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Abstract
Influenza viruses belong to the Orthomyxoviridae family and cause seasonal respiratory infections in humans and animals that are associated with worldwide morbidity and mortality. Current vaccines strategies are ineffective against these ever-changing viruses that undergo constant antigenic drift and shift since the vaccines that are developed every year are not always matched to the specific stains circulating for a given year. To overcome this challenge, the computationally optimized broadly reactive antigen (COBRA) methodology for designing influenza hemagglutinin (HA) and neuraminidase (NA) vaccines was employed. In this study, novel adjuvants with COBRA HA and NA vaccines were administered via different routes for enhancing the immunogenicity of these vaccines in naive mice and mice that had pre-existing immune responses to H1N1 and H3N2 historical influenza viruses. COBRA HA/NA proteins were formulated with either 1). a toll-like receptor 9 (TLR9) agonist (CpG1018), 2). a TLR4 agonist (INI 2002), 3). a TLR7/8 agonist (INI 4001), 4). a polysaccharide adjuvant derived from delta inulin (Advax) in combination with TLR9 agonist CpG55.2 (Advax-SM™), or 5). a mast cell-activating oligopeptide, mastoparan-7 (M7-NH2). Adjuvanting COBRA HA vaccines with INI 2002 or INI 4001 agonists in various formulation induced enhanced protective antibodies that fully protected mice from morbidity and mortality following influenza virus infection, or significantly reduced their morbidity and mortality compared to un-adjuvanted COBRA HA vaccines. Similarly, vaccinating naïve mice with Advax-SMTM-adjuvanted COBRA HA vaccines induced enhance protective serum antibodies and protected mice from morbidity and mortality, following influenza virus infection. Moreover, naïve mice that were vaccinated with M7-NH2-adjuvanted COBRA HA vaccines also had enhanced protective antibodies in their sera and in their lungs, that protected mice from H1N1 and H3N2 influenza virus infections. COBRA HA/NA mixed with CpG 1018 elicited protective antibodies in the sera and in the lungs of pre-immune mice that were vaccinated IM or IN. Furthermore, vaccinating pre-immune mice with COBRA HA and NA vaccines with CpG 1018 fully protected them from morbidity and mortality. In all, this project identified effective vaccine adjuvants that enhanced the effectiveness of parental and intranasal administration of COBRA HA and NA vaccines.