Heterotypic protection and induction of a broad heterotypic neutralizationresponse by rotavirus-like particles

The recognition that rotaviruses are the major cause of life-threatening di arrheal disease and significant morbidity in young children has focused eff orts on disease prevention and control of these viruses. Although the corre lates of protection in children remain unclear, some studies indicate that serotype-specific antibody is important. Based on this premise, current liv e attenuated reassortant rotavirus vaccines include the four predominant se rotypes of virus, We are evaluating subunit rotavirus vaccines, 2/6/7-VLPs and 2/4/6/7-VLPs, that contain only a single VP7 of serotype G1 or G3. In m ice immunized parenterally twice, G3 virus-like particles (VLPs) induced a homotypic, whereas G1 VLPs induced a homotypic and heterotypic (G3) serum n eutralizing immune response. Administration of three doses of G1 or G3 VLPs induced serum antibodies that neutralized five of seven different serotype test viruses. The inclusion of VP4 in the VLPs was not essential for the i nduction of heterotypic neutralizing antibody in mice. To confirm these res ults in another species, rabbits were immunized parenterally with two doses of 2/4/6/7-VLPs containing a G3 or G1 VP7, sequentially with G3 VLPs follo wed by G1 (G3/G1) VLPs, or with live or psoralen-inactivated SA11. High-tit er homotypic serum neutralizing antibody was induced in all rabbits, and lo w-level heterotypic neutralizing antibody was induced in a subset of rabbit s. The rabbits immunized with the G1 or G3/G1 VLPs in QS-21 were challenged orally with live G3 ALA rotavirus. Protection levels were similar in rabbi ts immunized with homotypic G3 2/4/6/7-VLPs, heterotypic G1 2/4/6/7-VLPs, o r Q3/G1 2/4/6/7-VLPs. Therefore, G1 2/4/6/7-VLPs can induce protective immu nity against a live heterotypic rotavirus challenge in an adjuvant with pot ential use in humans. Following challenge, broad serum heterotypic neutrali zing antibody responses were detected in rabbits parenterally immunized wit h G1, G3/G1, or G3 VLPs but not with SA11, Immunization with VLPs may provi de sufficient priming of the immune system to induce protective anamnestic heterotypic neutralizing antibody responses upon subsequent rotavirus infec tion. Therefore, a limited number of serotypes of VLPs may be sufficient to provide a broadly protective subunit vaccine.