A Hemagglutinin Stem Vaccine Designed Rationally by AlphaFold2 Confers Broad Protection against Influenza B Infection

Dian Zeng; Jiabao Xin; Kunyu Yang; Shuxin Guo; Qian Wang; Ying Gao; Huiqing Chen; Jiaqi Ge; Zhen Lu; Limin Zhang; Junyu Chen; Yixin Chen; Ningshao Xia

doi:10.3390/v14061305

A Hemagglutinin Stem Vaccine Designed Rationally by AlphaFold2 Confers Broad Protection against Influenza B Infection

Viruses. 2022 Jun 14;14(6):1305. doi: 10.3390/v14061305.

Authors

Dian Zeng¹, Jiabao Xin², Kunyu Yang³, Shuxin Guo⁴, Qian Wang¹, Ying Gao¹, Huiqing Chen¹, Jiaqi Ge¹, Zhen Lu², Limin Zhang¹, Junyu Chen², Yixin Chen¹, Ningshao Xia¹

Affiliations

¹ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, China.
² State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen 361102, China.
³ Xiamen International Travel Healthcare Center, Xiamen 361012, China.
⁴ Faculty of Health Sciences, University of Macau, Macau SAR 999078, China.

Abstract

Two lineages of influenza B viruses (IBV) co-circulating in human beings have been posing a significant public health burden worldwide. A substantial number of broadly neutralizing antibodies (bnAbs) have been identified targeting conserved epitopes on hemagglutinin (HA) stem domain, posing great interest for universal influenza vaccine development. Various strategies to design immunogens that selectively present these conserved epitopes are being explored. However, it has been a challenge to retain native conformation of the HA stem region, especially for soluble expression in prokaryotic systems. Here, using a structure prediction tool AlphaFold2, we rationally designed a stable stem antigen "B60-Stem-8071", an HA stem vaccine derived from B/Brisbane/60/2006 grafted with a CR8071 epitope as a linker. The B60-Stem-8071 exhibited better solubility and more stable expression in the E. coli system compared to the naïve HA stem antigen. Immunization with B60-Stem-8071 in mice generated cross-reactive antibodies and protected mice broadly against lethal challenge with Yamagata and Victoria lineages of influenza B virus. Notably, soluble expression of B60-stem-8071 in the E. coli system showed the potential to produce the influenza B vaccine in a low-cost way. This study represents a proof of concept for the rational design of HA stem antigen based on structure prediction and analysis.

Keywords: AlphaFold2; broad protection; influenza B viruses (IBV); stem hemagglutinin (HA); structure prediction; vaccine design.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Escherichia coli / metabolism
Hemagglutinin Glycoproteins, Influenza Virus
Hemagglutinins
Humans
Influenza B virus
Influenza Vaccines*
Influenza, Human*
Mice
Orthomyxoviridae Infections*

Substances

Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Hemagglutinin Glycoproteins, Influenza Virus
Hemagglutinins
Influenza Vaccines

Grants and funding

This research was supported by the National Natural Science Foundation of China (grant number:32000649 and 81871651), Natural Science Foundation of Fujian Province (grant number:2021J02006) and Health Education Joint Project of Fujian Province (grant number:2019-WJ-02/20720200061).