Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
2001-01-18
2003-04-22
Housel, James (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S009100, C424S093100, C424S818000, C424S078310, C424S450000, C530S228000, C530S230000, C530S811000, C530S812000, C530S815000, C530S816000, C530S826000, C514S04400A, C435S002000
Reexamination Certificate
active
06551598
ABSTRACT:
The present invention relates to immunization or vaccination against canine herpesvirus. The invention relates in particular to an immunization or vaccination method, to suitable immunogenic compositions and vaccines and to the use thereof in the context of these methods.
Canine herpesvirus (or CHV) was described for the first time in 1965 (L. E. Carmichael, Am. J. Vet. Res., 1965, 26, 803-814). Infection with canine herpesvirus was then identified in many countries (USA, France, United Kingdom, Switzerland, Italy, Japan, Australia, New Zealand etc.). CHV is responsible for reproductive problems in canine breeding and most particularly for mortality in newborn puppies, which may give rise to significant losses in certain breeding kennels. It is also responsible for abortions and still-births. Infection with CHV is moreover suspected of reducing fertility in bitches. The transmission of CHV takes place via the venereal route, the oronasal route or the transplacental route.
CHV belongs to the family of Herpesviridae and to the subfamily of Alphaherpesvirinae. To date, only one type of CHV has been identified. This is an enveloped virus containing a double-stranded DNA molecule. The envelope contains several glycoproteins of viral origin. The glycoproteins gB, gC and gD are responsible for the induction of neutralizing antibodies in mice.
CHV is antigenically similar to feline herpesvirus (J. A. Limcumpao et al., Arch. Virol., 1990, 111, 165-176) but has no significant cross-neutralization (X. Xuan et al., Arch. Virol., 1992, 122, 359-365).
CHV is strongly dependent on its host and multiplies only on cells of canine origin (Pierson et al., recueil de Médecine Vétérinaire, March/April 1998, 174 No. 3/4, 87-94).
Newborn puppies are highly sensitive to infection with CHV during the first 3 weeks of life. The contamination occurs during whelping or the first few days of life. Consequently, it is not possible to vaccinate the puppies. The only means of protection available are hygiene measures such as heating the puppies with an infrared lamp and serotherapy. However, CHV is relatively non-immunogenic and it is difficult to prepare a good serum (L. B. Carmichael, J. Am. Vet. Med. Assoc., 1970, 156, 1714-1721).
Under natural conditions, puppies can be protected with the CHV-neutralizing antibodies present in the colostrum of seropositive bitches: in the absence of these antibodies, the puppies are highly sensitive to infection with CHV (D. L. Huxsoll and I. E. Hemelt, J. Am. Vet. Med. Assoc., 1970, 156, 1706-1713). The at-risk animals are puppies born from uninfected bitches in contact with excreting animals, and puppies born from latent but seronegative or weakly seropositive infected bitches. The CHV-neutralizing antibodies do not persist for a long time, and an animal can be infected and seronegative.
In puppies less than 3 weeks old, CHV causes a neonatal hepesvirosis which is often fatal. The incubation is rapid and the puppies die within a few days, usually with no symptoms other than sudden hypothermia and devastating nervous disorders, in the vast majority of cases before the 5-day-old stage. In the less acute forms, the hypothermia is followed by symptoms such as anorexia, depression, bradycardia, hypoglycemia, subcutaneous edema, erythema and ventral papules, soft yellowish-gray stools, abdominal pains, vomiting, incessant whining, pedaling and death within 24 to 72 hours in opisthotonus. The necropsic examination may reveal an enlarged spleen, serous effusion in the pleural and peritoneal cavities and visceral petechia (Pierson et al., recueil de Médecine Vétérinaire, March/April 1998, 174 No. 3/4, 87-94). This article recalls that no vaccine against canine herpesvirosis is currently marketed and suggests that it would be useful to be able to vaccinate latent infected breeders in order to attenuate the re-excretion of the wild-type virus.
