Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1995-05-30
2001-09-04
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C435S236000, C435S237000
Reexamination Certificate
active
06284254
ABSTRACT:
BACKGROUND OF THE INVENTION
Respiratory syncytial (RS) virus infection of humans ranges from asymptomatic to severe respiratory tract disease. In infants and children, RS virus (RSV) is regarded as one of the most important causes of lower respiratory tract disease in all geographic areas of the world. RS virus outranks all other microbial pathogens as a cause of pneumonia and bronchiolitis in infants under one year of age, and is a major cause of fatal respiratory tract disease in these infants. Virtually all children are infected by two years of age. Reinfection occurs with appreciable frequency in older children and young adults. (Chanock et al., in
Viral Infections of Humans
, 3rd ed., A. S. Evans, ed., Plenum Press, N.Y. (1989)). Although most healthy adults do not have serious disease due to RS virus infection, elderly patients and immunocompromised individuals are more likely to have severe and possibly life-threatening infections.
Treatment of RSV infection has been problematic. Small infants have diminished serum and secretory antibody responses to RSV antigens and thus suffer more severe infections, whereas cumulative immunity appears to protect older children and adults against more serious forms of the infection. One antiviral compound, ribavirin, has shown promise in the treatment of severely infected infants, although there is no indication that it shortens the duration of hospitalization or diminishes the infant's need for supportive therapy.
The mechanisms of immunity in RSV infection have recently come into focus. Secretory antibodies appear to be most important in protecting the upper respiratory tract, whereas high levels of serum antibodies are thought to have a major role in resistance to RSV infection in the lower respiratory tract. Purified human immunoglobulin containing a high titer of neutralizing antibodies to RSV may prove useful in immunotherapeutic approaches for serious lower respiratory tract disease in infants and young children. Immune globulin preparations, however, suffer from several disadvantages, such as the possibility of transmitting blood-bome viruses and difficulty and expense in preparation and storage.
Despite an urgent need for an effective vaccine against RS virus, particularly for infants and young children, previous attempts to develop a safe and effective vaccine have met with failure. A formalin-inactivated virus vaccine tested in the mid-1960s failed to protect against RS virus infection or disease. Instead, disease was exacerbated during subsequent infection by RS virus. Kim et al.,
Am. J. Epidemiol
. 89:422-434, Chin et al.,
Am J. Epidemiol
. 89:449-463 (1969); Kapikian et al.,
Am. J. Epidemiol
. 89:405-421 (1969).
To circumvent the problems attendant with the inactivated vaccines and the possible alteration of neutralization epitopes, efforts were directed to developing attenuated RS mutants. Friedewald et al.,
J. Amer. Med. Assoc
. 204:690-694 (1968) reported the production of a low-temperature passaged mutant of RS virus which appeared to possess sufficient attenuation to be a candidate vaccine. This mutant exhibited a slight increased efficiency of growth at 26° C. compared to its wild-type parental virus, but its replication was neither temperature sensitive nor significantly cold-adapted. The cold-passaged mutant, however, was attenuated for adults. Although satisfactorily attenuated and immunogenic for infants and children who had been previously infected with RSV (i.e., seropositive individuals), the mutant retained a low level virulence for the upper respiratory tract of seronegative infants. This RSV mutant had been passaged in bovine kidney cell culture at low temperature (26° C.) and as a consequence it acquired host range attenuating mutations. The acquisition of these mutations allowed the mutant to replicate efficiently in bovine tissue, whereas these same mutations restricted growth of the mutant in the human respiratory tract compared to its RSV strain A2 parent.
Similarly, Gharpure et al.,
J. Virol
. 3:414-421 (1969) reported the isolation of temperature sensitive (ts) mutants which also were promising vaccine candidates. One mutant, ts-1, was evaluated extensively in the laboratory and in volunteers. The mutant produced asymptomatic infection in adult volunteers and conferred resistance to challenge with wild-type virus 45 days after immunization. Again, while seropositive infants and children underwent asymptomatic infection, seronegative infants developed signs of rhinitis and other mild symptoms. Furthermore, instability of the ts phenotype was detected, although virus exhibiting a partial or complete loss of temperature sensitivity represented a small proportion of virus recoverable from vaccinees, and was not associated with signs of disease other than mild rhinitis.
The aforementioned studies thus revealed that among the cold-passaged and temperature sensitive strains some were underattenuated and caused mild symptoms of disease in some vaccinees, particularly seronegative infants, while others were overattenuated and failed to replicate sufficiently to elicit protective immune responses. (Wright et al.,
Infect. Immun
. 37:397-400 (1982)). The genetic instability that allowed candidate vaccine mutants to lose their temperature-sensitive phenotype was also a disconcerting discovery. See generally Hodes et al.,
Proc. Soc. Exp. Biol. Med
. 145:1158-1164 (1974), McIntosh et al.
Pediatr. Res
. 8:689-696 (1974), and Belshe et al.,
J. Med. Virol
. 3:101-110 (1978).
Abandoning the attenuated RS virus vaccine approach, investigators tested potential subunit vaccine candidates using purified RS virus envelope glycoproteins from lysates of infected cells. The glycoproteins induced resistance to RS virus infection in the lungs of cotton rats, Walsh et al,
J. Infect. Dis
. 155:1198-1204 (1987), but the antibodies induced had very weak neutralizing activity and immunization of rodents with purified subunit vaccine led to disease potentiation (Murphy et al.,
Vaccine
8:497-502 (1990)).
Vaccinia virus recombinant-based vaccines which express the F or G envelope glycoprotein have also been explored. These recombinants express RSV glycoproteins which are indistinguishable from the authentic viral counterpart, and small rodents infected intradermally with the vaccinia-RSV F and G recombinant viruses developed high levels of specific antibodies that neutralized viral infectivity. Indeed, infection of cotton rats with vaccinia-F recombinants stimulated almost complete resistance to replication of RSV in the lower respiratory tract and significant resistance in the upper tract. Olmsted et al.,
Proc. Natl. Acad. Sci. USA
83:7462-7466 (1986). However, immunization of chimpanzees with vaccinia F and vaccinia G recombinant provided almost no protection against RSV challenge in -the upper respiratory tract (Collins et al.,
Vaccine
8:164-168 (1990)) and inconsistent protection in the lower respiratory tract (Crowe et al.,
Vaccine
11:1395-1404 (1993). This led to the conclusion that this approach was not likely to yield a successful vaccine.
While investigators examined several different approaches to producing an effective and safe RS vaccine over the years, RS virus has remained the most common cause of severe viral lower respiratory tract disease in infants and children. Consequently, an urgent need remains for a safe vaccine that is able to prevent the serious illness in this population that often requires hospitalization, and to prevent disease in other individuals. Quite surprisingly, the present invention fulfills these and other related needs.
SUMMARY OF THE INVENTION
The present invention provides vaccine compositions of attenuated respiratory syncytial virus. The attenuated virus is provided in an amount sufficient to induce an immune response in a human host, in conjunction with a physiologically acceptable carrier and may optionally include an adjuvant to enhance the immune response of the host. The invention contemplates several distinct antigenic subgroups of attenuated RS virus which are d
Chanock Robert M.
Connors Mark
Crowe, Jr. James E.
Davis Alan R.
Hsu Kuo-Hom Lee
Parkin Jeffrey S.
Scheiner Laurie
The United States of America as represented by the Department of
Townsend and Towsend and Crew LLP
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