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Rotavirus is a double-stranded RNA virus composed of 3 protein layers. These layers contain structural proteins (eg, VP4, VP6, and VP7) that are involved in the induction of immunity. Despite extensive research in animal models and humans, the mechanisms and effectors of protection against rotavirus after either natural infection or vaccination remain unclear. Complicating factors include the variety of immunologic responses produced after both natural infection and vaccination, and the fact that animal models do not fully mimic the human immunologic responses, even when inoculated with homologous rotaviruses. Nevertheless, it appears that neutralizing antibodies have a role in protection against rotavirus infection and disease, but that other effectors, such as non-neutralizing antibodies and T cells, have important effector properties as well. These effectors likely have overlapping functions, thus providing enhanced protection. The results of further research to elucidate the immunologic mechanism of protection will provide insight into improving the efficacy of current vaccines.