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

Background 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. Methods Sera from adults (n=300, birth year:1961-1998) collected in 2010-2016 were analyzed in HAI assays. To determine epitope-specific HAI-Ab-IDs, four reverse genetics (RG) viruses were generated, including RG-wt possessing CA/09 wild-type (wt) hemagglutinin (HA) and three 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 (n=100,277; 2010-2024) were analyzed for viral evolution. Results Four hemagglutination inhibition antibody immunodominances targeting the epitopes possessing K163, D127+N129+K130, K130, or D127+N129 were detected in over 50% donors during 2010-2016. 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 HA (four positions D127, N129, K130, and K163). So far, three escape mutations became fixed in 2013-2014 (K163Q), 2020-2021 (N129D), and 2022-2023 seasons (K130N). Conclusion HAI-Ab-IDs are common phenomenon in adults during 2010-2016. Preexisting HAI-Ab-IDs drove viral and antibody evolutions by HAI-Ab-mediated immune selection and HAI-Ab-mediated immune suppression. Monitoring viral and HAI-Ab-IDs evolution is of great importance to improve vaccine effectiveness.