A conserved pneumococcal antigen identified by CRISPRi-seq induces broad Th17-mediated serotype-independent protection

Streptococcus pneumoniae causes severe invasive diseases with greater health risks upon influenza virus infection. Current vaccines are made of capsule polysaccharide, are serotype-specific and protect against invasive pneumococcal disease. However, they are now leading to the emergence of non-vaccine serotypes and do not provide strong protection following flu infection. To define potential universal protective antigens, we performed CRISPRi-seq in a murine model of flu superinfection and identified the highly conserved pneumococcal gene spv_0960 (lafB) as novel virulence factor. We show that LafB is a membrane-associated, intracellular protein. Vaccination with recombinant LafB and mucosal adjuvant, in contrast to subcutaneous vaccination, was highly protective in mice during superinfection. Interestingly, protection did not require antibody but was dependent on Th17-mediated immunity. Importantly, LafB vaccination was effective against non-vaccine serotypes 15A and 24F. Finally, LafB-specific immune responses are elicited in healthy human individuals, paving the way for a universal pneumococcal vaccine.