The role of neutrophils in the age-driven decline in anti-pneumococcal vaccine responses

ABSTRACT Despite the availability of vaccines, Streptococcus pneumoniae (pneumococcus) infections in the elderly remain a health and economic burden in the USA. This calls for a better understanding of pathways driving immune dysregulation in aged hosts, reducing vaccine efficacy and rendering this population susceptible to infections. Our long-term goal is to elucidate the role of polymorphonuclear leukocytes (PMN) in the age- driven reduction in vaccine responses and increased susceptibility to S. pneumoniae infection. Background: A key immune cell following S. pneumoniae infection is PMN. PMNs are innate cells required for controlling bacterial numbers and whose function is known to decline with age. Recent work shows that PMNs are important regulators of adaptive immunity. However, the role of PMNs in clinically relevant vaccinations and their impact in the reduced vaccine efficacy seen in aging remains completely unexplored. We found that vaccination with the pneumococcal conjugate vaccine Prevnar-13, failed to protect old mice against pneumococcal infection. Further, in young hosts, optimal protection following vaccination required PMNs both at the time vaccine administration and at the time of pneumococcal-challenge, highlighting the role of PMNs as both inducers and effectors of vaccine responses. This led to the Hypothesis that age-driven changes in PMNs result in the decline of vaccine efficacy against S. pneumoniae in the elderly. Here we test this hypothesis in both murine models and human volunteers with the following Aims: 1) Test the role of PMNs as effectors in the decline of pneumococcal vaccine efficacy during aging. 2) Test the role of PMNs as inducers of the age-driven decline in pneumococcal vaccine efficacy. 3) Test the effect of host aging on PMN responses following vaccination in human donors. Significance/ innovation: Elucidating the role of PMNs in the decline in vaccine efficacy against pneumococci in the elderly will vastly contribute to our understanding of how aging alters innate immune responses and how innate immunity in turn regulates the decline in adaptive memory responses. Further, understanding the role of PMNs, which are involved in host defense against multiple pathogens, is imperative for future design of better preventative approaches against pneumococci and other relevant infections that target the vulnerable elderly population. This proposal is perfectly in line with NIA’s mission to promote healthy aging.