2). Other changes
also occurred in the capsid protein gene, residues 101 (Ile to
Thr), 297 (Ser to Ala) and 555 (Val to Ile), between originally
CPV-2 and -2a (Tsao et al., 1991; Agbandje et al., 1993;
Truyen et al., 1996a).
Antigenic variants CPV-2b and -2c
In addition to the original CPV-2a antigenic type, there are
two antigenic variants called CPV-2b (or VP2 426Asp) and
CPV-2c (or VP2 426Glu). Although not all scientists are in
agreement with the virus nomenclature, the reference to
CPV-2a, -2b and -2c is prevalent in the literature. CPV-2b
was first detected in 1984 in the USA (Parrish et al., 1991b)
and CPV-2c was identified in 2000 in Italy (Buonavoglia
et al., 2001). However, a recent study (Decaro et al., 2007)
showed that the oldest CPV-2c strain was isolated in 1996,
thus providing evidence that this variant had been circulating
in Germany 4 years before its first detection in Italy. Anti-
genic differences among the three variants are associated with
changes at residue 426 (Asn in CPV-2a, Asp in CPV-2b and
Glu in CPV-2c). This mutation affects the major antigenic
region (epitope A), which is located at the top of the threefold
spike in the VP2 protein. From the DNA sequence analysis of
CPV-2a and -2b, it was shown that the second variant differ
only two amino acids from the first, in the VP2 protein. The
two CPV-2b specific coding changes resulted in differences
in VP2 residues 426, previously referred, and 555 in the VP2
region (Fig. 2). The substitution of VP2 residue 555 (Ile to
Val) represented a reversion to or retention of the sequence
of CPV-2, and only the difference at residue 426 determined
the altered epitope recognized and represented a replacement
unique to CPV-2b (Parrish et al., 1991b). As the CPV-2b and
-2c antigenic strains differ from CPV-2a at only one position
(VP2 residue 426), they are now considered by some authors
to be variants of CPV-2a rather than distinct subtypes
(Organtini et al., 2015).
Other VP2 mutations reported in the antigenic
variants
Other non-synonymous substitutions at the VP2 region were
also reported in the variants. An amino acid change at VP2

(a) (b)
Residues
80
87
93
297
300
305
323
426
564
568

Fig. 1. The locations of the mutations between FPV and CPV variants in the structure of the capsid. (a) The surface of the
capsid is shown as a projection, where an icosahedral asymmetric unit of the capsid is shown as a triangle. (b)
Surface exposed of the CPV capsid, where the three VP2 426 residues (1 to 3) from the three different VP2 monomers
located on the top of the threefold spike are visible and are equivalent to shown in (a). VP2 residues 80, 564 and 568 in FPV,
as well as residues 87, 297, 300 and 305 in the new antigenic of CPV-2a, -2b and -2c (along with residue 101, which is not
surface exposed) appear to determine the ability to replicate in cats. Residues 93 and 323 differ between CPV-2 and FPV and
control canine host range and influence canine TfR binding, while residue 426 differs between the new antigenic variants
[Based on Steinel et al. (2000) and Allison et al. (2014)]. These locations were visualized using the PyMOL Molecular Graphics
System, version 1.5.0.4 Schrödinger, LLC.

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C. Miranda and G. Thompson

FPV CPV-2 CPV-2a CPV-2b CPV-2c

(<1900) (1974/78) (1979) (1984) (2000)

80 93 103 323 564 568

K KV D NA
FPV VP2
CPV-2 R NA N SG
87 101 300 305 555
M I AD V
CPV-2

CPV-2a
L T GY I 426 555
N I
CPV-2a

CPV-2b
D V
426
CPV-2b D

CPV-2c
E

Fig. 2. Some of the evolutionary processes of CPV-2 in dogs. Designation of CPV-2 antigenic variants and FPV based on
major antigenic sites occurring in the VP2 capsid protein, such as the host range players. Amino acid positions were based on
reference sequence with the accession number M24004 (FPV-b), M23255 (CPV-d), M24000 (CPV-31), M74849 (CPV-39)
and FJ005196 (G7).

