Intranasal delivery of a subunit protein vaccine provides protective immunity against JN.1 and XBB-lineage variants
Lei Hong, Weiqi Hong, H. J. Yang, Cai He, Yanan Zhou, Yu Zhang, Aqu Alu, Jie Shi, Jian Liu, Furong qin, Danyi Ao, Xiya Huang, Zimin Chen, Hao Yang, Yun Yang, Wenhai Yu, Cong Tang, Junbin Wang, Bai Li, Qing Huang, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Li Yang, Zhenling Wang, Wei Wang, Guobo Shen, Jinliang Yang, Zhiwei Zhao, Xiangrong Song, Guangwen Lu, Qiangming Sun, Youchun Wang, Shuaiyao Lu, Xiawei Wei
Abstract
Abstract The mucosal immune response plays a crucial role in the prevention of respiratory viruses. Given the risk of recurrent SARS-CoV-2 infections in the population, the rapid development of next-generation intranasal COVID-19 vaccines with high safety and efficacy is paramount. In the current study, we developed a protein-based intranasal vaccine comprising the XBB.1.5 receptor binding domain (RBD)-derived trimeric recombinant protein (RBD XBB.1.5 -HR) and an MF59-like oil-in-water adjuvant. Intranasal administration of RBD XBB.1.5 -HR vaccine elicited robust and sustained humoral immune responses in mice and rats, resulting in high levels of neutralizing antibodies against XBB-lineage subvariants, with protection lasting for at least six months. The intranasal RBD XBB.1.5 -HR vaccine generated potent mucosal immune responses, characterized by the inductions of tissue-resident T (T RM ) cells, local cellular immunity, germinal center, and memory B cell responses in the respiratory tract. The combination of intramuscular and intranasal delivery of the RBD XBB.1.5 -HR vaccine demonstrated exceptional systemic and mucosal protective immunity. Furthermore, intranasal delivery of RBD XBB.1.5 -HR vaccine as a heterologous booster shot showed more effective boosting effects after mRNA administration compared to homologous vaccination, as evidenced by the induction of superior systemic and extra mucosal immune response. Importantly, the intranasal RBD XBB.1.5 -HR vaccine conferred efficient protection against the challenge with authentic EG.5.1 viruses in vivo. These findings identify the intranasal RBD XBB.1.5 -HR vaccine as a potential mucosal vaccine candidate for the prevention of SARS-CoV-2 infection.