Rotavirus reassortant vaccine

Details Rotavirus reassortant vaccine Rotavirus reassortant vaccine

2000-07-28

2001-09-18

Stucker, Jeffrey (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Virus or component thereof

C424S215100, C424S093100, C424S093200, C424S093600, C435S235100, C435S236000

Reexamination Certificate

active

06290968

ABSTRACT:

FIELD OF THE INVENTION
The present invention refers generally to novel rotavirus reassortants, vaccines employing the novel reassortants and methods for their preparation and administration.
BACKGROUND OF THE INVENTION
Rotaviruses are the single most important agent of acute gastroenteritis, a disease which requires hospitalization of infants and young children in developed countries, and a frequent cause of death in children less than 5 years of age in developing regions of the world. Studies in the United States, Australia, and Japan have demonstrated that between 34 and 63% of hospitalizations of children for acute diarrheal disease are associated with rotavirus infection [A. Z. Kapikian et al,
Rev. Infect. Dis.,
2:459-469 (1980)]. The incidence of hospitalization for rotavirus gastroenteritis in a health maintenance organization in the U.S. was estimated to be 222 per 100,000 in children from 13 to 24 months of age, and 362 per 100,000 in those less than one year [W. Rodriguez et al,
Am. J. Dis. Child.,
13:777-779 (1980)]. Infection with rotavirus was associated with 63% of all hospitalizations for acute diarrhea in this pediatric population [W. Rodriguez et al, cited above]. A recent review of mortality data in the U.S. from 1973 to 1983 indicated that 500 deaths per year occur in children less than 4 years old due to diarrheal diseases, and that 20 to 80% of excess winter deaths due to diarrhea in the U.S. are associated with rotavirus infections [M -S. Ho et al;
JAMA,
26:3281-3285 (1988)]. Rotaviruses are also responsible for a substantial proportion of the mortality associated with diarrheal diseases in third world countries. An effective rotavirus vaccine would therefore have a major impact on the health of children in both the developed and developing areas of the world.
Rotaviruses have an inner and outer capsid with a double-stranded RNA genome formed by eleven gene segments. Multiple serotypes have been defined by plaque reduction neutralization tests, and studies of reassortant viruses have demonstrated that two outer capsid proteins, v.p.7 and v.p.4, are the determinants of virus serotype. The v.p.7 protein is coded for by either gene segment 7, gene segment 8 or gene segment 9 of the particular human rotavirus. The location of the v.p.7 encoding gene may be determined for each specific rotavirus by conventional experimental methods. The protein v.p.4 is an 88,000 dalton major surface structural protein product of gene 4 of a rotavirus. Like v.p.7, it functions as a major serotype-specific antigen, operative in serum neutralization (SN) tests, capable of inducing serotype-specific neutralizing antibody, and capable in a mouse system of inducing serotype specific immune protection against rotavirus disease. [See, Offit et al, (1986) supra]. In some earlier references, the v.p.4 was referred to as v.p.3. After 1988, a change in nomenclature, resulted in the more proper reference to this protein as v.p.4 [M. Liu et al,
Virol.,
16:26-32 (1988) and M. K. Estes et al,
Immunol. Invest.,
18:571-581 (1989)].
Since the gene segments encoding the v.p.7 and v.p.4 proteins segregate independently [Y. Hoshino et al,
Proc. Natl. Acad. Sci. USA,
12:8701-8704 (1985) and P. Offit et al,
J. Virol.,
57:376-378 (1986)], it has been proposed that serotyping nomenclature include both the G type, determined by v.p.7, and the P type, determined by v.p.4 [M. Estes et al,
Microbiological Reviews,
52:410-449 (1989)]. Most human rotavirus infections in the U.S. are caused by viruses of G types 1, 2, 3, or 4, and P types 1, 2, or 3 [V. Gouvea et al,
J. Infect. Dis.,
162:362-367 (1990), P. Woods et al,
J. Clin. Microbiol.,
30:781-785 (1992), and J. Gentsch et al,
J. Clin. Microbiol.,
30:1365-1373 (1992)]. However, other human rotavirus types, including for example, type G9, are more prevalent in Asia, Europe and certain third world countries.
