Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1996-09-16
1998-03-03
Smith, Lynette F.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4241841, 4242041, 530350, A61K 39155, A61K 3912, A61K 3900, C07K 500
Patent
active
057231303
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US94/05833 filed May 24, 1994.
BACKGROUND OF THE INVENTION
Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory disease in infancy and early childhood (McIntosh and Chanock, 1985, in Virology, Fields, B. (ed), Raven, N.Y., pp. 1285-1304). In all geographical areas, it is the major cause of bronchiolitis and pneumonia in infants and young children. The agent reinfects frequently during childhood, but illness produced by reinfection is generally milder than that associated with the initial infection and rarely causes major problems.
RS virus is an enveloped RNA virus of the family ParamyxoViridae and of the genus pneumovirus. The two major envelope proteins are the G protein, which is responsible for attachment of the virus to the host cell membrane, and the fusion protein (F protein), which is responsible for fusing the virus and cell membranes. Virus-cell fusion is a necessary step for infection. Fusion protein is also required for cell-cell fusion which is another way to spread the infection from an infected cell to an uninfected cell.
Antibodies directed against the fusion protein or against the G protein can neutralize the virus. However, only antibodies to the fusion protein will block the spread of the virus between cells, i.e., have anti-fusion activity. Thus, antibodies to the fusion protein will protect against circulating virus as well as inhibit the spread, between cells, of an established infection. Antibodies to the fusion protein (both polyclonal antisera against purified fusion protein and monoclonal antibodies which contain both neutralizing and anti-fusion activity) have been found to be protective in animal models against infection (Walsh et al., 1984, Infect. Immun. 43: 756-758).
A practical means for protection of infants and young children against upper and lower respiratory disease would be protective vaccination against RS virus. Vaccination of expectant mothers (active immunization) would protect young children by passive transfer of immunity, either transplacentally, or through the mother's milk. Several approaches to an RS virus vaccine are possible, but some of them have proven unsuccessful in the past.
Vaccination with killed RS virus vaccine has been tried and found to be ineffective (Kim et al., 1969, Am. J. Epid. 89: 422). Not only were children not protected, but in some cases, subsequent infections with RS virus resulted in atypical and more severe disease than in the unimmunized controls. This phenomenon is not unique to RS virus and has been seen also in killed paramyxovirus vaccines such as measles. It has been suggested that the reason for the failure of the past inactivated RS virus vaccine was due to inactivation of the biologically functional epitopes on either or both of the viral envelope qlycoproteins. That is to say, the neutralizing and fusion epitopes on the killed virus vaccine were "denatured". As a result, the vaccinated subject did not experience the biologically functional neutralizing and fusion epitopes. Therefore, when the vaccinated subject encountered a live virus, the resultant antibody response did not yield protective immunity. Instead, there was an antibody mediated inflammatory response which often resulted in a more severe disease (Choppin and Scheid, 1980, Rev. Inf. Dis. 2: 40-61).
The second approach to an RS virus vaccine has been to attenuate live virus. Temperature sensitive mutants (Wright et al., 1982, Infect. Immun. 37: 397-400) and passage attenuated virus (Belshe et al., 1982, J. Inf. Dis. 145: 311-319) have proven to be poorly infectious and not efficacious in the prevention of disease when used as immunogens in RS virus vaccines. However, in these cases, there was no atypical disease as a result of vaccination.
Based on our current knowledge of the structure of RS virus and the immune response to infection, it is clear that a useful vaccine to this virus must be effective in inducing production of antibodies to the fusion protein and/or the G protein. Of particular importance to p
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Schneerson, et al, 1991, "Evaluation of Monophosphoryl Lipid A as an Adjuvant . . . " J. Immunol. 147(7):2136-2140.
Stott, et al, 1986, "Human Respiratory Syncylial Virus . . . " J. of Virology 60(2):607-613.
Wertz, et al, 1987, "Expression of the Fusion Protein of Human . . . " J. Virol. 61(2):293-301.
Frenchick Patrick J.
Hancock Gerald E.
Speelman Dan J.
Gordon Alan M.
Smith Lynette F.
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