Jennewein Madeleine F, Schultz Michael D, Beaver Samuel, Battisti Peter, Bakken Julie, Hanson Derek, Akther Jobaida, Zhou Fen, Mohamath Raodoh, Singh Jasneet, Cross Noah, Kasal Darshan N, Ykema Matthew R, Reed Sierra, Kalange Davies, Cheatwood Isabella R, Tipper Jennifer L, Foote Jeremy B, King R Glenn, Silva-Sanchez Aaron, Harrod Kevin S, Botta Davide, Gerhardt Alana, Casper Corey, Randall Troy D, Lund Frances E, Voigt Emily A
Access to Advanced Health Institute (formerly Infectious Disease Research Institute), Seattle, WA 98102, USA.
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Mol Ther. 2025 Jul 2;33(7):3286-3306. doi: 10.1016/j.ymthe.2025.04.007. Epub 2025 Apr 9.
While mRNA vaccines have been effective in combating SARS-CoV-2, the waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 replicon vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident immunoglobulin G-secreting cells, and splenic T cell responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m.- and i.n.-administered vaccines durably protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naive cagemates. This replicon-NLC vaccine's potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens.
虽然mRNA疫苗在对抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）方面有效，但疫苗诱导的抗体反应减弱以及缺乏疫苗诱导的呼吸道免疫力导致持续感染和传播。在这项研究中，我们比较并对比了通过纳米结构脂质载体（NLC）递送的SARS-CoV-2复制子疫苗的鼻内（i.n.）和肌肉内（i.m.）给药。肌肉内和鼻内疫苗均诱导强效的全身血清中和抗体、骨髓驻留的分泌免疫球蛋白G的细胞以及脾脏T细胞反应。鼻内疫苗还额外诱导强大的呼吸道黏膜免疫反应，包括SARS-CoV-2反应性肺驻留记忆T细胞群体。作为先前肌肉内接种后的加强针，鼻内疫苗还引发黏膜病毒特异性T细胞的发育。肌肉内和鼻内给药的疫苗均能持久保护仓鼠免受病毒攻击后与感染相关的发病，显著降低病毒载量并防止受攻击的仓鼠将病毒传播给未感染的同笼伙伴。这种复制子-NLC疫苗强大的全身免疫原性以及鼻内给药时额外的黏膜免疫原性，可能是对抗SARS-CoV-2和其他呼吸道病原体的关键。
