Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans

Abstract

Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the virus undergoes extensive antigenic drift. Antibodies that target the highly conserved hemagglutinin stalk can protect against drifted viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal influenza virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and influenza B virus hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low influenza virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.)

Analysis of Anti-Influenza Virus Neuraminidase Antibodies in Children, Adults, and the Elderly by ELISA and Enzyme Inhibition: Evidence for Original Antigenic Sin

“…S1D to F) distribution of anti-N1, anti-N2, and anti-influenza B virus NA antibodies. In general, the pattern reflected the distribution seen with antibodies to HA (30–32), with the exception of elevated IgG4 titers against NC99 N1 and elevated IgG2 titers against Yam88 NB (Fig. S1).…”

Influenza A surface glycosylation and vaccine design

“…Recent development of universal influenza vaccines is focused on the use of conserved peptides or proteins as antigens with different adjuvants and administration methods to induce immune response (26)(27)(28)(29). Expression of the conserved regions of IAV proteins by using viral vector systems can induce CD8 + T cells against lethal IAV challenge in animals, but it still only recognizes one target (30).…”

Novel universal influenza virus vaccine approaches

“…Typically, three sequential vaccinations with cHAs that have the same stalk domain but different head domains are necessary in naive animals to induce protective immunity. However, humans already have low levels of B-cells and antibodies with specificities for stalk epitopes and are therefore already primed [12,37–40]. This pre-existing immunity is most likely induced by natural infection with influenza viruses and/or influenza vaccinations [41–44].…”