Gabriel Laghlali, Matthew J Wiest, Dilara Karadag, Prajakta Warang, Jessica J O'Konek, Lauren A Chang, Seok-Chan Park, Vivian Yan, Mohammad Farazuddin, Katarzyna W Janczak, Adolfo García-Sastre, James R Baker, Pamela T Wong, Michael Schotsaert
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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.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4448-4466"},"PeriodicalIF":12.1000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638833/pdf/","citationCount":"0","resultStr":"{\"title\":\"Enhanced mucosal SARS-CoV-2 immunity after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.\",\"authors\":\"Gabriel Laghlali, Matthew J Wiest, Dilara Karadag, Prajakta Warang, Jessica J O'Konek, Lauren A Chang, Seok-Chan Park, Vivian Yan, Mohammad Farazuddin, Katarzyna W Janczak, Adolfo García-Sastre, James R Baker, Pamela T Wong, Michael Schotsaert\",\"doi\":\"10.1016/j.ymthe.2024.10.016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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引用次数: 0
摘要
目前肌肉注射(IM)的 COVID-19 mRNA 疫苗可诱导有效的全身免疫,但粘膜部位的免疫效果不佳,从而限制了其传递灭菌免疫的能力。人们对通过粘膜疫苗接种将肠外疫苗接种在外周诱导的免疫反应重新引导到呼吸道病毒(如 SARS-CoV-2 )的入口部位非常感兴趣。我们以前曾证明,由纳米乳剂(NE)和基于 RNA 的 RIG-I 激动剂(IVT)组成的 NE/IVT 组合佐剂可在鼻内注射(IN)基于蛋白质的 SARS-CoV-2 疫苗时诱导有效的全身和粘膜免疫反应。在此,我们证明,与 IM/IM 和 IN/IN 的原代/强化方案相比,先用 mRNA 诱导 IM,再用 NE/IVT 佐剂重组抗原进行异源 IN 强化,可诱导强烈的粘膜和全身抗体反应,并增强粘膜淋巴结中的抗原特异性 T 细胞反应。虽然所有方案都能诱导针对不同变体的交叉中和抗体,并在受挑战小鼠的肺部产生灭菌免疫力,但要在上呼吸道产生灭菌免疫力,则需要在 IM mRNA 原代接种后进行同源原代/加强型或异源 IN 加强型粘膜接种。我们的数据证明了混合接种方案的益处,即通过 IM 疫苗接种产生的强大免疫反应通过 IN 疫苗接种重新传递到粘膜部位,从而提供对 SARS-CoV-2 的最佳保护。
Enhanced mucosal SARS-CoV-2 immunity after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.
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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.