position 297 (Ser to Ala) was observed both in CPV-2a and
-2b. Residue 297 is located in a minor antigenic site close to
epitope B, but no changes in the antigenicity of those variants
have been reported. CPV-2a/2b having a mutation at 297 res-
idue (Ser to Ala) have sometimes been designated as New
CPV-2a and -2b (Martella et al., 2005; Ohshima et al., 2008).
The mutation of VP2 residue 440 (Thr to Ala) has been
observed in the same isolates which showed a mutation of
VP2 residue 324 (Tyr to Ile). VP2 residue 440 may influence
the antigenic structure as it is located in the GH loop of the
VP2 protein on the surface of the capsid, while VP2 residue
324 is likely to have an effect on CPV host range similar to
the previously characterized residue 323 (Hong et al., 2007;
Mittal et al., 2014). An additional mutant, 300Asp, of CPV-
2a/2b has been detected in recent years in domestic or wild
felids in southern Asia, as well as in raccoons. The mutation
300Asp is probably the expression of a further adaptation of
the virus to replication in the feline or raccoon hosts (Ikeda
et al., 2000; Allison et al., 2012).
Nowadays, the three antigenic variants have a worldwide
distribution, and are found to infect a variety of different
hosts. The regaining of the feline host range and infection
of other hosts is likely to be a selective advantage for the
virus (Truyen et al., 1996a). While CPV-2 is considered a
host range variant of a virus closely related to FPV that
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gained the ability to infect dogs via wild carnivores, as previ-
ously reported, the emergence of CPV-2a was previously
suggested to be due to host adaptation in dogs (Allison
et al., 2012). A recent study (Allison et al., 2012) showed
that raccoons from the USA have harboured parvoviruses
similar to CPV for over 20 years. In a phylogenetic analysis
of the VP2 protein many RPV sequences, as well as a single
isolate from a bobcat, fell in intermediate locations between
the dog-associated CPV-2 and -2a strains. Hence, RPVs
may have played a central role in the transition between
CPV-2 and the later CPV-2a and related variants that not
only infected dogs but also regained the ability to infect
cats, a property lost by CPV-2. The CPV-2a-specific resi-
dues at 87 and 101 position were likely acquired during evo-
lution of the virus in raccoons, while the changes at 300 and
305 were acquired when the virus transferred back to the
canine host (Fig. 2). However, other wild animals may have
also played a role in the evolution and spread of CPV-2,
such as, wolves, foxes, jackals and coyotes that have been
found to be susceptible to CPV-2 disease (Thomas et al.,
1984; Steinel et al., 2001).
The significance of co-infections
Based on clinical signs, it is not possible to distinguish any
of the CPV sequence variants (Markovich et al., 2012).
Journal of General Virology 97

