Antigenic drift and subtype interference shape A(H3N2) epidemic dynamics in the United States.

Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE

Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-

Influenza A Virus, H3N2 Subtype*/genetics ; Influenza A Virus, H3N2 Subtype*/immunology ; Influenza, Human*/epidemiology ; Influenza, Human*/virology ; Influenza, Human*/immunology ; Hemagglutinin Glycoproteins, Influenza Virus*/genetics ; Hemagglutinin Glycoproteins, Influenza Virus*/immunology ; Epidemics* ; Antigenic Drift and Shift*/genetics; United States/epidemiology ; Humans ; Child ; Adult ; Neuraminidase/genetics ; Neuraminidase/immunology ; Adolescent ; Child, Preschool ; Antigens, Viral/immunology ; Antigens, Viral/genetics ; Young Adult ; Evolution, Molecular ; Seasons ; Middle Aged

Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997-2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity.
Competing Interests: AP, JH, JB, TR, XX, RK, DW, NL, LW, BE, RH, MG, RD, SF, KN, NK, SW, HH, TB No competing interests declared, CH Received personal fees from Sanofi outside the submitted work, JM Received consulting fees, honoraria, and travel support from Sanofi Pasteur and Sequris, SS The WHO Collaborating Centre for Reference and Research on Influenza in Melbourne has a collaborative research and development agreement (CRADA) with CSL Seqirus for isolation of candidate vaccine viruses in cells and an agreement with IFPMA for isolation of candidate vaccine viruses in eggs. SGS reports honoraria from CSL Seqirus, Moderna, Pfizer, and Evo Health, IB, KS The WHO Collaborating Centre for Reference and Research on Influenza in Melbourne has a collaborative research and development agreement (CRADA) with CSL Seqirus for isolation of candidate vaccine viruses in cells and an agreement with IFPMA for isolation of candidate vaccine viruses in eggs, FK The Icahn School of Medicine at Mount Sinai has filed patent applications relating to influenza virus vaccines (U.S. patent numbers: 12030928, 11865173, 11266734, 11254733, 10736956, 10583188, 10137189, 10131695, 9968670, 9371366; publication numbers: 20230181715, 20220403358, 20220249652, 20220242935, 20220153873, 20210260179, 20190125859, 20190106461, 20180333479), SARS-CoV-2 serological assays (publication number: 20240210415), and SARS-CoV-2 vaccines (publication numbers: 20230310583, 20230226171), which list FK as co-inventor. FK has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, GSK and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS‐CoV‐2 and with Dynavax on universal influenza virus vaccines, CV Received honoraria for serving as an Editor in Chief of the journal Epidemics (Elsevier)

Update of: medRxiv. 2024 May 22:2023.10.02.23296453. doi: 10.1101/2023.10.02.23296453. (PMID: 37873362)

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10111800 Ministry of Health, Labour and Welfare; 75N93019C00051 United States NH NIH HHS; FC001030 United Kingdom ARC_ Arthritis Research UK; 10110400 Ministry of Health, Labour and Welfare; JP22fk0108118 Japan Agency for Medical Research and Development; HHSN272201400008C United States NH NIH HHS; F31 AI140714 United States NH NIH HHS; 75N93021C00014 United States AI NIAID NIH HHS; United Kingdom WT_ Wellcome Trust; 75N93019C00051 United States AI NIAID NIH HHS; 75N93021C00014 United States NH NIH HHS; R01 AI165821 United States AI NIAID NIH HHS; R01 AI165821 United States NH NIH HHS; HHSN272201400008C United States AI NIAID NIH HHS; F31 AI140714 United States AI NIAID NIH HHS; 1354890 National Science Foundation; R35 GM119774 United States GM NIGMS NIH HHS; FC001030 United Kingdom WT_ Wellcome Trust; R35 GM119774 United States NH NIH HHS; R01 AI127893 United States NH NIH HHS; FC001030 United Kingdom MRC_ Medical Research Council; JP23fk0108662 Japan Agency for Medical Research and Development; FC001030 United Kingdom CRUK_ Cancer Research UK; R01 AI127893 United States AI NIAID NIH HHS

Keywords: H3N2; antigenic drift; epidemiology; global health; human; infectious disease; influenza virus; microbiology; virus
Local Abstract: [plain-language-summary] Seasonal influenza (flu) viruses cause outbreaks every winter. People infected with influenza typically develop mild respiratory symptoms. But flu infections can cause serious illness in young children, older adults and people with chronic medical conditions. Infected or vaccinated individuals develop some immunity, but the viruses evolve quickly to evade these defenses in a process called antigenic drift. As the viruses change, they can re-infect previously immune people. Scientists update the flu vaccine yearly to keep up with this antigenic drift. The immune system fights flu infections by recognizing two proteins, known as antigens, on the virus’s surface, called hemagglutinin (HA) and neuraminidase (NA). However, mutations in the genes encoding these proteins can make them unrecognizable, letting the virus slip past the immune system. Scientists would like to know how these changes affect the size, severity and timing of annual influenza outbreaks. Perofsky et al. show that tracking genetic changes in HA and NA may help improve flu season predictions. The experiments compared the severity of 22 flu seasons caused by the A(H3N2) subtype in the United States with how much HA and NA had evolved since the previous year. The A(H3N2) subtype experiences the fastest rates of antigenic drift and causes more cases and deaths than other seasonal flu viruses. Genetic changes in HA and NA were a better predictor of A(H3N2) outbreak severity than the blood tests for protective antibodies that epidemiologists traditionally use to track flu evolution. However, the prevalence of another subtype of influenza A circulating in the population, called A(H1N1), was an even better predictor of how severe A(H3N2) outbreaks would be. Perofsky et al. are the first to show that genetic changes in NA contribute to the severity of flu seasons. Previous studies suggested a link between genetic changes in HA and flu season severity, and flu vaccines include the HA protein to help the body recognize new influenza strains. The results suggest that adding the NA protein to flu vaccines may improve their effectiveness. In the future, flu forecasters may want to analyze genetic changes in both NA and HA to make their outbreak predictions. Tracking how much of the A(H1N1) subtype is circulating may also be useful for predicting the severity of A(H3N2) outbreaks.

0 (Hemagglutinin Glycoproteins, Influenza Virus)
EC 3.2.1.18 (Neuraminidase)
0 (Antigens, Viral)

Date Created: 20240925 Date Completed: 20240925 Latest Revision: 20240927

20240927

PMC11424097

10.7554/eLife.91849

39319780