Comparison of Three Licensed Influenza Vaccines

Summary

Participation Requirements

Description

Previous observations to date lead to the following model: Traditional egg-derived TIV have contaminating internal virion proteins that preferentially elicit memory CD4 T cells specific for these proteins. These CD4 T cells will have limited efficacy as helpers for the neutralizing Ab response and w...

Previous observations to date lead to the following model: Traditional egg-derived TIV have contaminating internal virion proteins that preferentially elicit memory CD4 T cells specific for these proteins. These CD4 T cells will have limited efficacy as helpers for the neutralizing Ab response and will suppress the CD4 T cell response to new HA epitopes in the vaccine. The current study will test this hypothesis by comparing CD4 cell responses to specific epitopes, and the subsequent B cell and antibody response, in subjects receiving a vaccine containing only HA protein to vaccines with more complex antigenic characteristics. The CD4 T cell reactivity to pools of unique, conserved, and total pH1 HA peptides as well as H3, influenza B HA, NP, and M1 peptides will be quantified using cytokine Elispot assays and flow cytometry, and then compared to the subsequent antibody and B cell response. Investigators will also use this study as an opportunity to evaluate the effects of prior vaccination. Recent studies have emphasized the potential negative effect of vaccination in prior years on both the immune response as well as the protective effectiveness of current vaccine. In order to evaluate this phenomenon in the context of multiple vaccine formulations, prior vaccination history of the subjects will be reviewed and subjects stratify vaccination based on vaccine history. In addition, subjects who participated in this study in a previous year are eligible to re-enroll, and will receive the same vaccine that they were randomized to previously. This will allow an evaluation of differences between vaccine formulations in the responsiveness to multiple vaccinations. Furthermore, recent studies indicate reports that the glycosylation pattern of viral hemagglutinins produced in cell culture can vary depending on the host cell used, and that this can affect CD4 T cell immunogenicity and antibody recognition. As a cell culture-based influenza vaccine production platform offers many advantages and may eventually supplant the traditional egg-based approach, it is of great value to understand the CD4 T cell response induced by this vaccine and how this affects neutralizing Ab production. Recent data have also suggested that the failure of seasonal influenza infection to induce substantial levels of stalk specific antibody may be due to the relatively inaccessible nature of this epitope. As part of this study, investigators will also compare the specificity of the human antibody response between the vaccine groups, with the hypothesis that the rHA vaccine will more readily allow targeting of these important, broadly conserved epitopes. There is compelling preliminary data demonstrating that multiple antibodies that we have isolated have a particularly slow on rate when they bind to the HA-stalk versus the HA-globular head epitopes on whole virions, but not on recombinant HA trimmers expressed in baculovirus. The hypothesis is that a free, recombinant HA vaccine will allow more efficient targeting of the HA-Stalk epitopes.

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