Although a few reports suggest that CPV-2c (426Glu) may
cause more severe clinical signs and mortality particularly
in adult dogs than other strains (Decaro et al., 2008), others
describe less-severe disease and lower mortality rates in
dogs infected with that virus (Decaro et al., 2005).
Co-infections by multiple CPV variants in domestic dogs
are not commonly reported, however, two cases have been
detected (Battilani et al., 2007; Vieira et al., 2008a). A recent
study by Perez et al. (2014) reported two co-infections, in
which one dog was infected by CPV-2c and -2a strains,
where the sequences examined differed in 29 nucleotides,
and in the other dog the CPV sequence included a minor
CPV-2a strain (13.3 % of the viral population) and a major
recombinant strain (86.7 %). The recombinant strain arose
from the inter-genotypic recombination between CPV-2c
and -2a strains within the VP1/VP2 gene boundary. These
data indicate that co-infections and recombination are cur-
rently occurring between circulating strains in natural pop-
ulations of CPV, indicating that both may be relevant forces
in the generation of viral diversity and the emergence of
new genotypes. Rapid genomic evolution by genetic inter-
change may be regulated by restricting recombination to
particular hotspots in the genome that favour the inter-
change of the entire VP2 gene (Perez et al., 2014).
The worldwide distribution of antigenic
CPV-2 variants
Spreading of antigenic variants in the global dog
population
The early evolutionary history of CPV was characterized by
global dissemination and strain replacement. CPV-2a
replaced the CPV-2 worldwide within 2 or 3 years, indica-
tive of an increased fitness in dogs (Parrish et al., 1988).
The end of 1983, Houston et al. (1996) showed that CPV
infection had been reported in 50 countries around the
world. The dynamics of the spread and evolution of CPV
may have changed since it emerged. In contrast to the early
period, the most recent endemic phase of the disease
appears to be characterized by geographical genetic differ-
entiation (Hoelzer et al., 2008b; Clegg et al., 2011).
Between 1979 and 2005, nearly 600 articles, papers, numer-
ous text chapters and monographs have been published on
the subject of CPV-2, according to Carmichael (2005), with
over 1000 listed in PubMed. CPV infection has been
reported from Africa, Asia, Australia, the Americas and
Europe (Steinel et al., 1998; Decaro et al., 2007; Meers et al.,
2007; Kumar & Nandi, 2010; Markovich et al., 2012; Perez
et al., 2012; Castanheira et al., 2014), and there are large
numbers of publications which have reported the frequen-
cies of different CPV variants in various countries and
regions. Table 1 summarizes the presence of the CPV var-
iants around the world in the domestic dog population,
based on the analysed references. Moreover, the CPV-2 var-
iants have been reported in 42 countries distributed
among five continents. The CPV-2a (VP2 426Asn) has been
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CPV: the worldwide occurrence of antigenic variants
reported in 37 countries, the CPV-2b (VP2 426Asp) in 31
countries and the CPV-2c (VP2 426Glu) reported in 21
countries. Those three strains have been reported to co-cir-
culate in 15 countries, mainly in European and South
American countries (Fig. 3). However, these numbers may
change as there are several other countries where current
studies are based on CPV positive serology testing, namely
Cape Verde (Castanheira et al., 2014), Pakistan (Muzaffar
et al., 2006) or Zimbabwe (McRee et al., 2014).
Recent epidemiological reports indicate that CPV-2a with
VP2 426Asn is the predominant variant in Australia (Meers
et al., 2007), most of Asian (Yoon et al., 2009, Phromnoi
et al., 2010; Chou et al., 2013; Yi et al., 2014; Timurkan
et al., 2015) and European countries (Ntafis et al., 2010;
Decaro et al., 2011, 2013; Cavalli et al., 2014; Filipov et al.,
2014), and this is the only variant reported in New Zealand
(Ohneiser et al., 2015), Nigeria (Dogonyaro et al., 2013),
Hungary (Demeter et al., 2010), Czech Republic (Decaro
et al., 2007), Slovenia and Romania (Decaro et al., 2012),
while it was not detected in Vietnam and Mexico, as well as,
from an outbreak in a litter in Sweden (Table 1, Fig. 4).
The prevalence of CPV-2b (VP2 426Asp) has been reported
in several countries within the five continents (Table 1),
and that was found to be the predominant antigenic variant
in Ireland (McElligott et al., 2011), the UK (Decaro et al.,
2007), the USA (Hong et al., 2007), African countries (Stei-
nel et al., 1998; Touihri et al., 2009; Dogonyaro et al., 2013)
and in four of nine Asian countries (Nakamura et al., 2004;
Kumar & Nandi, 2010; Ahmed et al., 2012; Soma et al.,
2013). Both CPV-2a and -2b were distributed in equal pro-
portion in Belgium (Decaro et al., 2013), Switzerland and
Austria where these antigenic types were exclusively isolated
(Truyen et al., 2000). Additionally, a sequence with VP2
426Asp was isolated from a dog in Russia (GenBank)
(Chausov, E.V., Ternovoi, V.A., Protopopova, E.V., Dury-
manov, A.G., Shestopalov, A.M., Loktev, V.B. and Netesov,
S.V., unpublished data, accession number JN033694).
Approximately 20 years after the emergence of the CPV-2c,
this has been found mainly in South American (Calderón
et al., 2011; Perez et al., 2012; Pinto et al., 2012; Aldaz et al.,
2013) and European countries (Decaro et al., 2011; Sutton
et al., 2013). However, that variant has not been detected in
Oceania. In Poland, all isolates were classified as CPV-2c
during 1995–2009, while between 1982 and 1985 the iso-
lates were CPV-2a and -2b (Majer-Dziedzic et al., 2011).
The VP2 residue 426 variants of CPV coexist in different
ratios in dog populations around the world (Truyen et al.,
1996a). Their relative frequencies and genetic characteristics
vary according to the geographic region analysed and the
time of sample collection. The reasons for the different
ratios in various countries are unknown, but immune-selec-
tion by vaccines based on different antigenic types seem
unlikely, as many vaccines used in different parts of the
world are based on the original type CPV-2 (Steinel et al.,
1998). Cross-protection has been demonstrated with the
use of these vaccines against infection with the different
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C. Miranda and G. Thompson

Fig. 3. Geographical distribution of three CPV variants based on 426 residue detected in domestic dogs worldwide. Orange,
presence of three CPV variants; green, presence of two of three CPV variants; yellow, presence of one of three CPV variants.

