Because there are vaccines for other viral diseases, varicella has emerged as the childhood exanthem with the highest risk of serious complications. As antiviral drugs and varicella vaccines are developed, decisions must be made about their administration to normal children, which requires a better understanding of varicella-zoster virus (VZV) immunity in the normal host. A sensitive radioimmunoassay for VZV specific IgG, IgM and IgA antibodies will be used to analyze early humoral immumity in children with varicella. Although deficiencies of cellular immunity are associated with severe variacella, information about cellular immunity to VZV is limited. T-lymphocyte proliferation and T-lymphocyte cytotoxicity will be assessed in this study. Studies of other viral infections indicate that T-lymphocyte cytotoxicity is an important early immune response; this response has not been studied in children with varicella. The analysis of immunity to specific VZV proteins following natural varicella is important for the evaluation of varicella-vaccine induced immunity and of the possible development of VZV sub-unit vaccines. VZV monoclonal antibodies will be used to purify VZV proteins for assays of humoral and cellular immunity to components of the virus. These methods will be used to analyze the responses of normal and immunocompromised children with varicella, VZV immune subjects and varicella vaccine recipients. The possibility that laboratory tests can be used to predict the severity of varicella will be investigated. The identification of such laboratory markers for the likelihood of serious infection would be very helpful in decisions about the initiation of antiviral therapy. The feasibility of producing human monoclonal antibodies to VZV has been demonstrated in preliminary studies. Antobodies produced by human hybridomas will be characterized by immunoprecipitation to determine reactivity with VZV proteins and for functional antiviral activity by neutralization. The production of a human VZV monoclonal antibody with potent neutralizing activity could provide an effective preparation for clinical use as passive antibody prophylaxis for varicella in high risk patients. Further studies of T-lymphocyte mediated immunity during acute varicella are planned to expand upon our observation that the expression of HLA antigens is increased on circulating T-lymphotyes from normal subjects with varicella and, particularly, that HLA-DR expression is present. These experiments are intended to take advantage of the unique opportunity for studies of immune response and immunoregulation during a systemic viral infection.
