Epitope-Specific Antibody Immunodominance Driving Antibody and Influenza Viral Evolution During 2010- 2024

Understanding hemagglutination inhibition antibody immunodominance (HAI-Ab-ID) is key to forecasting influenza virus antigenic drift and improving vaccine strain selection. We explored epitope-specific HAI-Ab-IDs in adults immunized with A/California/07/2009-like (CA/09) vaccine and A(H1N1)pdm09 viral evolutions.

Sera from adults (N = 300; birth year, 1961-1998) collected from 2010 to 2016 were analyzed in HAI assays. To determine epitope-specific HAI-Ab-IDs, 4 reverse genetics (RG) viruses were generated: RG-wt possessing CA/09 wild type hemagglutinin and 3 RG mutants containing K163Q, K130 deletion, or D127N/N129T mutations. To analyze cross-reactive or strain-specific HAI-Ab-IDs, 10 historical 1977-2007 A(H1N1) viruses were used. Antibody adsorption assays were used to verify the specificity of HAI-Ab-IDs. Publicly available sequences of A(H1N1)pdm09 viruses from GISAID (Global Initiative on Sharing All Influenza Data; n = 100 277, 2010-2024) were analyzed for viral evolution.

Four HAI-Ab-IDs targeting the epitopes possessing K163, D127 + N129 + K130, K130, or D127 + N129 were detected in >50% donors during 2010 to 2016. Three HAI-Ab-IDs (K163-Ab-IDs, D127/N129/K130-Ab-IDs, and K130-Ab-IDs) cross-inhibited some 1977-2007 viruses. Conversely, D127/N129-Ab-ID showed no cross-inhibition with historical 1977-2007 viruses. Low proportions of K130-Ab-IDs were presented mainly in prevaccination sera. Shifts of cross-reactive HAI-Ab-IDs to strain-specific D127/N129-Ab-ID occurred between 2010 and 2016. The HAI-Ab-IDs exerted immune selection pressures on hemagglutinin (4 positions: D127, N129, K130, and K163). So far, 3 escape mutations became fixed in the 2013-2014 season (K163Q), 2020-2021 season (N129D), and 2022-2023 season (K130N).

HAI-Ab-IDs were common phenomena in adults from 2010 to 2016. Preexisting HAI-Ab-IDs drove viral and antibody evolutions by HAI-Ab-mediated immune selection and suppression. Monitoring viral and HAI-Ab-ID evolution is of great importance to improve vaccine effectiveness.