Broadly Reactive Human Monoclonal Antibodies Targeting the Pneumococcal Histidine Triad Protein Protect against Fatal Pneumococcal Infection

Streptococcus pneumoniae remains a leading cause of bacterial pneumonia despite the widespread use of vaccines. While vaccines are effective at reducing the incidence of most serotypes included in vaccines, a rise in infection due to nonvaccine serotypes and moderate efficacy against some vaccine serotypes have contributed to high disease incidence. Additionally, numerous isolates of S. pneumoniae are antibiotic or multidrug resistant. Several conserved pneumococcal proteins prevalent in the majority of serotypes have been examined for their potential as vaccines in preclinical and clinical trials. An additional, yet-unexplored tool for disease prevention and treatment is the use of human monoclonal antibodies (MAbs) targeting conserved pneumococcal proteins. Here, we isolated the first human MAbs (PhtD3, PhtD6, PhtD7, PhtD8, and PspA16) against the pneumococcal histidine triad protein (PhtD) and the pneumococcal surface protein A (PspA), two conserved and protective antigens. MAbs to PhtD target diverse epitopes on PhtD, and MAb PspA16 targets the N-terminal segment of PspA. The PhtD-specific MAbs bind to multiple serotypes, while MAb PspA16 serotype breadth is limited. MAbs PhtD3 and PhtD8 prolong the survival of mice infected with pneumococcal serotype 3. Furthermore, MAb PhtD3 prolongs the survival of mice in intranasal and intravenous infection models with pneumococcal serotype 4 and in mice infected with pneumococcal serotype 3 when administered 24 h after pneumococcal infection. All PhtD and PspA MAbs demonstrate opsonophagocytic activity, suggesting a potential mechanism of protection. Our results identify new human MAbs for pneumococcal disease prevention and treatment and identify epitopes on PhtD and PspA recognized by human B cells.