Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
1995-04-17
2001-02-20
Bui, Phuong T. (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S007100, C435S235100, C435S236000, C435S239000, C424S218100, C424S202100, C424S184100, C536S023720, C530S300000, C530S350000, C530S388300, C530S389400
Reexamination Certificate
active
06190859
ABSTRACT:
INTRODUCTION
Dengue is an acute viral disease of man which is transmitted by mosquitos. It is endemic in the tropics and subtropics, worldwide, where an estimated 100,000,000 cases occur annually (Reviewed in Henchal and Putnak,
Clin. Microbiol. Revs
3: 376-96, 1990. The entire content of all documents cited herein are hereby incorporated by reference). Dengue is characterized clinically by biphasic fever, rash and hematopoietic depression, and by constitutional symptoms such as malaise, arthralgia, myalgia and headache (Reviewed in Monath, Flaviviruses. In: Fields, B. N. et al.
Fields Virology,
2nd ed. Vol 1, New York: Raven Press, 1990, p. 763-814). Infrequently, more severe disease is seen, manifested by hemorrhage which may progress to lethal shock (Halstead, S. B.
Yale J. Biol. Med.
37: 434-54, 1965). The timing of these manifestations, somewhat after the early febrile period, and their frequent association with secondary dengue infection and pre-existing antibody has led to the hypothesis that they are immunologically mediated (Halstead, S. B.
Yale J. Biol. Med.
42: 350-62, 1970; Sankawibha et al.
Am. J. Epidemiol.
120: 653-69, 1984). Although relatively rare, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) may be significant causes of death in children. At present, there is no vaccine to protect against dengue and attempts to prevent disease by controlling the mosquito vector have proven largely ineffective.
Dengue viruses are members of the family
flaviviradae
which includes over sixty members (Westaway, E. G. et al.
Intervirology
24:183-92, 1985). Within the dengue group are four serotypes, dengue-type-one (dengue-1), dengue-2, dengue-3, and dengue-4, among which there is considerable genetic and antigenic similarity but no significant cross-neutralization (Calisher C. H. et al.
J. Gen. Virol.
70: 37-43, 1989). Like the family prototype, yellow fever (YF) virus, they are enveloped, single-stranded RNA viruses approximately 50 nm in size (Reviewed in Henchal and Putnak, 1990, supra). Their 10.5 kilobase (kb) genome encodes ten proteins, three virion structural proteins at the 5′ end of the RNA beginning with capsid (C), matrix (M), its precursor pre-matrix (prM) and envelope (E), followed by seven nonstructural (NS) proteins, NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 (Chambers, T. J. et al. Annu. Rev. Microbiol. 44: 649-88, 1989). Virus neutralizing antibody, thought to play a primary role in immunity, is directed against the E protein (Qureshi, A. A. and Trent, D. W.
Infect. Immun.
8: 993-9, 1973; Gentry, M. K. et al.
Am. J. Trop. Med. Hyg.
31: 548-55, 1982), however, antibodies and T-cells directed against epitopes of other structural and even nonstructural proteins may also be important in subserving immunity to virus infection (Schlesinger, J. J. et al.,
J. Gen. Virol.
68:853-57, 1987).
Currently, only two flavivirus vaccines have been licensed by the United States Food and Drug Administration (FDA) for human use, live-attenuated yellow fever virus (17D strain) developed by Theiler and coworkers in the 1930s (Theiler, M. and Smith, H. H.
J. Exp. Med.
65: 748-800, 1937), and purified, formalin-inactivated Japanese encephalitis (JE) virus developed in the 1960s in Japan (Takaku , K. et al.,
Biken J.
11
:
25
-
39
,
1968
). Both have proven to be safe and effective, eliciting high titers of virus-neutralizing antibody and conferring solid protection (Hoke, C. H. et al.
N. Engl. J. Med.
319: 608-13, 1988; Reviewed in Monath, 1990, supra). Also of note is a purified, formalin-inactivated vaccine for tick-borne encephalitis virus developed in the 1970s in Austria (Kunz, C. et al. J. Med. Virol. 6: 103-9, 1980) which is used successfully in many European countries.
In recent attempts to develop second generation flavivirus vaccines, much work has been done using recombinant, complimentary DNA (cDNA) technology (Reviewed in Schlesinger, J. J. et al. In: Ellis R. W.
