Seasonal and universal Vaccination in aged populations with pre-existing immunity

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PROJECT SUMMARY Current influenza (flu) vaccination based on hypervariable hemagglutinin (HA) protein fails to provide effective cross protection. The efficacy of vaccination is low in the aged populations even with pre-existing immunity. The impacts of pre-existing immunity on the immunogenicity and efficacy of universal and seasonal vaccination largely remain not well understood in the aged populations. Development of new flu vaccines and vaccination strategies improving cross protective efficacy in young naïve and aged hosts with pre-existing immunity is of high priority. Mono conserved antigenic targets inducing cross protection tested in naïve animal models include the flu A virus M2 extracellular domain (M2e), HA-stalk domains, and neuraminidase (NA) were reported but insufficient for translation to humans. The multi-target universal vaccines in naïve and aged hosts with pre-existing immunity remain to be developed. We developed heterologous tandem repeat of M2e (5xM2e) presented on immunogenic virus-like particles (5xM2e VLP). Vaccination with 5xM2e VLP was effective in broadening cross protection but suboptimal. A further improved universal vaccine should be developed. Our preliminary studies found synergistic effects on improving cross protection by both M2e and NA immunity. Therefore, as a new universal vaccine candidate, we developed a multi NA + 5xM2e VLP vaccine containing multi-subtype NA and 5xM2e on the same VLP particle. In addition, we newly designed genetically linked novel recombinant M2e-stalk universal protein vaccines effectively inducing both M2e and HA-stalk immunity and conferring broad cross- group protection. Adjuvanted universal vaccination will overcome the aging-related immune senescence by activating T and B immune cells in naïve hosts or aged populations under pre-existing immunity. In this project, we will test the hypothesis that new universal vaccination inducing multi immunity (M2e, Stalk, NA) will enhance the breadth and efficacy of cross protection in adult and aged populations with or without pre-existing immunity. Under Aim 1, we will determine the efficacy of multi-target universal vaccines in young adult mice and ferrets under naïve and pre-existing immune conditions. In Aim 2 studies, we will determine the durability of cross protective immunity by multi targeting new universal vaccines and test a vaccination strategy enhancing cross protection in aged mouse and ferret animal models. In the Aim 3, we will investigate cross protective immune mechanisms of multi targeting universal vaccination in young and aged mouse models. The outcomes in this project will be highly significant in the aspect of translational science and relevance to improve the cross protective efficacy of flu vaccination.