Delivery of multiple PspA fragments by CyaA toxoid induces broad protection against Streptococcus pneumoniae

Abstract Streptococcus pneumoniae is a leading cause of lower respiratory tract (LRT) infections and invasive pneumococcal diseases (IPD). Conjugate vaccines are effective against IPD and nasal colonization but offer coverage limited to serotypes included in the formulations. Pneumococcal surface protein A (PspA) stands out as a promising vaccine antigen. We had previously shown that recombinant adenylate cyclase toxoid from Bordetella pertussis (CyaA) carrying PspA fragments induces humoral responses and protection against pneumococcal infection in mice. Here, we present an optimized construct combining fragments derived from four PspA variants (CyaA-A2-A4/A1-A3). Immunization of mice with CyaA-A2-A4/A1-A3 conferred protection against IPD and promoted a rapid control of LRT infection. Antibody reactivity and protection were observed across strains expressing distinct PspAs and capsular serotypes. Importantly, CyaA-A2-A4/A1-A3 protected mice against serotype 3 isolates from clonal complex 180, a major clone causing disease worldwide. CyaA-A2-A4/A1-A3 may be proposed as a complementary vaccine to induce broad protection against pneumococcal infections.