Influenza hemagglutinin and neuraminidase multivalent vaccine elicits broader protective immune responses compared to vaccine formulations composed of hemagglutinin or neuraminidase

Developing a more effective seasonal influenza vaccine is necessary to reduce the global health and economic burdens caused by influenza virus infections. Next-generation influenza vaccines using computationally optimized broadly reactive antigen (COBRA) methodology elicit protective immune responses against strains over multiple seasons. Most influenza virus vaccines are currently administered intramuscularly and elicit systemic immune responses. Intranasal administration elicits mucosal immune responses at the site of infection, as well as systemic immunity. It was hypothesized that COBRA-derived hemagglutinin and/or neuraminidase recombinant protein combined with the c-di-AMP adjuvant will elicit broadly reactive mucosal and systemic immune responses when administered intranasally against seasonal influenza viruses in mice and ferrets that were pre-immune to influenza viruses. Multivalent COBRA-based antigens were formulated with c-di-AMP adjuvant and administered intranasally. Animals were vaccinated with either a trivalent COBRA H1, H3, and influenza B rHA vaccine, bivalent COBRA N1 and N2 rNA, or a pentavalent mixture of COBRA rHA and rNA antigens. Mice and ferrets vaccinated with COBRA rHA proteins had sera with HAI activity against a panel of influenza A and B strains isolated from multiple seasons. Vaccines containing rHA in the formulation had less weight loss and viral lung titers compared to animals vaccinated with rNA only or mock vaccinated animals following challenge. Pentavalent COBRA HA and NA vaccines delivered intranasally were the most effective vaccine combination tested with the broadest protective immunity against drifted seasonal influenza viruses.

研发更高效的季节性流感疫苗，对于降低流感病毒感染带来的全球健康与经济负担具有重要意义。采用计算优化广谱反应抗原（computationally optimized broadly reactive antigen, COBRA）技术的下一代流感疫苗，可诱导针对多季流行毒株的保护性免疫应答。当前多数流感疫苗通过肌内注射给药，仅能诱导系统性免疫应答；而鼻内给药则可在感染部位触发黏膜免疫应答，同时兼顾系统性免疫。本研究提出假说：将COBRA技术制备的血凝素（hemagglutinin, HA）和/或神经氨酸酶（neuraminidase, NA）重组蛋白与环二腺苷酸（c-di-AMP）佐剂联合，经鼻内给药后，可在预先免疫过流感病毒的小鼠与雪貂体内，诱导针对季节性流感病毒的广谱反应性黏膜与系统性免疫应答。研究团队将多价COBRA抗原与c-di-AMP佐剂配制后，采用鼻内给药方式免疫受试动物。受试动物分别免疫以下三种制剂：三价COBRA H1、H3及乙型流感病毒重组血凝素（rHA）疫苗、二价COBRA N1与N2重组神经氨酸酶（rNA）疫苗，或是五价COBRA重组HA与NA抗原混合制剂。免疫COBRA重组HA蛋白的小鼠与雪貂，其血清中可检测到针对多季分离甲型、乙型流感毒株的血凝抑制（HAI）活性。攻毒试验后，与仅免疫rNA疫苗或空白免疫对照组动物相比，制剂中含有rHA的疫苗可使受试动物体重损失更少，肺部病毒滴度更低。经鼻内给药的五价COBRA HA与NA联合疫苗，是本次测试中最有效的制剂组合，可针对抗原漂移的季节性流感病毒提供最广泛的保护性免疫。