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
1999-07-09
2002-06-25
Park, Hankyel T. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C424S185100, C424S199100, C424S211100, C424S212100, C435S069100, C435S440000, C435S252300, C435S320100
Reexamination Certificate
active
06410023
ABSTRACT:
BACKGROUND OF THE INVENTION
Introduction
Human parainfluenza virus type 3 (HPIV3) is a common cause of serious lower respiratory tract infection in infants and children less than one year of age. It is second only to respiratory syncytial virus (RSV) as a leading cause of hospitalization for viral lower respiratory tract disease in this age group (Collins et al., p. 1205-1243. In B. N. Fields (Knipe et al., eds), Fields Virology, 3rd ed, vol. 1. Lippincott-Raven Publishers, Philadelphia, 1996; Crowe et al.,
Vaccine
13:415-421, 1995; Marx et al.,
J. Infect. Dis.
176:1423-1427, 1997). Infections by this virus results in substantial morbidity in children less than 3 years of age. HPIV1 and HPIV2 are the principal etiologic agents of laryngotracheobronchitis (croup) and also can cause severe pneumonia and bronchiolitis (Collins et al., 3rd ed.
In “Fields Virology,”
B. N. Fields, D. M. Knipe, P. M. Howley, R. M. Chanock, J. L. Melinck, T. P. Monath, B. Roizman, and S. E. Straus, Eds., Vol. 1, pp. 1205-1243. Lippincott-Raven Publishers, Philadelphia, 1996). In a long term study over a 20-year period, HPIV1, HPIV2, and HPIV3 were identified as etiologic agents for 6.0, 3.2, and 11.5%, respectively, of hospitalizations for respiratory tract disease accounting in total for 18% of the hospitalizations, and, for this reason, there is a need for an effective vaccine (Murphy et al.,
Virus Res
11, 1-15, 1988). The parainfluenza viruses have also been identified in a significant proportion of cases of virally-induced middle ear effusions in children with otitis media (Heikkinen et al.,
N Engl J Med
340:260-4, 1999). Thus, there is a need to produce a vaccine against these viruses that can prevent the serious lower respiratory tract disease and the otitis media that accompanies these HPIV infections.
Despite considerable efforts to develop effective vaccine therapies against HPIV, no approved vaccine agents have yet been achieved for any HPIV strain, nor for ameliorating HPIV related illnesses. To date, only two live attenuated PIV vaccine candidates have received particular attention. One of these candidates is a bovine PIV (BPIV3) strain that is antigenically related to HPIV3 and which has been shown to protect animals against HPIV3. BPIV3 is attenuated, genetically stable and immunogenic in human infants and children (Karron et al.,
J. Inf. Dis.
171:1107-14 (1995a); Karron et al.,
J. Inf. Dis.
172:1445-1450, (1995b)). A second PIV3 vaccine candidate, JS cp45 is a cold-adapted mutant of the JS wildtype (wt) strain of HPIV3 (arron et al., (1995b), supra; Belshe et al.,
J. Med. Virol.
10:235-42 (1982)). This live, attenuated, cold-passaged (cp) PIV3 vaccine candidate exhibits temperature-sensitive (ts), cold-adaptation (ca), and attenuation (att) phenotypes which are stable after viral replication in vivo. The cp45 virus is protective against human PIV3 challenge in experimental animals and is attenuated, genetically stable, and immunogenic in seronegative human infants and children (Hall et al.,
Virus Res.
22:173-184 (1992); Karron et al., (1995b), supra).
To facilitate development of PIV vaccine candidates, recombinant DNA technology has recently made it possible to recover infectious negative-stranded RNA viruses from cDNA (for reviews, see Conzelmann,
J. Gen. Virol.
77:381-89 (1996); Palese et al., Proc. Natl. Acad. Sci. U.S.A. 93:11354-58, (1996)). In this context, recombinant rescue has been reported for infectious respiratory syncytial virus (RSV), rabies virus (RaV), vesicular stomatitis virus (VSV), measles virus (MeV), rinderpest virus, simian virus 5 (SV5), Newcastle disease virus (NDV), and Sendai virus (SeV) from cDNA-encoded antigenomic RNA in the presence of essential viral proteins (see, e.g., Garcin et al.,
EMBO J.
14:6087-6094 (1995); Lawson et al., Proc. Natl. Acad. Sci. U.S.A. 92:4477-81 (1995); Radecke et al.,
EMBO J.
14:5773-5784 (1995); Schnell et al.,
EMBO J.
