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

Raffael Nachbagauer, Angela Choi, Ruvim Izikson, Manon M Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer, Angela Choi, Ruvim Izikson, Manon M Cox, Peter Palese, Florian Krammer

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.)

Importance: The present study provides evidence that titers of broadly neutralizing hemagglutinin stalk-reactive antibodies increase with age, possibly due to repeated exposure to divergent influenza viruses. These relatively high levels of antistalk titers may be responsible for lower circulation rates of influenza viruses in older individuals. Our findings suggest that the level of antistalk antibodies is a good surrogate marker for protection against influenza virus infection. In addition, the levels of antistalk antibodies might determine the breadth of protection against different drifted strains.

Copyright © 2016 Nachbagauer et al.

Figures

FIG 1
FIG 1
Titers of antistalk antibodies are age dependent. (A) Group 1/H1 stalk antibodies increase with age. Mean baseline titers for children (165.3) are lower than for adults (1674.4) and are significantly higher in elderly individuals (5740.6, P < 0.0001). (B) Induction of group 1/H1 stalk antibodies after vaccination with a recombinant HA vaccine is highest in adults (2.7) and relatively low in children (1.6) and the elderly (1.4). (C) Group 2/H3 baseline stalk antibody levels are higher (436.2) than H1 antibodies in children but do not increase as steadily with age (adults, 981.6; elderly, 1412.3). (D) Induction of group 2/H3 stalk antibodies postvaccination is not significantly higher in children (1.5) than in adults (1.3) and elderly individuals (1.3). (E) Influenza B baseline stalk antibody titers increase with age in a manner similar to that seen with H1 and H3 stalk antibodies. They are low for children (324.9), higher for adults (714.1), and highest in elderly individuals (1139.1). (F) Influenza B stalk antibodies increase slightly in adults (1.9) after vaccination but barely for children (1.2) and not at all in elderly individuals (1.0). (G) Baseline titers for group 1/H1 stalk are plotted against fold induction after vaccination. The sizes of the symbols correspond to the numbers of samples. Induction is generally low for individuals with baseline titers lower than 800 and higher than 12,800. Most of the adult population consists of high inducers, while children show mostly low titers and low induction and elderly individuals have high titers and low induction.
FIG 2
FIG 2
IgA but not IgM anti-group 1/H1 stalk titers are induced postvaccination. (A) IgA baseline titers against the H1 stalk domain follow a pattern similar to (but lower than) that shown for IgG titers. Children start at a low titer (186.6), while adults show slightly higher titers (224.1) and elderly individuals have the highest titers (778.5). (B) Adults show the strongest induction for IgA against the H1 stalk domain (2.2), while children remain close to baseline (1.1) and elderly individuals increase slightly (1.6). (C) IgM titers against the H1 stalk domain are higher in adults (1,218.1) than in children (492.5) and elderly individuals (746.4). (D) No induction of IgM is seen in adults and elderly individuals 28 days after vaccination and very low induction is seen in children (1.2).
FIG 3
FIG 3
Isotype composition of the group 1/H1 antistalk response. (A) IgG antibodies against the group 1/H1 stalk domain are predominantly of the IgG1 and IgG3 subclasses, while there is very low reactivity for IgG2 and no reactivity for IgG4. (B) Responses against the full-length H1 protein used in the vaccine. Interestingly, adults and the elderly seem to have low IgG2 reactivity to the H1 head domain.
FIG 4
FIG 4
Antistalk neutralization titers. (A) Neutralizing titers against a virus with an H1 stalk domain show a pattern of age-related titer increases similar to that for the ELISA titers. The mean of the IC50 values is very low in children (13.2) but increases after vaccination (19.7). The adults start with medium titers (34.8) and increase to a titer of 97.3. Elderly individuals start at a titer of 93.0 and increase slightly to a titer of 109.8 after vaccination. (B) The microneutralization IC50s against a virus containing the H1 stalk domain correlate very well with the H1 titers measured by ELISA (Spearman r = 0.7094, P < 0.0001).
FIG 5
FIG 5
In vivo efficacy of antistalk antibodies. (A) Day 0 and day 28 serum samples were pooled separately for each age group and intraperitoneally injected into five 6- to 8-week-old BALB/c mice for each pool. Two hours later, mice where challenged with the cH9/1N3 virus. Six days later, lungs were harvested and virus titers in lungs were measured. (B) The virus titers in the lungs of mice that received the children’s prevaccination serum were almost as high as in the naive challenged mice. The titers were lower in the mice receiving the postvaccination children’s serum. There was virus detectable in the mice that received adult prevaccination sera but not in those receiving adult postvaccination sera. Both the pre- and the postvaccination sera of the elderly individuals were protective in mice. (B) The virus lung titers negatively correlate with the IgG titers against the H1 stalk.

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