The incidence of invasive pneumococcal disease (IPD) changed markedly after the introduction in 2000 of a protein conjugate vaccine with capsular polysaccharides (PPS) of seven of the most common disease-causing serotypes (ST) of Streptococcus pneumoniae (pneumococcus) (PCV7). The most dramatic change was a major reduction in IPD with PCV-included STs due to herd protection, but this was accompanied by the emergence of non-vaccine STs and a marked rise in serotype 3 (ST3). ST3 is a leading cause of pneumonia and empyema in adults and children in the U.S. and globally and portends an independent, higher risk of death than other STs. Though there is a ST3 moiety, pneumococcal capsular polysaccharide 3 (PPS3) in the 23- valent PPS vaccine (PV23) used in adults, data on whether PV23 prevents pneumonia are conflicting and the ability of a new conjugate with PPS3, PCV13 to prevent ST3 is uncertain. Thus, there is an urgent need for a better understanding of antibody immunity to ST3 and to find better new ways to treat ST3 disease. The goal of this application is to identify and characterize human antibodies that protect against ST3. To accomplish this we will isolate human monoclonal antibodies (huMAbs) to PPS3 from PPS vaccine recipients by an innovative, single cell expression cloning approach and determine their efficacy in mouse models of ST3 colonization, pneumonia and sepsis as a function of their gene use and diversity, PPS3 epitope specificity, and functional activity against ST3 in vitro, taking the first steps in identifying therapeutic huMAbs for ST3. In addition, we wil use the epitopes and functional aspects of protective huMAbs as probes to interrogate PPS3 responses of PPS vaccine recipients. The huMAbs developed in this project will serve as candidate therapeutics for ST3 and the new scientific information it provides on antibody immunity to ST3 will make it possible to dissect PPS3 responses to vaccines in a way that has not been possible before and to identify novel, protective PPS3 antigens for ST3 vaccines. Thus, the project will have a major impact on clinical medicine by removing what have been formidable roadblocks in prevention of ST3 via novel therapeutic agents and on basic science via new insights into antibody immunity, ST3 pathogenesis and host-ST3 interaction.
Two types of vaccines are currently available for prevention of disease caused by the bacterial pathogen, Streptococcus pneumoniae (pneumococcus). The 23-valent pneumococcal polysaccharide vaccine (PV23), which is recommended in those e65 and 9-64 yrs with chronic and underlying disease, including those with HIV/AIDS, and polysaccharide conjugate vaccines that are recommended in infants and young children and was recently approved for use in adults. Nonetheless, the ability of these vaccines to prevent certain types of pneumococcus is limited and one such type is called serotype 3 (pneumococcus), which is one of commonest causes of pneumonia in adults and children in the United States and globally. Pneumonia leads to substantial morbidity, mortality, and health care costs. The goal of this application is to make monoclonal antibodies from people who receive pneumococcal vaccines and identify the characteristics of those that are protective in experimental models of serotype 3 pneumonia and sepsis. The development of these monoclonal antibodies will provide novel therapeutic agents for the treatment of serotype 3 pneumonia and serve as the basis for developing assays to determine if people make protective antibodies in response to the vaccine as well as a platform for making a more protective serotype 3 vaccine. The public health significance and impact of this proposal is high. Data generated will overcome roadblocks to use of pneumococcal vaccines to prevent serotype 3 disease and pneumonia and inform the development of new vaccines and therapies.
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