Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or...
Reexamination Certificate
1992-07-10
2004-08-24
Salimi, Ali R. (Department: 1648)
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
C435S005000, C435S236000
Reexamination Certificate
active
06780630
ABSTRACT:
This invention was supported in part through a grant or award from the National Institute of Health. The U.S. Government, therefore, may have certain rights to this invention.
FIELD OF THE INVENTION
This invention generally relates to the development of vaccines against rotavirus-induced diarrheal disease and methods of using them. More specifically, the invention relates to the development of an improved parenteral immunization using live or inactivated rotavirus preparations, alone or in combination with each other or in combination with an oral vaccine or a rotavirus subunit vaccine.
BACKGROUND OF THE INVENTION
Rotaviruses are the single most important pathogen causing severe diarrhea in children in both developed and developing countries. Conner et al.,
Current Topics in Microbiology and Immunology
, in press (1992). Rotavirus infections result in over 500,000 deaths each year among children less than 2 years of age in developing countries. Institute of Medicine, “Prospects for immunizing against rotavirus” in
New Vaccine Development, Establishing Priorities. Vol.
1
Diseases of Importance in the United States
. (National Academy Press, Washington D.C. 1985). For children with rotavirus infections in developed countries, the case mortality rate is lower, but hospitalizations are frequent.
In the United States, despite the effectiveness and availability of oral rehydration solutions, about 11% of children with symptomatic rotavirus infections who seek medical care become moderately dehydrated and require hospitalization. Koopman et al.,
Am. J. Epidemiol
. 119:114-123 (1984); Rodriguez et al.,
Pediatr. Infect, Dis. J
., 6:170-176 (1987); Glass et al.,
J. Pediatr
., 118:27-33 (1991). The Centers for Disease Control has estimated that 220,000 children are hospitalized for gastroenteritis in the United States each year and that more than half of these children have rotavirus-associated illness. Ho et al.,
J. Infect. Dis
., 158:1112-1116 (1988); LeBaron et al.,
Morbid. Mortal. Weekly Rep
., 39:1-14 (1990); Glass et al. (1991). A recent analysis of the effect of rotavirus infections at a large pediatric hospital in Houston, Tex., estimated that the risk for hospitalization for rotavirus gastroenteritis during childhood is 1 in 48; the extrapolated hospital bed costs alone for the United States were $352 million annually. Matson and Estes,
J. Infect. Dis
. 162:598-604 (1990). This estimate agrees closely with the Centers for Disease Control estimate that the annual inpatient cost of rotavirus-gastroenteritis is one billion dollars. Le Baron et al. (1990). Such data emphasize the need for a vaccine to prevent rotavirus-induced gastroenteritis during the first 2 years of life.
Several strategies have been pursued for development of a rotavirus vaccine for children. Conner et al, (1992); Kapikian et al., Adv. Exp. Med. Biol. 257:67-90 (1990). To date, most effort has been focused on the development and testing of live oral vaccines for children because these were assumed to be necessary to stimulate local mucosal antibody. Kapikian et al. (1990). Unfortunately, vaccination of young children with live oral animal (bovine, rhesus) or human (M37) vaccines or animal-human reassortant vaccines has not yet achieved sufficient take rates with good heterotypic protection in all settings. Conner et al., (1992).
The presence of pre-existing maternal antibody in children administered oral live rotavirus vaccine can interfere with the replication of the vaccine virus, and therefore, reduce the take rate of the vaccine. Cadranel et al.,
J. Pediatr. Gastroenterol. Nutr
. 6: 525-528 (1987); Tajimra et al.,
Vaccine
8:71-74 (1990). Interference by maternal antibody should not be a problem with parenterally administered vaccines. Additionally, multivalent vaccines are being tested to stimulate heterotypic immunity, but achieving a balanced formulation of several live viruses has proven difficult. Perez-Schael et al.,
J. Clin. Microbiol
. 28:553-558 (1990); Flores et al.,
Lancet
336:330-334 (1990); Vesikari et al.,
Vaccine
9:334-339 (1991); Wright et al.,
J. Infect. Dis
. 164:271-276 (1991).
