Although studies of rotavirus immunity in experimental animals and humans have often yielded conflicting data, a preponderance of evidence supports the following answers to the questions initially posed. 1. What is the importance of virus serotype in formulating an optimal vaccine? Both vp4 and vp7 induce virus-neutralizing antibodies after either natural infection or immunization; the capacity of vp4 to induce rotavirus-specific neutralizing antibodies is probably greater than that of vp7. However, protection against disease after immunization of infants and young children is induced by strains heterotypic to the challenge virus (e.g., immunization with WC3 induces protection against disease induced by serotypically distinct human G1 strains). In addition, oral inoculation of infants with primate or bovine reassortant rotaviruses containing genes that encode human vp7 has not consistently induced a higher level of protection against challenge than that induced by parent animal rotaviruses (see Table I). Therefore, although vp4 or vp7 or both are probably important in inducing protection against challenge, it has not been clearly demonstrated that inclusion of the epidemiologically important human (as distinct from animal) P or G type is important in protection against human disease. 2. Which immunological effector arm most likely protects against rotavirus disease? No immunological effector arm clearly explains protection against heterotypic challenge. Protection against disease is not predicted by rotavirus-specific neutralizing antibodies in serum. Rotavirus-specific, binding sIgA in feces [detected by enzyme-linked immunosorbent assay (ELISA)] induced after natural infection does correlate with protection against disease induced by subsequent infection. However, protection after immunization with WC3 may occur in the absence of a detectable fecal sIgA response. The relationship between rotavirus-binding sIgA and sIgA-mediated neutralizing activity directed against the challenge virus remains to be determined. Binding rotavirus-specific sIgA in feces detected by ELISA may only be a correlate of other events occurring at the intestinal mucosal surface. The presence of broadly cross-reactive, rotavirus-specific CTLs at the intestinal mucosal surface of mice acutely after infection is intriguing. It would be of interest to determine the degree to which the presence of cross-reactive, rotavirus-specific CTLs in the circulation is predictive of the presence of virus-specific CTLs among intestinal lymphocytes and protection against challenge. Unfortunately, studies of virus-specific CTLs are difficult to perform in children. 3. By what means is virus antigen best presented to the host to elicit a protective immune response? Oral inoculation may not be necessary to induce a protective, virus-specific immune response at the intestinal mucosal surface.(ABSTRACT TRUNCATED AT 400 WORDS)