In this proposal, a program is presented that will facilitate the career development of Stefan Gravenstein who has recently completed fellowship training in Geriatrics and has been appointed Assistant Professor of Medicine. Initially, this career development award will allow him the opportunity to develop and apply essential bench skills to study the proposed research question. Over the long term, this study will greatly enhance his research capabilities in his focused area of interest, immune senescence and vaccines. The funds in this award will help him develop an independent laboratory. Despite commercially available vaccine, influenza remains a major cause of morbidity and mortality in elderly people. There are several proposed quantitative and qualitative explanations for this. Many older vaccine recipients (perhaps 50%) do not achieve the fourfold increase in antibody titer that is conventionally considered """"""""protective"""""""". In others, influenza infection occurs despite a measurable antibody response. In these individuals there may a qualitative difference in antibody. The influenza vaccine in comprised of purified hemagglutinin (HA) molecules which are glycoproteins found on the surface of the viral particle. The structure of the HA molecule has been well characterized and it is now appreciated that there are four antigenic domains. The domains are not equivalent in their immuno-genicity and it is our hypothesis that with advancing age the majority of antibody is made increasingly to only one or two of the four domains. We also propose that antibody diversity is less in frail elderly than in healthy elderly. Finally, we propose that post- vaccination antibody diversity, i.e., antibody specificity to each of the HA antigenic domains, is reduced in those individuals who eventually succumb to influenza. In this research we plan to develop a panel of epitope-specific monoclonal antibodies (mAb) to the four immunodominant antigenic domains on HA. The training and development for this will occur at the UW Hybridoma Facility. We will use these antibodies to select HA-variant viruses. The HA RNA from these viruses will be sequenced to determine the mAb specificity.The sera to be tested are from over 700 frail elderly people receiving influenza vaccine in clinical trials under ny direction. Sera from healthy vaccinated young (n=50) or elderly (n>35) subjects sampled at the same time will be compared. If our hypothesis is true, we should demonstrate that with advancing age there is a less diverse antibody response to vaccine, and that diversity is less in frail elderly than healthy elderly. Finally, we would like to show an association between diversity of antibody repertoire after influenza vaccination and subsequent influenza illness.
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