Efficacy of a bivalent inactivated non-adjuvanted feline calicivirus vaccine: Relation between in vitro cross-neutralization and heterologous protection in vivo

doi:10.1016/j.vaccine.2008.04.082

Vaccine

Volume 26, Issues 29–30, 4 July 2008, Pages 3647-3654

https://doi.org/10.1016/j.vaccine.2008.04.082 Get rights and content

Abstract

Feline calicivirus (FCV) is a major pathogen of the cat characterized by a strong genomic, antigenic and clinical diversity. Despite vaccination, FCV infection is highly prevalent, and for a few years, outbreaks of virulent systemic disease (VSD) have been reported in North America and Europe. An inactivated non-adjuvanted bivalent vaccine was recently developed by combining antigens derived from two broadly cross-reactive FCV strains. The antigenic relatedness between the vaccine strains and other antigenic variants was demonstrated by cross-neutralization studies in vitro. This study showed that vaccine-induced protection against heterologous challenges was correlated to in vitro cross-neutralization, and it validated the use of cross-neutralization tests to select vaccine FCV strains. This correlation applies also for the highly virulent strains causing VSD (VS-FCV).

Introduction

Feline calicivirus (FCV) is a major pathogen of the cat, causing a variety of clinical conditions including upper respiratory tract disease [1], [2], chronic stomatitis [3], dermatitis [4] and lameness [5]. Recently, outbreaks of virulent systemic disease (VSD) have been reported in North America [6], [7], [8] and Europe [9], and are characterized by a high rate of mortality, even in vaccinated cats. Despite vaccination, prevalence of FCV infection in the cat population remains high [1].

FCV is a single-stranded positive sense RNA virus, characterized by a strong genetic variability and antigenic diversity [10], [11], [12], [13]. The humoral immune response plays a critical role in the protection against FCV-induced disease, and the E region of the capsid protein is a major target of neutralizing antibodies [14], [15]. This area is subdivided into the 5′ and 3′ hypervariable regions, separated by a short relatively conserved domain [16]. These hypervariable areas contain the immunodominant antigenic sites and have been shown to be under positive selection [17], [18].

Immunofluorescence profiles with monoclonal antibodies mapped in region E and sequencing of the capsid protein have highlighted the antigenic diversity of FCV [13]. Cross-neutralization has been used to compare variants, and in particular, to evaluate the ability of vaccine strains to protect against circulating antigenic variants [13], [19], [20].

To improve cross-protection, two strains with broad cross-antigenicity have been selected [21] and used to develop an inactivated non-adjuvanted bivalent vaccine (PUREVAX^®¹ RCPCh-FeLV). The selection of the vaccine strains was based on cross-neutralization studies. The objective of this study was to assess the relation between cross-neutralization in vitro and protection in vivo in experimental conditions. This is also the first demonstration of the efficacy of a vaccine against multiple heterologous FCV challenges.

Section snippets

Vaccine

Cats were vaccinated with a bivalent inactivated non-adjuvanted FCV vaccine combined with other feline antigens (same components as PUREVAX RCPCh-FeLV vaccine). The calicivirus antigen consisted of inactivated concentrated purified virus particles, derived from two different strains (FCV431 and FCVG1) and combined in equal amounts. The vaccine was not adjuvanted. A group of non-vaccinated cats was used as control.

In studies Nos. 1 and 2, another group of cats was vaccinated with the reference

Homology of region E between FCVG1, FCV431 and other strains

At the amino acid level, homology of region E between the nine strains included in the analysis ranged from 61% to 75% (Table 1). The divergence within region E between FCV431 or FCVG1 and the various challenge strains (FCV255, 33585, ENVT, 91-11 and 91-25) ranged from 28% to 37%.

The phylogenetic analysis of the amino acids sequence of region E confirmed the strong antigenic diversity of FCV. FCV33585 and FCV-ENVT but not FCV100869 clustered with other VS-FCV strains (Fig. 1). The analysis

Discussion

Despite vaccination, FCV is still a major infectious disease of cats, and conditions like VSD or chronic stomatitis pose a serious problem to veterinarians. One of the reasons for the high prevalence of FCV infection is the inability of vaccines, whatever the technology, to prevent infection [23], [24], [25], [26]. Even vaccines aiming at inducing a strong local immunity, like feline herpesvirus or spumavirus-vectored vaccines, have a limited efficacy [23], [25]. Currently, most commercially

Conclusion

This study was the first report on the vaccinal protection against several heterologous FCV strains, including VS-FCV strains. It showed that cross-neutralization is a relevant technique to select FCV vaccine strains. For this vaccine, cross-neutralization was predictive of a significant protection against FCV, including a reduction in the severity of VSD. This method made it possible to select FCV strains with broad cross-reactivity and to develop a vaccine affording protection against a large

References (38)

