Several nonliving rotavirus vaccine candidates have been evaluated in animal models. Among them is the VP6 protein that comprises the intermediate layer of the rotavirus particle. This protein was expressed as a chimera with maltose binding protein (MBP::VP6) and was administered intranasally to mice. When later challenged with rotavirus, vaccinated mice were nearly 100% protected from fecal shedding of rotavirus, a result strictly dependent on coadministration of an effective adjuvant. Protection was stimulated by only 1 dose of MBP::VP6, remained fully intact for at least 1 year, was effective in all strains of mice tested, and could also be effectively delivered orally or intrarectally. When VP6 was derived from a human rotavirus, it stimulated protection comparable to that found when derived from the challenge murine EDIM strain. In contrast to live rotavirus vaccines, CD4(+) T cells were found to be the only lymphocytes required for protection. If VP6 elicits comparable protection in humans, it would represent a potential second-generation vaccine candidate.