Characterization of Novel Cross-Reactive Influenza B Virus Hemagglutinin Head Specific Antibodies That Lack Hemagglutination Inhibition Activity
- 9 November 2020
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 94 (23)
- https://doi.org/10.1128/jvi.01185-20
Abstract
Humoral immune responses to influenza virus vaccines in elderly individuals are poorly adapted towards new antigenically drifted influenza virus strains. Instead, older individuals respond in an original antigenic sin-fashion and produce much more cross-reactive but less potent antibodies. Here, we investigated four influenza B hemagglutinin head specific, hemagglutination inhibition inactive monoclonal antibodies (mAbs) from elderly individuals. We found that they were broadly reactive within the B/Victoria/2/1987-like lineage and two were highly cross-reactive with B/Yamagata/16/1988-like lineage viruses. The mAbs were found to be neutralizing, utilize Fc-effector functions and protective against lethal viral challenge in a mouse model. In order to identify residues on the influenza B virus hemagglutinin interacting with the mAbs, we generated escape mutant viruses. Interestingly, escape from these mAbs led to numerous HA mutations within the head domain, including the defined antigenic sites. We observed that each individual escape mutant virus was able to avoid neutralization from its respective mAb along with other mAbs in the panel, although in many cases binding activity was maintained. Point mutant viruses indicated that K90 is critical for neutralization of two mAbs, while escape from the other two mAbs require a combination of mutations in the hemagglutinin. Three out of four escape mutant viruses had increased lethality in the DBA2/J mouse model. Our work indicates that these cross-reactive antibodies have the potential to cause antigenic drift in the viral population by driving mutations that increase virus fitness. However, binding activity and cross-neutralization was maintained by a majority of antibodies in the panel suggesting that this drift may not lead to escape from antibody mediated protection. IMPORTANCE Understanding the immune response that older individuals mount to influenza virus vaccination and infection is critical in order to design better vaccines for this age group. Here we show that older individuals make broadly-neutralizing antibodies that have no hemagglutination inhibiting activity and are less potent than strain specific antibodies. These antibodies could drive viral escape from neutralization but did not result in escape from binding. Given their different mechanisms of action, they might retain protective activity even against escape variants.Funding Information
- HHS | NIH | National Institute of Allergy and Infectious Diseases (75N93019C00051, AI117287)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (HHSN272201400008C)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (HHSN272201400005C)
This publication has 29 references indexed in Scilit:
- Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly IndividualsCell Host & Microbe, 2019
- Cross-lineage protection by human antibodies binding the influenza B hemagglutininNature Communications, 2019
- Universal influenza virus vaccines and therapeutics: where do we stand with influenza B virus?Current Opinion in Immunology, 2018
- Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virusProceedings of the National Academy of Sciences of the United States of America, 2016
- Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contactProceedings of the National Academy of Sciences of the United States of America, 2016
- Heads, stalks and everything else: how can antibodies eradicate influenza as a human disease?Current Opinion in Immunology, 2016
- Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protectionJCI Insight, 2016
- Development of a robust reporter-based ADCC assay with frozen, thaw-and-use cells to measure Fc effector function of therapeutic antibodiesJournal of Immunological Methods, 2014
- Highly Conserved Protective Epitopes on Influenza B VirusesScience, 2012
- Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic DriftScience, 2009