A locally administered single cycle influenza vaccine expressing a non-fusogenic stabilised haemagglutinin stimulates strong T-cell and neutralising antibody immunity

Current influenza vaccination approaches protect against specific viral strains, but do not consistently induce broad and long-lasting protection to the diversity of circulating influenza viruses.  Single cycle viruses delivered to the respiratory tract may offer a promising solution as they safely express a diverse array of viral antigens by undergoing just one round of cell infection in their host and stimulate broadly protective resident memory T-cell responses in the lung. We have previously developed a vaccine candidate called S-FLU that is limited to a single cycle of infection by inactivation of the hemagglutinin signal sequence and induces a broadly cross-reactive T-cell response and antibodies to neuraminidase, but fails to induce neutralising antibodies to hemagglutinin after intranasal administration. This study describes the development of CLEARFLU, a derivative of S-FLU that is designed to add a neutralising antibody response to hemagglutinin. In contrast to S-FLU, which does not express a hemagglutinin molecule at the infected cell surface, CLEARFLU viruses express a stabilised non-fusogenic hemagglutinin. They are equally limited to a single cycle of infection, but induce a neutralising antibody response to the expressed hemagglutinin in addition to the cytotoxic T lymphocyte (CTL) responses to internal proteins and antibodies to neuraminidase induced by S-FLU. This represents a notable advantage as CLEARFLU viruses may provide sterile immunity against strain-matched challenge as well as non-sterile protection against a broad range of influenza viruses.