S.H. Binns et al.
A study of feline upper respiratory tract disease with reference to prevalence and risk factors for infection with feline calicivirus and feline herpesvirus
J Feline Med Surg
(2000)
N.C. Pedersen et al.
An isolated epizootic of hemorrhagic-like fever in cats caused by a novel and highly virulent strain of feline calicivirus
Vet Microbiol
(2000)
E.M. Schorr-Evans et al.
An epizootic of highly virulent feline calicivirus disease in a hospital setting in New England
J Feline Med Surg
(2003)
K. Geissler et al.
Genetic and antigenic heterogeneity among feline calicivirus isolates from distinct disease manifestations
Virus Res
(1997)
M. Glenn et al.
Nucleotide sequence of UK and Australian isolates of feline calicivirus (FCV) and phylogenetic analysis of FCVs
Vet Microbiol
(1999)
C. Baulch-Brown et al.
Sequence variation within the capsid protein of Australian isolates of feline calicivirus
Vet Microbiol
(1999)
B.S. Seal
Analysis of capsid protein gene variation among divergent isolates of feline calicivirus
Virus Res
(1994)
A. Lauritzen et al.
Serological analysis of feline calicivirus isolates from the United States and United-Kingdom
Vet Microbiol
(1997)
C.J. Porter et al.
Comparison of the ability of feline calicivirus (FCV) vaccines to neutralise a panel of current UK FCV isolates
J Feline Med Surg
(2008)
H. Poulet et al.
Immunization with a combination of two complementary feline calicivirus strains induces a broad cross-protection against heterologous challenges
Vet Microbiol
(2005)

L.M. Sommerville et al.

DNA vaccination against feline calicivirus infection using a plasmid encoding the mature capsid protein

Vaccine

(2002)

A.D. Radford et al.

The challenge for the next generation of feline calicivirus vaccines

Vet Microbiol

(2006)

L.C. Kreutz et al.

Phenotypic and genotypic variation of feline calicivirus during persistent infection of cats

Vet Microbiol

(1998)

V.J. McCabe et al.

Potential for broad-spectrum protection against feline calicivirus using an attenuated myxoma virus expressing a chimeric FCV capsid protein

Vaccine

(2005)

A.D. LoBue et al.

Multivalent norovirus vaccines induce strong mucosal and systemic blocking antibodies against multiple strains

Vaccine

(2006)

J. Foley et al.

Virulent systemic feline calicivirus infection: local cytokine modulation and contribution of viral mutants

J Feline Med Surg

(2006)

B. Di Martino et al.

Assembly of feline calicivirus-like particle and its immunogenicity

Vet Microbiol

(2007)

S. Rong et al.

Characterization of a highly virulent feline calicivirus and attenuation of this virus

Virus Res

(2006)

C.R. Helps et al.

Factors associated with upper respiratory tract disease caused by feline herpesvirus, feline calicivirus, Chlamydophila felis and Bordetella bronchiseptica in cats: experience from 218 European catteries

Vet Rec

(2005)

