mTOR regulates protection against lethal H5N1 influenza infection by modulating the antibody response (VAC2P.926)

Highly pathogenic H5N1 avian influenza viruses pose a continuing global threat. Current vaccines will not protect against novel pandemic viruses. Creating “universal” vaccines has been unsuccessful because the immunological mechanisms promoting heterosubtypic immunity are incompletely defined. We show that rapamycin, an immunosuppressive drug that inhibits mTOR, promotes cross-strain protection against a lethal H5N1 infection when administered during H3N2 virus immunization. Rapamycin reduced germinal center formation and inhibited B cell class-switching, yielding a unique repertoire of antibodies that mediated heterosubtypic protection. Our data establish a requirement for mTORC1 in B cell class-switching and demonstrate that rapamycin skews the antibody response away from high affinity variant epitopes, targeting more conserved elements of hemagglutinin. Our current data indicate that a primary intranasal infection with FluMist enhances heterosubtypic immunity even more, which can be further enhanced with rapamycin. In this model the CD8 T cells contribute to enhanced protection providing us a model to study the synergy between cross-reactive antibodies and CD8 T cells. These findings have intriguing implications for influenza vaccine design.