Influenza virus infection history drives and shapes antibody responses to influenza vaccination

Abstract

\n Background The controversial hypothesis that recalled immunological memory limits responses to variant virus strains has been revived by recent reports linking poor vaccine effectiveness against A(H3N2) influenza viruses with prior vaccination. The impact of memory induced by prior infection is rarely considered, and is difficult to ascertain because infections are often sub-clinical. This study investigates influenza vaccine immunogenicity among participants who had been monitored for 9 years for clinical influenza infection or seroconversion. Methods In 2007, 269 households from Ha Nam, Viet Nam commenced ongoing monitoring for influenza infection. In 2016, 72 adult participants with documented prior A(H3N2) infection and 28 without infection received trivalent inactivated influenza vaccine for the first time. Serological responses were assessed by hemagglutination inhibition assay against 40 A(H3N2) viruses spanning 1968-2018. Effects of prior infection were determined by comparing geometric mean titres and titre rises. Generalized additive and lowess models were used to fit, and compare, titre landscapes across strains. Findings Participants with documented prior A(H3N2) virus infection had higher pre-vaccine titres against strains circulating since 2004 compared to those without prior infection. Moreover, they had higher titre rises on days 7, 14, 21 and 280 post-vaccination against vaccine and subsequently circulating strains. Accordingly, 1/72 versus 4/28 of vaccinees with and without documented prior infection experienced illness due to A(H3N2) in the season after vaccination (p = 0.021). The range of A(H3N2) virus clades recognized by vaccine-induced antibodies was associated with the clade that last caused infection, indicating that recalled immunity drove antibody production against shared epitopes. Interpretation These results suggest that immunological memory from prior infection drives and shapes antibody production induced by inactivated influenza vaccine, and underpins the capacity for vaccine to induce sufficient antibody for protection.