VP2 426 variants (Spibey et al., 2008; Wilson et al., 2013).
The co-existence of those three variants in various popula-
tions in the world and in different ratios shows that there is
likely no strong evolutionary advantage for one type or the
other (Steinel et al., 1998).
The temporal and geographic variability and the
relative frequencies
Depending on the year of collection of the canine samples,
the frequency of the CPV variants has revealed interesting
changes in their distribution and variability. Table 1 shows
the variant types reported globally in the dog population,
while Table 2 shows their temporal variation within differ-
ent countries.
During 6 years, the variants’ prevalence was analysed on col-
lected samples of the Uruguayan dog population. CPV-2c
was the main variant retrieved on samples from 2006, with
only one CPV-2a (Perez et al., 2007) and CPV-2c was the
only variant detected from samples collected between 2007
and 2009. However, an unexpected epidemiological change
has occurred in Uruguay in 2010, where a divergent CPV-2a
strain emerged in the CPV-2c homogenous population. This
variant rapidly spread through the national dog population
and the sequence analysis showed amino acid substitutions
(267Tyr, 324Ile and 440Ala) that were not observed in the
Uruguayan CPV-2c (Perez et al., 2012). In 2011, the fre-
quency of the CPV-2a increased to levels of 85 % in the
canine population (Maya et al., 2013). In Argentina, the
high prevalence of CPV-2c strains seen in the last years
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continues nowadays. CPV-2c appeared in the year 2003
(Calderón et al., 2009) and has been the predominant strain
(>90 %) since 2008 (Calderón et al., 2015). However, unex-
pectedly four CPV-2a samples were found during the year
2012, while it has reappeared with a low prevalence (<10 %).
No CPV2b strains have been detected among local samples
since 2009 (Calderón et al., 2009, 2011, 2012, 2015). The
results obtained in Argentina, together with those reported
previously in Uruguay (Perez et al., 2012) strongly suggest
that, in spite of the geographical proximity, wild-type CPV
strains undergo different evolutive pathways in each coun-
try, resulting in the prevalence of different strains in related
dog populations (Calderón et al., 2015).
In Brazil, all the three variants were found circulating in the
canine population, however in different proportions, being
the predominant variant type dependent on the year of study.
CPV-2a was the predominant variant during 1980–1986,
which was substantially replaced by CPV-2b from 1990 to
1995 (Pereira et al., 2000). All samples from 1995 to 2003
were identified as CPV-2a, and from 2004 to 2006, both CPV-
2a and -2b were observed. From 2006 to 2009, most of the
samples were characterized as CPV-2b, with only one sample
classified as CPV-2c in 2008 (Castro et al., 2010), and that
become the most predominant variant circulating in Brazil
between 2008 and 2010 (Pinto et al., 2012).
The predominance of variants may also vary according to
the regions of the country where the samples are collected
(Yi et al., 2014). For example in Portugal, the predominant
CPV-2 variants found in the continental south regions and
Journal of General Virology 97
 CPV: the worldwide occurrence of antigenic variants

Table 1. The worldwide distribution of the antigenic CPV variants in the domestic dog population

ND, no data.