A number of animal rotaviruses are attenuated in humans, and have been evaluated as potential live rotavirus vaccines, including the bovine serotype G6 WC3 rotavirus. The WC3 vaccine virus was shown to be immunogenic and non-reactinogenic in infants [H F. Clark et al,
American Journal Diseases of Children,
140:350-356 (1986) and H F. Clark et al,
J. Infect. Dis.,
158:570-587 (1988)], but was inconsistent in providing protective immunity against human rotavirus infection [H F. Clark et al,
J. Infect. Dis.,
15:570-587 (1988), D. Bernstein et al,
J. Infect. Dis.,
162:1055-1062 (1990), and M. Georges-Courbot et al,
Res. Virol.,
142:405-411 (1991)]. However, it has been proposed that serotype-specific immunity is necessary to induce consistent protection against rotavirus diarrhea [J. Flores et al,
Lancet,
1:882-884 (1987) and C. Christy et al,
Pediatr. Infect. Dis.,
7:645-650 (1988)].
There exists a need in the art for effective vaccines providing protective immunity against rotavirus infection and the severe clinical symptoms associated therewith.
SUMMARY OF THE INVENTION
The present invention provides rotavirus reassortants useful as safe and efficacious vaccines for preventing human rotavirus infection and the clinical symptoms associated with severe rotavirus disease.
In one aspect the invention provides a rotavirus reassortant derived from human and non-human rotavirus parental strains, which reassortant contains from a human rotavirus parental strain at least the gene (or gene segment) encoding the virion surface protein v.p.7 neutralization antigen. The non-human gene segments of the reassortant are preferably provided by the WC3 bovine rotavirus strain or progeny thereof.
In another aspect the invention provides a rotavirus reassortant containing from a human rotavirus parental strain at least the gene encoding the v.p.4 neutralization antigen. The non-human gene segments are preferably provided from the WC3 bovine rotavirus parental strain or progeny thereof.
As another aspect of this invention there is provided a vaccine for providing immunological protection against acute diarrhea caused by human rotavirus which contains at least one of the novel rotavirus reassortants of the present invention. One particularly preferred univalent vaccine of the invention comprises the reassortant WI79-3,9 (serotype G1). Particularly desirable vaccines contain the reassortant WI79-3,9 in combination with at least one other rotavirus-reassortant selected from a G2, G3, G4, P1 and P2 rotavirus reassortant of the invention.
Another aspect of the invention provides a method of vaccinating humans against human rotavirus infection employing the reassortant vaccines of the invention. This vaccination method may also employ more than one of the vaccine compositions of this invention.
Other aspects and advantages of the present invention will be apparent upon consideration of the following detailed description of the invention, including illustrative examples of the practice thereof.
DETAILED DESCRIPTION OF THE INVENTION
This invention involves rotavirus reassortants suitable for use as vaccines, which are characterized by safety to humans and the ability to confer immune protection against human rotavirus infection. The reassortants are produced by genetic reassortment between an attenuated bovine rotavirus (preferably WC3 or progeny thereof) and at least one rotavirus representing an epidemiologically important human serotype. In one embodiment of this invention, the human rotavirus contributes to the reassortant at least the gene segment encoding the v.p.7 protein. In another embodiment of this invention, the human rotavirus parent contributes to the reassortant at least the gene segment encoding the v.p.4 protein. In still a further embodiment, the human rotavirus parental strain contributes at least both the v.p.7 and v.p.4 gene segments. In additional embodiments, the human rotavirus parental strain may contribute gene segments in addition to those which encode the v.p.7 and/or v.p.4 antigens.
The human rotavirus

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