PROPOSAL SUMMARY/ABSTRACT Streptococcus pneumoniae is estimated to cause over 1.6 million deaths/year worldwide. Pneumococcal disease and related deaths are much more frequent in the elderly. The growing emergence of antibiotic-resistant S. pneumoniae strains places increasing reliance on effective pneumococcal vaccines to protect this at-risk population. The native pneumococcal vaccine currently used in adults consists of capsular polysaccharides (PPS) derived from 23 different serotypes and therefore provides broad coverage against invasive disease with an estimated efficacy of ~65-70%. Nonetheless, protection eventually wanes as antibody titers diminish, typically by 5-10 years post-immunization, and protection against pneumonia is limited. Optimizing protective vaccine responses in the elderly is therefore a major goal. However, in humans there are clear differences between elderly males and females with respect to humoral responses to pneumococcal polysaccharide antigens. We have found the same to be true in mice. The cause of these differences has gone uninvestigated and therefore highlights a significant gap in our understanding of how sex-related differences impact humoral immunity in the aged. Given the continued burden of pneumococcal disease in the elderly, an investigation of the underlying factors contributing to altered immunity to S. pneumoniae with a strong consideration for sex bias is long overdue. Three specific aims are designed to probe factors regulating B cell immunity to pneumococcal polysaccharides and phosphorylcholine (PC) in aged males and females. In Aim 1, we will determine the extent to which age and sex hormones impact the development, phenotype, and functional responses of B-1b cells and PPS3-specific B cells. In Aim 2, we will investigate the mechanisms contributing to altered PC-specific B cell populations and natural antibody secretion between aged males and females and examine the consequences these alterations have for protection against pneumococcal infections. In Aim 3, we will investigate the extent to which sex-driven differences impact protective mucosal responses to S. pneumoniae. Our studies will thereby investigate the extent to which biological sex and gender-influencing hormones intersect to impact the regulation of protective pneumococcal immunity throughout the lifespan. Our results are expected to have a significant impact on the future design and administration of sex- and age- appropriate vaccines, as well as promote informed decision-making for patients receiving hormone replacement or gender-affirming therapy, such that optimal protection against pneumococcal infections can be achieved.

RELEVANCE The goal of the research proposed in the current application is to understand how the immune system is regulated to respond to polysaccharide vaccines important for protection against Streptococcus pneumoniae. We are specifically focusing on the aged population and on identifying key differences between males and females. The knowledge gained from these studies may lead to improved sex- and age-appropriate vaccines that provide enhanced protection against pneumococcal infections currently threatening global public health.