Continent/country Number of CPV variants detected Year of collection Reference

2a 2b 2c

Europe
Portugal 2 94 102 2012–2014 Miranda et al. (2016)
Spain 3 1 9 2008–2009 Decaro et al. (2011)
France 4 2 1 2009–2012 Decaro et al. (2013)
Germany 5 2 1 2009–2012 Decaro et al. (2013)
Belgium 1 1 0 2009–2012 Decaro et al. (2013)
Italy 13 3 5 2008–2009 Decaro et al. (2011)
Switzerland a a 0 ND Truyen et al. (2000)
Slovenia 1 0 0 ND Decaro et al. (2012)
Austria a a 0 ND Truyen et al. (2000)
Ireland 3 4 0 2008–2009 McElligott et al. (2011)
Sweden 0 0 4 ND Sutton et al. (2013)
UK 18 21 1 2005–2006 Decaro et al. (2007)
Albania 29 0 24 2011–2013 Cavalli et al. (2014)
Bulgaria 171 40 5 2004–2014 Filipov et al. (2014)
Greece 81 1 2 2008–2009 Ntafis et al. (2010)
Romania 2 0 0 ND Decaro et al. (2012)
Hungary 24 0 0 2004–2008 Demeter et al. (2010)
Czech Republic 1 0 0 2005–2006 Decaro et al. (2007)
Poland 11 2 19 1982–1985/1995–2009 Majer-Dziedzic et al. (2011)
Asia
India 27 39 12 2006–2009 Kumar & Nandi (2010)
Vietnam 0 7 4 2002 Nakamura et al. (2004)
Taiwan 35 19 0 2011 Chou et al. (2013)
China 20 2 0 2009–2013 Yi et al. (2014)
Korea (South) 41 3 0 2007 Yoon et al. (2009)
Japan 9 95 0 2009–2011 Soma et al. (2013)
Thailand 19 7 0 2003–2004/2008–2009 Phromnoi et al. (2010)
Iraq 3 6 0 2011 Ahmed et al. (2012)
Turkey 17 8 0 2009–2011 Timurkan et al. (2015)
Russia b 1993 Chausov et al. (2011)
Africa
Tunisia 15 21 14 2007–2008 Touihri et al. (2009)
Nigeria 6 0 0 2010 Dogonyaro et al. (2013)
Namibia 3 9 0 1995–1998 Steinel et al. (1998)
South Africa 6 13 0 2010 Dogonyaro et al. (2013)
North America
USA 1 19 7 2006–2007 Hong et al. (2007)
Mexico 0 0 5 2013–2014 Pedroza-Roldan et al. (2015)
South America
Brazil 1 8 33 2008–2010 Pinto et al. (2012)
Uruguay 20 0 130 2007–2010 Perez et al. (2012)
Argentina 2 3 50 2008–2010 Calderón et al. (2011)
Paraguay 0 0 1 2009 Calderón et al. (2011)
Ecuador 2 22 29 2011–2012 Aldaz et al. (2013)
Oceania
Australia 41 1 0 1980–2005 Meers et al. (2007)
New Zealand 69 0 0 2009–2010 Ohneiser et al. (2015)

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C. Miranda and G. Thompson

a, From 14 samples from Switzerland, 35 samples from Austria and 82 samples from Germany exclusively the new antigenic types CPV-2a and
CPV-2b were isolated.
b, accession number JN033694.

in the Islands differed from those detected in the samples
collected in the continental north of country (Miranda
et al., 2016), however, the distribution of CPV in China did
not show any geographical correlation (Yi et al., 2014). The
reason for the uneven world distribution of the different
viral variants is still not clearly understood but could be
related to the changing dynamics that the virus has experi-
enced since its emergence in the 1970s (Hoelzer et al.,
2008b). These data provide new evidence of the role of local
genetic diversity and migration events during CPV evolu-
tion and, emphasize the dynamic changes in CPV variants
and highlight the importance of ongoing surveillance pro-
grams to provide a better understanding of the virus epide-
miology (Perez et al., 2012; Maya et al., 2013). However,
this variability did not happen within certain countries, like
Hungary (Demeter et al., 2010; Decaro et al., 2013; Csagola
et al., 2014), Japan (Ohshima et al., 2008; Soma et al., 2013)
and China (Zhang et al., 2010; Yi et al., 2014), where differ-
ent studies during several years showed the presence of the
same predominant variant type. Based on these data, the
three different antigenic variants of parvovirus, 2a, 2b and
2c, are currently circulating worldwide, being however diffi-
cult to state which is predominant.
On the other hand, this variability should include the analy-
sis of the other unnamed mutations that are probably just
as or more important than the mutations in the residue
426. In recent years, several other mutations have been
reported around the world simultaneously within the VP2
region (Pinto et al., 2012; Yi et al., 2014). For example, the
amino acid substitution Thr440Ala has been described in
CPV-2a and -2b strains from India, Brazil, South Africa and
China (Chinchkar et al., 2006; Castro et al., 2010; Dogo-
nyaro et al., 2013; Yi et al., 2014) and in CPV-2c strains
from the USA (Hong et al., 2007) and Argentina (Calderón
et al., 2011). The 440 position is an important residue
because it is located at the top of the threefold spike, the
main antigenic site of the virus (Tsao et al., 1991). This resi-
due is undergoing positive selection and has evolved inde-
pendently in different populations, which explains its
worldwide presence in unrelated CPV-2 populations
(Decaro et al., 2007). The Tyr324Ile change appeared in
CPV-2a, -2b and -2c. This was first reported in 2004 in
CPV-2a strains from China (Zhang et al., 2010), however, it
has been described in the USA (Hong et al., 2007), Brazil
(Perez et al., 2012) and Hungary (Csagola et al., 2014). Pre-
vious studies have shown that residue 324 is undergoing
strong positive selection in the parvoviruses of all carnivores

