Rational design of an influenza-COVID-19 chimeric protective vaccine with HA-stalk and S-RBD
Yulei Li, Peipei Liu, Tianjiao Hao, Sheng Liu, Xi Wang, Yufeng Xie, Ke Xu, Wenwen Lei, Cheng Zhang, Pu Han, Ying Li, Xiyue Jin, Huan Yu, Yafei Lu, Rong Zhang, Xiaoyan Li, Xin Zhao, Kun Xu, Pu Liao, Xuancheng Lu, Yuhai Bi, Hao Song, Guizhen Wu, Baoli Zhu, George F. Gao
Abstract
Highly contagious respiratory illnesses like influenza and COVID-19 pose serious risks to public health. A two-in-one vaccine would be ideal to avoid multiple vaccinations for these diseases. Here, we generated a chimeric receptor binding domain of the spike protein (S-RBD) and hemagglutinin (HA)-stalk-based vaccine for both SARS-CoV-2 and influenza viruses. The S-RBD from SARS-CoV-2 Delta was fused to the headless HA from H1N1 (H1Delta), creating a chimera that forms trimers in solution. The cryo-electron microscopy structure of the chimeric protein complexed with the RBD-targeting CB6 and the HA-stalk-targeting CR9114 antibodies shows that the trimeric protein is stable and accessible for neutralizing antibody binding. Immunization with the vaccine elicited high and long-lasting neutralizing antibodies and effectively protected mice against the challenges of lethal H1N1 or heterosubtypic H5N8, as well as the SARS-CoV-2 Delta or Omicron BA.2 variants. Overall, this study offers a two-in-one universal vaccine design to combat infections caused by both SARS-CoV-2 variants of concern and influenza viruses.