Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1999-03-24
2001-08-28
Mosher, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S226100, C435S235100, C435S325000, C435S975000, C514S04400A, C536S023720
Reexamination Certificate
active
06280734
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to molecular approaches to the development of a live hepatitis A vaccine. In particular, the invention relates to nucleic acid sequences which encode hepatitis A viruses having a chimeric 2C protein. More specifically, the nucleic acid sequences of the invention comprise a genome of a human hepatitis A virus strain which contains a chimeric 2C gene consisting of sequences from both a human strain and the simian AGM-27 strain. The invention further relates to the use of these viruses, or the nucleic acid sequences encoding them, as vaccines.
BACKGROUND OF THE INVENTION
Hepatitis A virus (HAV) is a picornavirus with a ~7.5 kb positive strand RNA genome and is the sole member of the Hepatovirus genus (Francki, R. I. B., et al. (1991) Classification and Nomenclature of Viruses. (Arch. Virol./Suppl. 2). Springer, Vienna). The clinical manifestations of HAV infection in humans can vary greatly, ranging from asymptomatic infection, commonly seen in young children, to fulminant hepatitis, which in some cases can result in death (Ross, B. C., et al. (1991)
Adv. Virus Res.,
39:209-253).
In attempting to prevent hepatitis A, three general strategies are possible: 1) increasing hygiene standards; 2) passive immunization of those known to be exposed to HAV with normal human immune globulin; and 3) the development of HAV vaccines. However, because sanitation levels in underdeveloped countries remain low and passive immunization offers little hope for control of endemic hepatitis A since most cases of hepatitis A occur in individuals who do not have a specific exposure history, considerable research efforts have been devoted to the development of either live or killed vaccines.
With respect to killed or inactivated vaccines, numerous laboratories have reported the development of inactivated HAV vaccines (see, for example, Binn, L. N. et al. (1986)
J. Inf. Dis.,
153:749; Provost, P. J. et al. (1986)
J. Med. Virol.,
19:23; Flehmig, B. et al. (1989) Lancet i:1039 and Andre, F. E. et al. (1990)
Progress in Med. Virol.,
37:72) and SmithKline Beecham and Merck have recently licensed and sold inactivated HAV vaccines containing different strains of HAV. However, the high cost of inactivated HAV vaccines makes their use in other than high-risk individuals unlikely. In addition, questions concerning the duration of immunity induced by inactivated HAV vaccines suggests that multiple doses may need to be administered to confer continued protection. Thus, for these reasons, the widespread use of live attenuated HAV vaccines in underdeveloped countries where hepatitis A is endemic may be more feasible and more efficacious than use of inactivated vaccines.
In attempting to develop a live attenuated vaccine, numerous investigators have selected attenuated hepatitis A viruses by passage of wild-type HAV strains in cell culture (see, for example, Provost et al. (1986)
J. Med. Virol.,
20:165-176; Karron, R. A. et al. (1988)
J. Infect. Dis.,
157:338-345). However, attenuation of HAV strains during adaptation to growth in cell culture has been observed to result in overattenuation such that the attenuated viruses, when administered as live vaccines,are no longer effective inducers of anti-HAV antibodies in vivo (Provost, P. J. et al. (1986)
J. Med. Virol.,
20: 165-175).
A potential alternative approach to the production of a candidate live attenuated vaccine strain which grows sufficiently well in a cell line to make vaccine production economically feasible and which is also infectious, immunogenic and avirulent in humans, is the use of recombinant DNA methodology to construct chimeric HAV genomes.
SUMMARY OF THE INVENTION
The present invention relates to nucleic acid sequences which comprise a genome of a human hepatitis A strain which contains a chimeric 2C gene consisting of sequences from both the human strain and the simian AGM-27 strain. The nucleic acid sequences of the invention are designated “2C chimeric genomes”.
It is therefore an object of the invention to provide nucleic acid sequences which encode hepatitis A viruses having a chimeric 2C protein. For the purposes of this application, nucleic acid sequence refers to RNA, DNA, CDNA or any variant thereof capable of directing host organism synthesis of hepatitis A viruses having a chimeric 2C protein.
The invention also relates to hepatitis A viruses encoded by the 2C chimeric genomes. These viruses are designated “2C chimeric hepatitis A viruses.”
The invention further provides vaccines for use in immunizing a mammal against hepatitis A. In one embodiment, the vaccine comprises a 2C chimeric hepatitis A virus. In a second embodiment, the vaccine comprises a 2C chimeric genome which encodes a hepatitis A virus having a chimeric 2C protein.
The invention therefore also relates to methods for preventing hepatitis A in a mammal. In one embodiment, the method comprises administering to a mammal an amount of a 2C chimeric genome of the invention effective to induce protective immunity against hepatitis A. In another embodiment, the method of prevention comprises administering to a mammal a 2C chimeric hepatitis A virus in an amount effective to induce protective immunity against hepatitis A.
The invention also provides pharmaceutical compositions comprising the 2C chimeric genome of the invention and/or their encoded hepatitis A viruses.
The invention further provides kits comprising the 2C chimeric nucleic acid sequences of the invention.
The invention further relates to antibodies to 2C chimeric hepatitis A viruses and to pharmaceutical compositions comprising these antibodies.
REFERENCES:
patent: 5476658 (1995-12-01), Tsarev et al.
Emerson et al Journal of Infectious Diseases 173(3): 592-597, Mar. 1996.*
Emerson et al Journal of Virology 66(11):6649-6654, 1992.*
McDonnell et al New England Journal of Medicine 334(1): 42-45, Jan. 1996.
Emerson Suzanne U.
Purcell Robert H.
Raychaudhuri Gopa
Morgan & Finnegan , LLP
Mosher Mary E.
The United States of America as represented by the Department of
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