(a) (b)

(c)

Fig. 4. Worldwide distribution of CPV-2 variants in domestic dogs. Red, presence of CPV-2a variant (a); pink, presence of
CPV-2b variant (b); green, presence of CPV-2c variant (c).

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 CPV: the worldwide occurrence of antigenic variants

Table 2. Temporal variability of the three CPV variants within different countries

Continent/country Number of CPV variants detected Year of collection Reference

2a 2b 2c

Europe
Spain 3 1 9 2008–2009 Decaro et al. (2011)
4 11 4 2009–2012 Decaro et al. (2013)
France 0 9 7 2008–2009 Decaro et al. (2011)
4 2 1 2009–2012 Decaro et al. (2013)
Germany 5 18 14 1996–2005 Decaro et al. (2007)
8 0 7 2008–2009 Decaro et al. (2011)
5 2 1 2009–2012 Decaro et al. (2013)
Italy 80 17 0 1997–1999 Martella et al. (2005)
123 6 31 2000–2003 Martella et al. (2005)
24 4 42 2004 Martella et al. (2005)
43 3 57 2006 Decaro et al. (2007)
13 3 5 2008–2009 Decaro et al. (2011)
186 50 94 2009–2012 Decaro et al. (2013)
Asia
India 18 4 0 2003–2005 Chinchkar et al. (2006)
27 39 12 2006–2009 Kumar & Nandi (2010)
22 1 0 2011–2012 Mukhopadhyay et al. (2014)
Taiwan 10 1 0 1994–1995 Chang et al. (1996)
2 34 0 2003–2004 Wang et al. (2005)
15 13 0 2008–2012 Lin et al. (2014)
35 19 0 2011 Chou et al. (2013)
North America
USA 1 19 7 2006–2007 Hong et al. (2007)
0 9 25 2008–2009 Markovich et al. (2012)
South America
Brazil 13 0 0 1980–1986 Pereira et al. (2000)
0 21 0 1990–1995 Pereira et al. (2000)
10 0 0 1995–2001 Castro et al. (2010)
6 4 0 2002–2006 Castro et al. (2010)
2 9 1 2007–2009 Castro et al. (2010)
1 8 33 2008–2010 Pinto et al. (2012)
Uruguay 1 0 24 2006 Perez et al. (2007)
0 0 98 2007–2009 Perez et al. (2012)
20 0 32 2010 Perez et al. (2012)
39 0 7 2011
Argentina 9 4 14 2002–2008 Calderón et al. (2009)
2 3 50 2008–2010 Calderón et al. (2011)
1 1 9 2003–2010 Gallo Calderón et al. (2012)
4 0 37 2010–2013 Calderón et al. (2015)

(Hoelzer et al., 2008b). Residue 324 is adjacent to 323, that these field viruses are under strong positive selection
which together with residue 93 plays an important role in pressure for CPV-2 local types.
binding to the canine TfR and affects the canine host range
(Hueffer et al., 2003), and presumably, this Tyr324Ile alter- Host ranges for antigenic CPV-2 variants
ation can result in stronger receptor binding (Csagola et al.,
2014). In addition, the Ala516Thr Hungarian-specific Domestic cats
change (Csagola et al., 2014) and the Ala297Asp circulating The original CPV-2 does not replicate in cats, on the other
in South African strains (Dogonyaro et al., 2013), suggest hand, it replicates in feline cells in vitro (Parrish, 1991a;
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C. Miranda and G. Thompson

