The influenza hemagglutinin stem antibody CR9114: Evidence for a narrow evolutionary path towards universal protection

Frontiers in Virology

Virology

Gerry A. F. Nicolaes¹  Kanin Wichapong¹  Angela Phillips²  Michael M. Desai²  Wouter Koudstaal³  Clarissa M. Koch³  Jaco M. Klap³  Jacopo Frallicciardi³  Anna L. Beukenhorst⁴  Jaap Goudsmit⁵  Galit Alter⁶ 

[1] Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands;Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, United States;Leyden Laboratories B.V., Amsterdam, Netherlands;Leyden Laboratories B.V., Amsterdam, Netherlands;Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, United States;Leyden Laboratories B.V., Amsterdam, Netherlands;Departments of Epidemiology, Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, United States;Leyden Laboratories B.V., Amsterdam, Netherlands;Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard, Cambridge, MA, United States;

关键词: broadly neutralizing antibodies;    influenza virus;    pan-influenza protection;    CR9114;    correlate of protection;    antiviral therapies;    immunization;    vaccination;   

DOI  :  10.3389/fviro.2022.1049134

 received in 2022-09-20, accepted in 2022-10-11,  发布年份 2022

来源: Frontiers

【 摘 要 】

Human monoclonal antibodies (hmAbs) that protect against all influenza A and B strains are considered the road to universal influenza vaccines. Based on publicly-available data, we analyze the mechanistic and structural basis of pan-influenza protection by CR9114, a hemagglutinin (HA) stem-reactive antibody that protects against influenza subtypes from groups A1, A2, and B. The mechanistic basis of CR9114’s universal protection is not limited to in vitro neutralization, as CR9114 also protects in vivo from strains that escape its neutralizing activity: some H2 strains and influenza B. Fusion inhibition, viral egress inhibition, and activation of Fc-mediated effector functions are key contributors to CR9114’s universal protection. A comparative analysis of paratopes – between CR9114 (pan-influenza protection) and structurally similar VH1-69 hmAb CR6261 (influenza A1 protection) – pinpoints the structural basis of pan-influenza protection. CR9114’s heterosubtypic binding is conferred by its ability to bind HA with multiple domains: three HCDR loops and FR3. In contrast to other VH1-69 hmAbs, CR9114 uses a long and polar side chain of tyrosine (Y) residues on its HCDR3 for crucial H-bonds with H3, H5, and B HA. The recognition of a highly conserved epitope by CR9114 results in a high genetic barrier for escape by influenza strains. The nested, hierarchical structure of the mutations between the germline ancestor and CR9114 demonstrates that it is the result of a narrow evolutionary pathway within the B cell population. This rare evolutionary pathway indicates an immuno-recessive epitope and limited opportunity for vaccines to induce a polyclonal CR9114-like response.

【 授权许可】

Unknown   
Copyright © 2022 Beukenhorst, Frallicciardi, Koch, Klap, Phillips, Desai, Wichapong, Nicolaes, Koudstaal, Alter and Goudsmit