A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine

Wu, Nicholas C.; Zost, Seth J.; Thompson, Andrew J.; Oyen, David; Nycholat, Corwin M.; McBride, Ryan; Paulson, James C.; Hensley, Scott E.; Wilson, Ian A.; Palese, Peter

doi:10.1371/journal.ppat.1006682

Title: A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine

Journal Article · Mon Oct 23 00:00:00 EDT 2017 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1006682· OSTI ID:1422227

^[1];

^[2]; Thompson, Andrew J. ^[1];

^[1]; Nycholat, Corwin M. ^[1];

^[1]; Paulson, James C. ^[1];

^[2]; Wilson, Ian A. ^[1]; Palese, Peter ^[3]

The Scripps Research Inst., La Jolla, CA (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States)
Icahn School of Medicine at Mount Sinai, New York City, NY (United States)

The effectiveness of the annual influenza vaccine has declined in recent years, especially for the H3N2 component, and is a concern for global public health. A major cause for this lack in effectiveness has been attributed to the egg-based vaccine production process. Substitutions on the hemagglutinin glycoprotein (HA) often arise during virus passaging that change its antigenicity and hence vaccine effectiveness. Here, we characterize the effect of a prevalent substitution, L194P, in egg-passaged H3N2 viruses. X-ray structural analysis reveals that this substitution surprisingly increases the mobility of the 190-helix and neighboring regions in antigenic site B, which forms one side of the receptor binding site (RBS) and is immunodominant in recent human H3N2 viruses. Importantly, the L194P substitution decreases binding and neutralization by an RBS-targeted broadly neutralizing antibody by three orders of magnitude and significantly changes the HA antigenicity as measured by binding of human serum antibodies. The receptor binding mode and specificity are also altered to adapt to avian receptors during egg passaging. Overall, these findings help explain the low effectiveness of the seasonal vaccine against H3N2 viruses, and suggest that alternative approaches should be accelerated for producing influenza vaccines as well as isolating clinical isolates.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

Grant/Contract Number:: R56 AI117675; R56 AI127371; R01 AI114730; R01 AI113047; R01 AI108686

OSTI ID:: 1422227

Journal Information:: PLoS Pathogens, Vol. 13, Issue 10; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 145 works

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Influenza Vaccine Effectiveness Against Influenza-Related Mortality in Australian Hospitalized Patients: A Propensity Score Analysis Nation, Monica L.; Moss, Robert; Spittal, Matthew J. Clinical Infectious Diseases https://doi.org/10.1093/cid/ciz1238	journal	January 2020
Influenza Vaccine Effectiveness in the United States During the 2016–2017 Season Flannery, Brendan; Chung, Jessie R.; Monto, Arnold S. Clinical Infectious Diseases, Vol. 68, Issue 11 https://doi.org/10.1093/cid/ciy775	journal	September 2018
Prediction of influenza vaccine effectiveness for the influenza season 2017/18 in the US Paessler, Slobodan; Veljkovic, Veljko F1000Research, Vol. 6 https://doi.org/10.12688/f1000research.13198.1	journal	January 2017
Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies Pardi, Norbert; Parkhouse, Kaela; Kirkpatrick, Ericka Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-05482-0	journal	August 2018
Major antigenic site B of human influenza H3N2 viruses has an evolving local fitness landscape Wu, Nicholas C.; Otwinowski, Jakub; Thompson, Andrew J. Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-15102-5	journal	March 2020
H3N2 influenza viruses in humans: Viral mechanisms, evolution, and evaluation Allen, James D.; Ross, Ted M. Human Vaccines & Immunotherapeutics, Vol. 14, Issue 8 https://doi.org/10.1080/21645515.2018.1462639	journal	May 2018
Low population serum microneutralization antibody titer against the predominating influenza A(H3N2) N121K virus during the severe influenza summer peak of Hong Kong in 2017 Zhu, Houshun; Lee, Andrew C. Y.; Li, Can Taylor & Francis https://doi.org/10.6084/m9.figshare.7936904	text	January 2019
Assessment of enhanced influenza vaccination finds that FluAd conveys an advantage in mice and older adults Kavian, Niloufar; Hachim, Asmaa; Li, Athena PY Clinical & Translational Immunology, Vol. 9, Issue 2 https://doi.org/10.1002/cti2.1107	journal	January 2020
Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein–Based Influenza Vaccines During the 2017–2018 Season Gouma, Sigrid; Zost, Seth J.; Parkhouse, Kaela Clinical Infectious Diseases, Vol. 71, Issue 6 https://doi.org/10.1093/cid/ciz996	journal	October 2019
“Gnothi Seauton”: Leveraging the Host Response to Improve Influenza Virus Vaccine Efficacy Stacey, Hannah; Barjesteh, Neda; Mapletoft, Jonathan Vaccines, Vol. 6, Issue 2 https://doi.org/10.3390/vaccines6020023	journal	April 2018
Defining the interval for monitoring potential adverse events following immunization (AEFIs) after receipt of live viral vectored vaccines Kochhar, Sonali; Excler, Jean-Louis; Bok, Karin Vaccine, Vol. 37, Issue 38 https://doi.org/10.1016/j.vaccine.2018.08.085	journal	September 2019
A Tale of Two Mutations: Beginning to Understand the Problems with Egg-Based Influenza Vaccines? Subbarao, Kanta; Barr, Ian Cell Host & Microbe, Vol. 25, Issue 6 https://doi.org/10.1016/j.chom.2019.05.012	journal	June 2019
Uptake and effectiveness of influenza vaccine in those aged 65 years and older in the United Kingdom, influenza seasons 2010/11 to 2016/17 Pebody, Richard G.; Warburton, Fiona; Andrews, Nick Eurosurveillance, Vol. 23, Issue 39 https://doi.org/10.2807/1560-7917.es.2018.23.39.1800092	journal	September 2018
Viral Entry Properties Required for Fitness in Humans Are Lost through Rapid Genomic Change during Viral Isolation Iketani, Sho; Shean, Ryan C.; Ferren, Marion mBio, Vol. 9, Issue 4 https://doi.org/10.1128/mbio.00898-18	journal	September 2018

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59 BASIC BIOLOGICAL SCIENCES
vaccines
antibodies
antigens
influenza
influenza viruses
enzyme-linked immunoassays
viral vaccines
electron density

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