Truyen & Parrish, 1992). In contrast, the new variants of
CPV-2 have also penetrated the feline host range and they are
able to infect and replicate in cats, causing disease indistin-
guishable from FPV (Truyen et al., 1996a; Battilani et al.,
2011). In Vietnam and Taiwan, Ikeda et al. (2000) revealed
that more than 80 % of the isolates from cats were of the CPV
type, rather than FPV. CPV-2a and -2b viruses have been also
isolated in feline cells in vitro and in domestic cats in vivo
from Japan, USA, Taiwan and Vietnam (Truyen et al., 1995,
1996a; Mochizuki et al., 1996; Ikeda et al., 2000). Diseased
cats have also been detected with CPV-2c (Miranda et al.,
2014) or co-infections by multiple CPV variants (Battilani
et al., 2006) or mixed infections with FPV and CVP-2-like
(Url et al., 2003; Battilani et al., 2011). Some studies have also
reported the presence of CPV-2 variants in faecal and bone
marrow samples of healthy cats (Clegg et al., 2012; Haynes &
Holloway, 2012). Retrospective typing of parvovirus isolates
in clinically affected domestic cats has revealed a small per-
centage (about 5 %) of CPV infections caused by CPV-2a or
-2b (Truyen et al., 1996b).
Wild animals
Parvoviruses are relatively stable in the environment and
indirect transmission likely plays an important role in the
transmission and maintenance of the viruses in a popula-
tion, particularly in wild carnivore populations which may
be characterized by low contact rates between animals.
Transmission between domestic and wild carnivores may
also readily occur, while direct transmission through close
contact or predation on smaller carnivores has been pro-
posed, the viruses are probably readily transmitted across
long distances by fomites (Baker & Parrish, 2001; Hoelzer &
Parrish, 2010).
The host ranges of the CPV variants are complex and
diverse. Although CPV isolates have been recovered from
domestic cats and dogs, they have naturally been detected
in a variety of related carnivores. Infection with CPV has
already been demonstrated in Canidae, Felidae, Procyonidae
and Mustelidae family (Barker & Parrish, 2001; Steinel et al.,
2001) and the families of wild carnivores where the pres-
ence of CPV were detected are summarized in Table 3.
However, several studies reported the detection of CPV in
other wild carnivores by serological analysis (Santos et al.,
2009; Woodroffe et al., 2012), and consequently there are
no sequences available on GenBank database.
The residue 300 is important in distinguishing the antige-
nicity and host range among parvovirus but may vary
among CPV isolates (Qin et al., 2007). Alanine holds the
position in CPV-2, in CPV-2a and -2b it is Gly and in CPV-
2c of the Vietnamese leopard cat Asp (Ikeda et al., 2000).
During 1995–1997, CPV-2a or -2b variants were isolated
from three leopard cats (Felis bengalensis) in Vietnam and
Taiwan. Other three leopard cats showed the substitution
(Gly to Asp) at the conserved residue 300, were designated
as Leopard cat parvovirus (LCPV), but currently designated
by CPV-2c (Ikeda et al., 2000). In 2004, nucleotide and
phylogenetic analysis of the capsid protein VP2 gene classi-
fied the Red panda parvovirus (RPPV) as a CPV-2a from
red panda (Ailurus fulgens) in China. The substitution of
Val for Gly at the conserved residue 300 in RPPV presents
an unusual variation in the CPV-2a amino acid sequence
and is a further evidence for the continuing evolution of the
virus (Qin et al., 2007). Chen et al. (2011) showed that the
isolates from the RDPV and Masked palm civet parvovirus
(MCPV) were antigenically similar to CPV-2a, but had a
change at G300S and classified as CPV-2a-like. The G300S
mutation would have contributed to the adaptation of
CPV-2a to raccoon dogs (Nyctereutes procyonoides) and

Table 3. Species and taxonomic family of wild carnivores infected by CPV variants, according to the references analysed

