ArticleFrontiers in immunology2026
Intranasal delivery of a COBRA-based protein vaccine adjuvanted with c-di-AMP enhances breadth of protective immune responses against seasonal influenza viruses.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Seasonal influenza vaccines provide variable protection against antigenically drifted influenza A (H1N1 and H3N2) and influenza B viruses. Broadly protective approaches using computationally optimized broadly reactive antigens (COBRAs) can enhance immunity against diverse strains. Bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) is a mucosal adjuvant that boosts vaccine-induced immune responses. Here, we hypothesized that intranasal multivalent COBRA hemagglutinin (HA) and neuraminidase (NA) vaccination with c-di-AMP would induce broad humoral and cellular immunity in mice. Immunologically naïve and pre-immune DBA/2J mice were intranasally immunized with pentavalent vaccine formulations containing COBRA recombinant HA and NA or corresponding wild-type antigens. Formulations were administered at low or high antigen doses, with or without the mucosal adjuvant c-di-AMP. Humoral and cellular immune responses were evaluated, along with protection following influenza A (H1N1 and H3N2) and influenza B viral challenge. Pentavalent COBRA HA/NA intranasal vaccination adjuvanted with c-di-AMP induced strong humoral and cellular immune responses in murine models. Vaccination induced robust, dose-dependent total IgG and hemagglutination inhibition (HAI) titers, along with high frequencies of antigen-specific antibody-secreting cells and interferon-γ (IFN-γ)-producing cells in pre-immune mice. Naïve mice were also seroprotected mainly against H1N1 at higher vaccine doses. Following lethal challenge with H1N1, H3N2, and influenza B viruses, vaccinated mice exhibited reduced weight loss, decreased lung viral titers, and enhanced survival, with the strongest protection observed in adjuvanted groups across both naïve and pre-immune models. These findings highlight the value of combining broadly protective COBRA vaccine candidates with advanced mucosal adjuvants to enhance efficacy against antigenically drifted influenza virus strains.
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