Novel Immune History-Based Correlates of Risk and Protection for Influenza

Introduction

Vaccination, the most cost-effective public health intervention, stimulates the immune system to generate protective memory response. Seasonal influenza vaccines effectiveness varies by year and wanes over time. A variety of factors contribute to high heterogeneity in vaccine induced immune responses, such as age, gender and individual’s ‘immune history’ – the memory antibody repertoire of previously encountered pathogens and vaccines. The current gold standard correlate of protection is the hemagglutinin inhibition assay, which has limited prediction power and is time and sample consuming. Here, we designed a novel Antigen Microarray (AM) assay to study the immune history of influenza IgG and IgA antibody repertoires and to identify novel correlates of protection based on these measurements.

Material and Methods

To study the role of immune-history of previous influenza infections, we have developed a novel influenza antigen microarray spotted with whole- inactivated influenza viruses, recombinant surface glcyoproteins and their respective overlapping peptides. Viruses from influenza A H3N2, H1N1 and B subtypes were included on the array.

We used serum samples from FluVacs – a randomized double-blind placebo-controlled influenza vaccine efficacy trial comparing the vaccine efficacy of the inactivated (IIV) and live-attenuated (LAIV) vaccines in adults aged 18-65, conducted in 2007-2008.

We analyzed serum samples from a case-control set of 162 individuals including all participants that were infected with influenza during the trial. Samples were collected at 3 timepoints for each subject: pre-vaccination baseline (d0), post vaccination (d21) and at the end of the season (d90). IgG and IgA antibody profiles at all timepoints were captured using our novel antigen array.

Results and Discussion

We observed a high heterogeneity of responses to historical influenza strains at baseline and divided them to high, medium and low responders. We compared the antibody profiles at baseline and post-vaccination of all subjects who subsequently became infected to those who did not. Low responders in both the placebo and vaccine arms had infections rates > 80%. In contrast, high responders had infections rates of 22% in placebos and 0% in IIV vaccinated subjects. We further found that stratifying individuals based on their post-vaccination responses allowed to identify additional vaccinated subjects that were at high or low risk to acquire infection.

Conclusion

Our data suggests that serum IgA immune history profiles are novel correlates of risk and protection from influenza infection. They further suggest that individuals can be stratified at baseline to identify a sub-population of low responders who are at high risk of acquiring influenza infection.