Influenza virus infection remains a serious threat to human health, particularly in the elderly, in whom it tends to cause severe morbidity associated with high mortality. Unfortunately, current influenza virus vaccines are less than 50 percent effective in preventing serious disease and hospitalization in the elderly. This could be due to the declining ability of aging immune systems to generate effective antibody (Ab) responses to antigens encountered for the first time. The latter is the basis of current vaccines, which attempt to induce Ab responses that are largely specific for determinants of the hemagglutinin and neuraminidase of newly emerging epidemic virus strains. By contrast, since established memory Ab responses can often be sustained for decades, a protective cross-reactive Ab response may provide increased protection in elderly people. This proposal aims to explore the protective efficacy of such a cross-reactive Ab response that is directed to the ektodomain of the M2 protein, a highly conserved influenza virus transmembrane protein. The specific aims are: 1) to construct a multiple antigenic peptide vaccine that comprises several M2 ektodomains and helper T cell determinants; 2) to identify, in a murine model, a vaccination protocol that induces a strong M2-specific Ab response and protection against influenza virus induced morbidity; 3) to test the ability of virus to escape this Ab-mediated protection through mutation; 4) to test whether a sustained M2-specific memory response provides enhanced protection in old mice; and 5) to determine how the M2-specific protection is modified by infections occurring prior or subsequent to vaccination. The proposed research will tell whether a cross-reactive M2-specific Ab-mediated immunity has the potential of providing improved protection in the elderly.