ABSTRACT Pneumococcal polysaccharide (PPS conjugate vaccines (PCV) have had remarkable impact in preventing invasive pneumococcal disease (IPD), but there is still a gap in treatment and prevention of pneumococcal disease as current vaccines are less effective for pneumonia than IPD and less immunogenic in patients most at risk for disease. My group has a longstanding interest in vaccine-elicited PPS antibodies and how they work. We made the paradigm-shifting discovery that while some PPS3 monoclonal antibodies (MAbs) that protect mice from serotype 3 (ST3) pneumococcus mediate phagocyte killing of ST3 in vitro (opsonic), others do not (non-opsonic). These MAb types have distinct PPS3 specificities and require different effectors and FcγRs to protect mice from ST3 pneumonia. Opsonic antibodies induce early lung bacterial clearance, but non-opsonic MAbs do not, instead they reduce lung inflammation. These findings challenge prevailing dogma that vaccine efficacy is solely a function of opsonic antibodies and show there is still much to learn about how PPS antibodies mediate protection. The goal of this application is to make human monoclonal antibodies (huMAbs) to treat ST3 pneumonia. Ultimately, we wish to develop a multi-ST huMAb cocktail, but ST3 will be our first target as PCV13 is less effective for ST3, an important cause of pneumonia that still carries higher risk of death than other STs. We hypothesize huMAbs that balance ST3 clearance and control of host inflammation will provide the most protection. We will generate PPS3 huMAbs from pneumococcal vaccine recipients, use a novel ST3 glycan array to identify huMAb PPS3 epitopes, and determine their functional activities in vitro and efficacies against ST3 in vivo in colonization, pneumonia, and sepsis models in normal and human (hu)FcγR transgenic mice. This will identify candidate huMAbs to advance for therapy, reveal potentially new correlates of protection, and identify potential adjunctive PPS3 antigens to enhance vaccine efficacy for pneumonia. This project will advance understanding of mechanisms of antibody action and have a major impact on clinical medicine and public health by removing roadblocks to prevention and treatment of pneumococcal pneumonia with ideas and an approach that can be applied to any pathogen.