13:4195-203 (1994); Whelan et al.,
Proc. Natl. Acad. Sci. U.S.A.
92:8388-92 (1995); Hoffman et al.,
J. Virol.
71:4272-4277 (1997); Kato et al.,
Genes to Cells
1:569-579 (1996), Roberts et al.,
Virology
247(1), 1-6 (1998); Baron et al.,
J. Virol.
71:1265-1271 (1997); International Publication No. WO 97/06270; Collins et al.,
Proc. Natl. Acad. Sci. USA
92:11563-11567 (1995); U.S. patent application Ser. No. 08/892,403, filed Jul. 15, 1997 (corresponding to published International Application No. WO 98/02530 and priority U.S. Provisional Application Nos. 60/047,634, filed May 23, 1997, 60/046,141, filed May 9, 1997, and 60/021,773, filed Jul. 15, 1996); Juhasz et al.,
J. Virol.
71(8):5814-5819 (1997); He et al.
Virology
237:249-260 (1997); Baron et al.
J. Virol.
71:1265-1271 (1997); Whitehead et al.,
Virology
247(2):232-9 (1998a); Whitehead et al.,
J. Virol.
72(5):4467-4471 (1998b); Peeters et al.
J. Virol.
73:5001-5009, 1999; Jin et al.
Virology
251:206-214 (1998); Bucholz et al.
J. Virol.
73:251-259 (1999); and Whitehead et al.,
J. Virol.
73:(4)3438-3442 (1999), each incorporated herein by reference in its entirety for all purposes).
In more specific regard to the instant invention, a method for producing HPIV with a wt phenotype from cDNA was recently developed for recovery of infectious, recombinant PIV3 JS strain (see, e.g., Durbin et al.,
Virology
235:323-332, 1997; U.S. patent application Ser. No. 09/083,793, filed May 22, 1998; U.S. Provisional Application No. 60/047,575, filed May 23, 1997 (corresponding to International Publication No. WO 98/53078), and U.S. Provisional Application No. 60/059,385, filed Sep. 19, 1997, each incorporated herein by reference). In addition, these disclosures allow for genetic manipulation of cDNA clones to determine the genetic basis of phenotypic changes in biological mutants, e.g., which mutations in the HPIV3 cp45 virus specify its ts, ca and att phenotypes, and which gene(s) of BPIV3 specify its attenuation phenotype. Additionally, these disclosures render it feasible to construct novel PIV vaccine candidates and to evaluate their level of attenuation, immunogenicity and phenotypic stability.
Thus, infectious wild type recombinant PIV3 (r)PIV3, as well as a number of ts derivatives, have now been recovered from cDNA, and reverse genetics systems have been used to generate infectious virus bearing defined attenuating mutations and to study the genetic basis of attenuation of existing vaccine viruses. For example, the three amino acid substitutions found in the L gene of cp45, singularly or in combination, have been found to specify the ts and attenuation phenotypes. Additional ts and attenuating mutations are present in other regions of the PlV3cp45. In addition a chimeric PIV1 vaccine candidate has been generated using the PIV3 cDNA rescue system by replacing the PIV3 HN and F open reading frames (ORFs) with those of PIV1 in a PIV3 full-length cDNA that contains the three attenuating mutations in L. The recombinant chimeric virus derived from this cDNA is designated rPIV3-1.cp45L (Skiadopoulos et al.,
J Virol
72:1762-8, 1998; Tao et al.,
J Virol
72:2955-2961, 1998; Tao et al.,
Vaccine
17:1100-1108, 1999, incorporated herein by reference). rPIV3-1.cp45L was attenuated in hamsters and induced a high level of resistance to challenge with PIV1. A recombinant chimeric virus, designated rPIV3-1.cp45, has been produced that contains 13 of the 15 cp45 mutations, i.e., excluding the mutations in HN and F, and is highly attenuated in the upper and lower respiratory tract of hamsters (Skiadopoulos et al.,
Vaccine
In press, 1999).
Despite these numerous advances toward development of effective vaccine agents against different PIV groups, there remains a clear need in the art for additional tools and methods to engineer safe and effective vaccines to alleviate the serious health problems attributable to PIV, particularly illnesses among infants and children due to infection by HPIV3. Among the remaining challenges in this context is the need for additional tools to generate suitably attenuated, immunogenic and geneticall
Collins Peter L.
Durbin Anna P.
Murphy Brian R.
Brown Stacy S.
Park Hankyel T.
United States of America
Woodcock Woodcock LLP
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