Family Species Regular name CPV variants

Canidae Canis lupus Grey wolf 2a, 2b, 2c

Otocyon megalotis Bat-eared fox 2b
Vulpes vulpes Red fox 2a
Canis latrans Coyote 2b, 2c
Nyctereutes procyonoides Raccoon dog 2a
Felidae Acinonyx jubatus Cheetah 2b
Panthera tigris altaica Siberian tiger 2c
Felis bengalensis Leopard cat 2a, 2b, 2c
Puma concolor Puma 2b, 2c
Lynx rufus Bobcat 2a, 2c
Viverridae Paguma larvata Masked palm civet 2a
Mustelidae Martes foina Stone marten 2a, 2b
Aonyx cinerea Asian small-clawed otters 2c
Ailuridae Ailurus fulgens Red panda 2a
Ursidae Ailuropoda melanoleuca Giant panda 2a
Procyonidae Procyon lotor Raccoon 2a, 2b

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masked palm civets (Paguma larvata). In addition, the
MCPV had a change at T301A in VP2 protein. Residue 301,
following residue 300, is located in loop 3 at the extremities
of the threefold spike on the viral surface. Therefore, its
changes might also affect antigenicity and host range of
CPV. Other evidence for the continuing evolution of the
CPV was the identification of the Q370R point mutation in
the VP2 gene from a giant panda (Ailuropoda melanoleuca)
classified as CPV-2a (Guo et al., 2013). All variants have
succeeded in regaining the feline/carnivores host and new
genomic mutations can be expected in future (Steinel et al.,
1998).
Steinel et al. (2000) reported the detection of CPV-2b viral
DNA in six cheetahs (Acinonyx jubatus) from Namibia and
USA and, in a bat-eared fox (Otocyon megalotis) from
Namibia. CPV-2a sequence was also found in the faecal
sample of the Siberian tiger (Panthera tigris altaica) from a
German zoo. The very high prevalence of CPV-2a/2b infec-
tions in these large cats compared to domestic cats may sug-
gest a higher susceptibility of these species for these virus
types (Steinel et al., 2000). An isolate from a stone marten
(Martes foina) collected in Portugal revealed the presence of
CPV-2b (Duarte et al., 2013), such a stone marten CPV-2a
strain was referred by Steinel et al. (2001). In Italy, four iso-
lates from wolves analysed by Battilani et al. (2001) were
antigenically and genetically identified as CPV-2b. The phy-
logenetic analysis from several non-domestic animals, such
as, raccoon (Procyon lotor), coyote (Canis latrans), grey wolf
(Canis lupus baileyi/nubilus/occidentalis), puma (Puma con-
color), striped skunk (Mephitis mephitis) and bobcat (Lynx
rufus) (Allison et al., 2012, 2013) revealed the presence of
the three CPV variants. A recent study by Filipov et al.
(2014) detected two wild carnivores parvovirus positive, a
wolf (Canis lupus) and a red fox (Vulpes vulpes), both being
infected by CPV-2a strains. A diagnosis of CPV-2c was also
made in a group of Asian small-clawed otters (Aonyx cin-
erea) (Gjeltema et al., 2015).
Conclusions
In approximately 40 years after the emergence of original
CPV-2, three antigenic CPV variants are disseminated in 42
countries. The different antigenic variants of CPV-2 are
prevalent in varying proportions in different countries. The
prevalence of variants by country was found to depend on
the year and region of collection of samples, however,
results can differ due to the lack of current studies and the
continuous monitoring of the CPV-2 within countries.
Unexpectedly, the last reported variant (CPV-2c) has been
only detected in 21 countries around the world.
As a result of multiple cross-species transmission events,
there was a significant diversity of nondomestic animals
infected by CPV-2 variants. A better understanding on the
epidemiology and the evolution of CPV in other hosts than
domestic cats and dogs appears essential. The summary of
the data presented here contributes to map the actual geo-
graphical spread of the antigenic CPV variants worldwide
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CPV: the worldwide occurrence of antigenic variants
and may be used as a handy information source for veteri-
narians and researchers interested in CPV and its evolution.
Acknowledgements
This work was supported in part by the Foundation for Science and
Technology (FCT) Portugal grant SFRH/BD/76291/2011 to C.
Miranda, such as the Human Potential Operational Programme
(POPH) and the European Union. The author(s) received no finan-
cial support for the authorship and/or publication of this article.
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