Vaccines: New Approaches to Immunological Problems
. Boston: Butterworth-Heinemann, 1992, p. 289-307; and Putnak, R. In:
Kurstak E. Modem Vaccinology.
New York: Plenum Medical, 11: 231-52, 1994). Full-length, infectious, cDNA clones which are now available for YF (Rice, C. M. et al.
New Biologist
1: 285-96, 1989), JE (Sumiyoshi, H. et al.
J. Virol.
66: 5425-31, 1992), and dengue-4 (Lai, C. J. et al.
Proc. Natl. Acad. Sci. U.S.A.
88: 5139-43, 1991) viruses offer the exciting possibility of making genetically-engineered attenuated vaccines, while in vitro expression systems allow production of recombinant subunit antigens (Reviewed in Putnak, 1994, supra). Although promising, these technologies have yet to yield practical alternatives to existing vaccines.
The history of dengue virus vaccine development goes back more than fifty years, beginning with attempts in the 1920s to inactivate dengue viruses from infectious human plasma with ox bile or formalin (Simmons, J. S. et al. In:
Brown W. H. Monographs of the Bureau of Science, Monograph
29. The philippines: Manila Bureau of Printing 1:489, 1931), and attempts in the 1940s to attenuate viruses by serial passage in the brains of suckling mice (Sabin, A. B. and Schlesinger, R. W.
Science
101: 640-42, 1945). More recent attempts to make attenuated dengue vaccines by serial passage of viruses in primary cell cultures have met with some success (Eckels, K. H. et al.
Infect. Immun.
27: 175-80, 1980
, Am. J. Trop. Med. Hyg.
33: 684-89, 1984; Halstead, S. B. et al.
Am J. Trop. Med. Hyg.
33: 679-83, 1984; Bancroft, W. H. et al.
J. Infect. Dis.
149: 1005-10, 1984; Bhamarapravati, N. et al. WHO Bull. 65: 189-95, 1987; Bhamarapravati, N. and Yoksan, S.
Lancet
8646: 1077, 1989; Hoke, C. H. Jr. et al.
Am. J. Trop. Med. Hyg.
43: 219-26, 1990; Reviewed in Brandt, W. et al.
Am J. Trop. Med. Hyg.
16: 339-47, 1967; Edelman, R. et al.
J. Infect. Dis.
170: 1448-55, 1994), although it has been difficult to identify candidates which are both suitably attenuated and immunogenic, nor is it certain that these viruses will prove to be genetically stable.
Despite the existence of several safe, effective, and economical inactivated viral vaccines, it has been contended that such an approach is neither feasible nor practical for dengue because of the relatively poor growth of these viruses in culture and their questionable antigenic stability after purification. A dengue virus vaccine candidate has been produced previously using unpurified, formalin-inactivated type 2 viurs (Dubois, D. R., Ph.D. Thesis, The Catholic University of America, 1980). However, this preparation did not elicit high titers of anti-dengue virus antibody nor did it uniformly protect mice, an accepted animal model, against virus challenge. In addition, this study did not demonstrate that dengue viruses could be propagated to high titers or employ purified viruses in making the vaccine, thus, the vaccine described in this study was not likely to be practical or suitable for use in humans.
Therefore, in view of the above, there is a need for a dengue virus vaccine which will elicit high titers of virus neutralizing antibody, protect against viral infection without risk of disease to the immunized mammal, is physically stable allowing easy and economical transport and storage, and is suitable for human use.
SUMMARY
The present invention is directed to a vaccine that satisfies this need. The purified inactivated dengue viruses vaccine of the present invention has a major advantage over attenuated dengue virus in that inactivated viruses are not infectious and therefore, can not revert to virulence or cause disease. Another advantage of inactivated over attenuated dengue viruses is their potentially greater physical stability (e.g., to temperature changes) allowing easy and economical transport and storage of the vaccine. In addition, inactivated dengue viruses may be expected to afford enhanced immunogenicity and greater protection against disease than recombinant dengue proteins due to their native conformation.
The purified, inactivated dengue viru
Cassidy Kevin
Dubois Doria R.
Eckels Kenneth
Putnak J. Robert
Arwine Elizabeth
Bui Phuong T.
Harris Charles H.
Moran John Francis
The United States of America as represented by the Secretary of
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