Alternative strategies using non-replicating subunit vaccines have been proposed, but to date, the ability of such vaccines to induce active protective immunity has not been demonstrated. One reason for this is that relatively few animal models are available to test the ability of a vaccine candidate to induce active protection. For example, only passive protection can be studied in the widely used neonatal mouse model of rotavirus infection because mice are only susceptible to diarrheal disease up to 14 days of age. Wolf et al.,
Infect. Immun
. 33:565-574 (1981); Ramig, Microb. Pathog. 4:189-202 (1988).
A model of rotavirus infection in rabbits that mimics infections in children has been developed. The model is useful to monitor the development of active serum and mucosal immunity and protection from challenge against rotavirus. Conner et al.,
J. Virol
. 62:1625-1633 (1988); Conner et al.,
J. Virol
. 65:2563-2571 (1991); Thouless et al.,
Arch. Virol
. 89:161-170 (1986); Hambraeus et al.,
Arch. Virol
. 107:237-251 (1989).
Currently, measurement of protection in the rabbit model is not based on clinical illness, as diarrhea is not consistently seen in the rabbit following rotavirus inoculation due to the extremely efficient fluid absorption of the rabbit cecum. However, histopathologic changes observed over the entire length of the small intestine of infected rabbits (Gilger et al.,
Gastroenterology
194:A146 (1989)), changes in the amount and consistency of intestinal fluid, and the kinetics of virus shedding after infection of antibody-negative rabbits with virulent Ala virus are evidence of productive virus infection, as seen in experimental infections in other animal models and in natural infections in children where clinical diarrhea is observed. Other experiments have shown that detection of infectious virus by plaque assay and excretion of rotavirus antigen by ELISA were of comparable sensitivity. Conner et al. (1988).
The ability of anti-rotavirus IgG to mediate protection has previously been reported in passive protection studies in the suckling mouse model. Offit and Clark,
J. Virol
. 54:58-64 (1985); Offit and Dudzik,
J. Clin. Microbiol
. 27:885-888 (1989); Offit et al.,
J. Virol
. 58:700-703 (1986); Matsui et al.,
J. Clin. Micobiol
. 27:780-782 (1989); Sheridan et al.,
J. Infect Dis
. 149:434-438 (1984). The ability of IgG present in the intestine to mediate protection from infection, ameliorate disease, or reduce virus excretion in children has been shown by the use of bovine milk or serum immunoglobulin from hyperimmunized cows for passive treatments in children. Barnes et al., Lancet 1:1371-1373 (1982); Losonsky et al.,
J. Clin. Invest
. 76:2362-2367 (1985); Brussow et al.,
J. Clin Microbiol
. 25:932-986 (1987); Hilpert et al.,
J. Infect. Dis.
156:158-166 (1987). Circulating anti-rotavirus antibody which mediated protection in colostrum-deprived calves has been reported following administration of high titer antibody by subcutaneous injection. Besser et al.,
J. Virol
. 62:2238-2242 (1988a). This protection was shown to be mediated by the transfer of circulating IgG, to the intestine. Besser et al. (1988a); Besser et al.,
J. Virol
. 62:2234-2237 (1988b).
Little information is available on the direct comparisons of live and inactivated virus as it relates to changes in immunogenicity of inactivated rotaviruses. Inactivation of bovine RIT 4237 rotavirus strain by formalin was reported to cause alterations of the virus and parenteral (intramuscular) or intragastric vaccinations with such virus failed to induce cross-protection of piglets challenged with human rotaviruses. Zissis et al.,
J. Infec. Dis
. 148:1061-1068 (1983). Inactivation of rotavirus strain RRV by &bgr;-propiolactone has been reported to cause changes in VP4 reactivity, determined by comparison of hemagglutination titers of live and inactivated virus, although passive protection of mice pups still was ac
Conner Margaret E.
Estes Mary K.
Baylor College of Medicine
Fulbright & Jaworski L.L.P.
Salimi Ali R.
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