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Feline Calicivirus Infections
2022, Greene's Infectious Diseases of the Dog and Cat, Fifth Edition
- •
  First Described: 1957 (New Zealand, Fastier).
- •
  Causes: FCV, family Caliciviridae, genus Vesivirus.
- •
  Affected Hosts: Domestic cat and many other Felidae. Similar viruses also isolated occasionally from dogs.
- •
  Geographic Distribution: Worldwide.
- •
  Primary Mode of Transmission: Oronasal, fomite spread.
- •
  Major Clinical Signs: Oral ulceration, oculonasal discharges, lethargy. Less commonly lameness, lower respiratory tract infection, and signs of enteritis. Rare virulent forms may also cause edema, icterus, skin necrosis, and death.
- •
  Differential Diagnosis: Differential diagnoses for FCV infection are other respiratory viral infections (FCV, influenza viruses), infections with bacteria such as Bordetella bronchiseptica, Mycoplasma spp., Streptococcus spp., or Chlamydia felis; other causes of rhinitis such as cryptococcosis, aspergillosis, neoplasia, foreign bodies, chronic idiopathic feline rhinosinusitis, nasopharyngeal stenosis, or nasopharyngeal polyps; feline chronic airway disease. For cats with oral ulcerations, exposure to caustic substances may be suspected.
- •
  Human Health Significance: None known.
A multi-national European cross-sectional study of feline calicivirus epidemiology, diversity and vaccine cross-reactivity
2017, Vaccine
Citation Excerpt :
Whilst vaccines reduce clinical signs, none are licensed to reduce virus shedding post-challenge and FCV infection remains highly prevalent in both vaccinated and unvaccinated populations [1]. Most live vaccines include FCV-F9 [19,20], whereas inactivated vaccines commonly include strains FCV-255, or a combination of FCV-431 and FCV-G1 [18,21,22]. These vaccine antigens are chosen based on their ability to induce broadly cross-reactive antisera against contemporary isolates circulating at the time of vaccine development [17,20,22].
Feline calicivirus (FCV) is an important pathogen of cats for which vaccination is regularly practised. Long-term use of established vaccine antigens raises the theoretical possibility that field viruses could become resistant. This study aimed to assess the current ability of the FCV-F9 vaccine strain to neutralise a randomly collected contemporary panel of FCV field strains collected prospectively in six European countries.
Veterinary practices (64) were randomly selected from six countries (UK, Sweden, Netherlands, Germany, France and Italy). Oropharyngeal swabs were requested from 30 (UK) and 40 (other countries) cats attending each practice. Presence of FCV was determined by virus isolation, and risk factors for FCV shedding assessed by multivariable logistic regression. Phylogenetic analyses were used to describe the FCV population structure. In vitro virus neutralisation assays were performed to evaluate FCV-F9 cross-reactivity using plasma from four vaccinated cats.
The overall prevalence of FCV was 9.2%. Risk factors positively associated with FCV shedding included multi-cat households, chronic gingivostomatitis, younger age, not being neutered, as well as residing in certain countries. Phylogenetic analysis showed extensive variability and no countrywide clusters. Despite being first isolated in the 1950s, FCV-F9 clustered with contemporary field isolates. Plasma raised to FCV-F9 neutralized 97% of tested isolates (titres 1:4 to 1:5792), with 26.5%, 35.7% and 50% of isolates being neutralized by 5, 10 and 20 antibody units respectively.
This study represents the largest prospective analysis of FCV diversity and antigenic cross-reactivity at a European level. The scale and random nature of sampling used gives confidence that the FCV isolates used are broadly representative of FCVs that cats are exposed to in these countries. The in vitro neutralisation results suggest that antibodies raised to FCV-F9 remain broadly cross-reactive to contemporary FCV isolates across the European countries sampled.
Practical Guidelines for Handling and Administration of Vaccine Products
2016, August's Consultations in Feline Internal Medicine, Volume 7
Strategies for Infectious Disease Management in Shelter Cats
2016, August's Consultations in Feline Internal Medicine
Three-year duration of immunity for feline herpesvirus and calicivirus evaluated in a controlled vaccination-challenge laboratory trial
2015, Veterinary Microbiology
Citation Excerpt :
Importantly, the FCV challenge was performed with a heterologous strain. The FCV431 and G1 vaccine strains respectively share only 69 and 68% homology at amino acid level with FCV100869 in the immune-dominant E region (amino acids 426 to 520 of precursor protein) (Poulet et al., 2008). In the field, circulating variants are heterologous to vaccine strains.
Feline vaccination guidelines recommend less frequent boosters for the core vaccines (rhinotracheitis, calicivirosis and infectious panleucopenia). Most guidelines recommend boosters at 3-yearly intervals after a basic vaccination including primary vaccination and revaccination one year later.
The objective of this study was to assess the duration of immunity induced by PUREVAX^® RCPCh FeLV, a non-adjuvanted vaccine against feline rhinotracheitis, calicivirosis, infectious panleucopenia, chlamydiosis and leukemia. After primary vaccination followed by revaccination one year later with a vaccine formulated at minimum dose, the cats were kept in a confined environment and challenged 3 years later with a virulent heterologous strain of feline calicivirus (FCV) and subsequently a virulent strain of feline herpesvirus (FHV). Clinical signs and viral excretion were recorded for two weeks after each viral inoculation. Contemporary unvaccinated cats and new animals added at the time of challenge were used as controls.
The vaccination regimen induced a stable and long-lasting humoral response. Vaccination resulted in a significant reduction in the severity of the disease after FHV challenge and in the frequency of cats showing a severe calicivirosis (defined as a combination of systemic clinical symptoms and oronasal ulcers). As opposed to the significant reduction of excretion observed a few weeks after primo-vaccination or even one year after vaccination for FCV, viral shedding was not reduced 3 years after revaccination.
This study showed that primary vaccination and revaccination one year later with PUREVAX^® RCPCh FeLV was able to induce 3-year duration of immunity against FCV and FHV. The results and conclusion of this study are consistent with current vaccination guidelines and will allow the veterinarian to adapt the vaccination regimen to the way of life of the cat.
Chapter 13 - Biology and Diseases of Cats
2015, Laboratory Animal Medicine: Third Edition
Domestic cats (Felis cattus) comprise a small (2%) percentage of the non-rodent animals used in biomedical research. In 2011, 21,700 cats of a total 1,134,693 non-rodent animals were used in research (APHIS, 2011). According to the National Research Council Committee on Scientific and Humane Issues in the Use of Random Source Dogs and Cats in Research (National Research Council, 2009), peak use of cats occurred in 1974. Since that time, the number of cats used in research has fallen by 71%, with more than 98% of those cats being purpose bred for research. Cats are a U.S. Department of Agriculture (USDA) covered species with special housing requirements defined in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals (NRC, 2011). At the request of congress, a committee of experts formed by the National Research Council examined the use of random source dogs and cats and concluded that obtaining dogs and cats from Class B dealers is not necessary for NIH funded research (National Research Council, 2009). While the number of cats used in biomedical research has declined, cats continue to contribute uniquely to biomedical science and are valuable research model for several disciplines, including aspects of neurology involved in locomotion and spinal trauma, retrovirus and zoonotic disease research, and for developing therapeutic strategies for inherited diseases.

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