Effective vaccination against Streptococcus pneumoniae, the most common and serious cause of bacterial pneumonia in children and adults, is complicated by the high number of antigenically-distinct capsular serotypes that cause disease. Multiple capsular serotypes must be included in a vaccine, but failure to protect against one is failure of the vaccine. Moreover, disease- and vaccine-associated strains are shifting toward non-vaccine types in response to vaccine pressure. We propose to promote protection against colonization and subsequent invasive disease by S. pneumoniae with an immunogenic protein that is conserved among pneumococcal serotypes. This protein, IgA1 protease (IgA1P), likely contributes to microbial pathogenesis by subverting mucosal host defense. Indeed, we and others have shown that capsule-specific IgA supports killing of S. pneumoniae, and that the IgA1P of S. pneumoniae inhibits such IgA-dependent killing. Moreover, capsule-specific IgA cleaved by the protease enhances adherence to epithelial surfaces by modifying the bacterial surface, which may promote colonization and subsequent disease. In our preliminary studies, adults with pneumococcal bacteremia generated IgG antibodies that neutralize the proteolytic activity of IgA1P. We propose to characterize the diversity of the enzyme and the ability of and mechanisms by which IgG antibodies to IgA1P generated by the host inhibit the enzyme, and block protease-related inhibition of killing and enhancement of adherence. This early translational study will evaluate the feasibility of incorporating IgA1P as a protein vaccine antigen to facilitate cross-serotype protection against S. pneumoniae colonization, pneumonia and invasive disease. PUBLIC HEALTH RELEVANCE: The pneumococcus is the leading cause of bacterial pneumonia worldwide in children and adults. The infection starts in the upper airway where antibodies attempt to bind and inhibit bacterial virulence factors. The bacteria disarm these potentially protective local antibodies by producing an enzyme, IgA1 protease that cuts them in half. We propose to block the activity of IgA1 protease to enhance the effectiveness of local vaccines and of natural host defenses.