Human monoclonal antibodies to respiratory syncytial virus (RSV) are being developed for passive immunoprophylaxis of infants and children who are at high risk for serious lower respiratory tract disease due to RSV as well as for therapy of serious RSV disease. Two genetically distinct Fab fragments of IgG were selected from a combinatorial library expressed on the surface of filamentous DNA bacteriophage. These Fabs are specific for the F glycoprotein of RSV and have high neutralizing activity. These observations suggest that it should be possible to develop whole (i.e., Fab + Fc) IgG antibodies that will be useful for prevention and therapy of serious RSV lower respiratory tract disease. The vaccinia-RSV recombinant expressing the RSV M2 gene induced resistance in mice that was mediated by CD8+ T-cells. The level of primary pulmonary CD8+ cytotoxic T-cell (CTL) activity correlates with the resistance induced. The resistance induced by Vac-M2 (but not that induced by Vac-F or Vac-G) and the pulmonary CTL activity were short-lived and were not demonstrable 45 days following immunization. This suggests that inclusion of CTL epitopes in vaccines may not be important for vaccine efficacy since resistance to reinfection is primarily mediated by antibodies. Mice immunized with formalin-inactivated RSV (FI-RSV) vaccine did not develop RSV-specific CTLs, whereas mice infected with RSV developed high levels of CTL activity. This finding, considered in the context of last year's observation that FI-RSV vaccine preferentially stimulates CD4 cells, supports the view that a primary defect of the inactivated RSV vaccine was an imbalance in the T-cell response. This unbalanced cell-mediated immune response likely played a major role in disease potentiation that occurred in the 1960s when young FI-RSV vaccinees underwent subsequent RSV infection. A program to develop live attenuated RSV vaccines was initiated and several mutants have been identified that could be useful as RSV vaccines.