On the other hand, in her article (Rec. Med. Vet., 1982, 158, 669-676), F. Delisle proposes vaccinating bitches before gestation with an inactivated vaccine or injecting the puppies with a serum at whelping. She recalls, however, that no commercial vaccine is available. See also L. E. Carmichael, J. Am. Vet. Med. Assoc., 1970, 156, 1714-1721. In his article (“Canine Herpesvirus” in Virus Infections of Vertebrates, vol. 1, M. C. Horzinek, Ed. M. J. Appel, Elsevier Science Publisher, 1987, 5-15), A. Appel proposes vaccinating bitches before or at the very start of gestation with an inactivated vaccine.
H. Poulet and P. Dubourget (Point Vét., 1993, 25, 69-75) suggested in 1992, in general terms, the vaccination of the mother with a booster vaccination at the end of gestation. The authors also recall that tests using attenuated variants were carried out (L. E. Carmichael et al., Infection and Immunity, 1978, 20(1), 108-114; U.S. Pat. No. 4,213,965; attenuated live vaccine, composed of a heat-sensitive variant of the CHV virus, referred to as being “of small plaque”), but these tests did not yield any convincing results and did not lead to the marketing of vaccines.
In his article (Vet. Med., April 1991, 4, 394-403), J. O. Anvik points out that the production of neutralizing antibodies in the mother and consequently the protection of the litter is unpredictable on account of the low immunogenicity of the CHV virus.
Faced with the difficulty of vaccination, Pierson et al. (recueil de Médecine Vétérinaire, March/April 1998, 174 No.3/4, 87-94) even went as far as to propose vaccinating the mother with an inactivated vaccine against felid herpesvirus (FHV) or administering anti-FHV antibodies to puppies at whelping.
To date, none of the vaccination hypotheses has been confirmed, no vaccine is commercially available and no publication has presented convincing vaccination results announcing the impending marketing of such a vaccine.
In addition, in gestating bitches, infection with CHV can lead to embyronic resorption, fetal mummification, abortion or premature whelping, still-birth or neonatal mortality. Placental lesions may appear.
Although vaccines against various herpesviruses exist in other animal species, including cats, it has never been possible to propose effective vaccination against canine herpesvirosis.
The object of the present invention is to develop a method for vaccination against canine herpesvirosis which allows puppies to be protected.
Another object of the invention is to produce efficient and pharmaceutically acceptable vaccines which can be used in the context of this vaccination method.
The Applicant has found, surprisingly, that it is possible to vaccinate gestating bitches and newborn puppies by administering a vaccine during the gestation period and in particular as close as possible to whelping, so as to have a high level of anti-CHV antibodies in the gestating bitch at the time of whelping, this level providing protection to the puppies at whelping by transmission of the maternal antibodies during suckling. In addition, these antibodies are substantially maintained in the puppies during the first weeks of their life, this being the period during which they are prone to disease (3 to 4 weeks). A titer of neutralizing antibodies in the bitch of greater than or equal to 0.9 log10 is preferred, more particularly a titer greater than or equal to 1.2 log10. The titers indicated are calculated according to the method described in Example 7. Vaccination of the bitch moreover leads to a reduction in the pressure of infection in the puppies. The Applicant has moreover observed, in bitches vaccinated and maintained in a contaminated environment, a higher weight of puppies at whelping and a tendency toward a higher level of gestation. These phenomena can be explained by a reduction or absence of placental lesions in the vaccinated bitches (A. Hashimoto et al., Am. J. Vet. Res., 1979, 40(9), 1236-1240; A. Hashimoto et al., Am. J. Vet. Res., 1982, 43(5), 844-850).
The objects of the invention already mentioned, as well as others, are obtained with the aid of a method for immunizing or vaccinating gestating bitches which comprises the a
Frommer William S.
Frommer & Lawrence & Haug LLP
Housel James
Kowalski Thomas J.
Li Bao Qun
LandOfFree
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