Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN). Herein, we demonstrate priming IM with mRNA followed by heterologous IN boosting with NE/IVT adjuvanted recombinant antigen induces strong mucosal and systemic antibody responses and enhances antigen-specific T cell responses in mucosa-draining lymph nodes compared to IM/IM and IN/IN prime/boost regimens. While all regimens induced cross-neutralizing antibodies against divergent variants and sterilizing immunity in the lungs of challenged mice, mucosal vaccination, either as homologous prime/boost or heterologous IN boost after IM mRNA prime, was required to impart sterilizing immunity in the upper respiratory tract. Our data demonstrate the benefit of hybrid regimens whereby strong immune responses primed via IM vaccination are rerouted by IN vaccination to mucosal sites to provide optimal protection against SARS-CoV-2.

中文翻译：

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异源肌内 mRNA 初免/鼻内蛋白联合佐剂加强疫苗接种后粘膜 SARS-CoV-2 免疫力增强


目前肌肉注射 （IM） 的 COVID-19 mRNA 疫苗可诱导有效的全身免疫，但在粘膜部位的免疫力不佳，限制了它们赋予消毒免疫的能力。通过粘膜疫苗接种，将肠外疫苗接种诱导的免疫反应重新路由到呼吸道病毒（例如严重急性呼吸系统综合症冠状病毒 2 （severe acute respiratory syndrome coronavirus 2， SARS-CoV-2））的入口进入部位，人们对此非常感兴趣。我们之前证明了由纳米乳剂 （NE） 和基于 RNA 的 RIG-I 激动剂 （IVT） 组成的联合佐剂 NE/IVT 在鼻内 （IN） 接种的基于蛋白质的 SARS-CoV-2 疫苗中诱导有效的全身和粘膜免疫反应。在此，我们证明了与 IM/IM 和 IN/IN 初免/加强方案相比，用 mRNA 引发 IM，然后用 NE/IVT 佐剂重组抗原进行异源 IN 增强诱导强烈的粘膜和全身抗体反应，并增强粘膜引流淋巴结中的抗原特异性 T 细胞反应。虽然所有方案都在攻击小鼠的肺部诱导针对不同变异的交叉中和抗体和绝育免疫，但粘膜疫苗接种，无论是作为同源初免/加强还是 IM mRNA 初免后的异源 IN 加强，都需要在上呼吸道赋予绝育免疫。我们的数据证明了混合方案的好处，即通过 IM 疫苗接种引发的强烈免疫反应通过 IN 疫苗接种重新路由到粘膜部位，以提供针对 SARS-CoV-2 的最佳保护。