Currently licensed pneumococcal conjugate vaccines have been successful in preventing invasive disease; however, overall colonization rates have remained fairly constant and serotype replacement by non-vaccine serotypes is now common. This along with other weaknesses points to a need for a broadly protective protein-based vaccine. Current protein candidates for such a vaccine have primarily been identified based on their immunogenicity during natural infection, but this strategy overlooks one critical fact: Humans are repetitively colonized by pneumococcus throughout their lives. This indicates that a majority of highly antigenic pneumococcal proteins may elicit strong but not protective immune responses against colonization. The long-term goal is to develop a broadly and consistently protective vaccine against all forms of pneumococcal disease. The overall objective of this proposal is to identify highly conserved pneumococcal adhesins vital for colonization but poorly immunogenic in natural infections. The central hypothesis is that vaccination with pneumococcal adhesins, poorly immunogenic during natural infections, will provide supplemental immunity for preventing pneumococcal adherence and colonization, the prerequisite for all pneumococcal disease. This hypothesis is based on strong preliminary data obtained by our group and others that show a critical role for surface adhesins in colonization and subsequent pneumococcal infections. The rationale for the proposed research is that identifying novel conserved adhesin/host cell interactions will allow for the design a broadly protective protein-based vaccine effective at limiting colonization. To accomplish the objective of this application, the hypothesis will be tested by pursuing the following three specific aims: 1) Identify conserved pneumococcal adhesins differentially expressed between planktonic and biofilm growth; 2) Determine the role of pneumococcal adhesins in adherence and colonization, and 3) Determine the protective effect of vaccination with pneumococcal adhesins. The approach is innovative, in the applicant’s opinion, because it represents a substantive departure from the status quo by focusing specifically on pneumococcal proteins predicted to be surface-expressed and play a role in colonization, without overlooking candidates with limited immunogenicity. This contribution is significant because it will identify novel targets that can be exploited to prevent pneumococcal colonization in a capsule-independent fashion, thus overcoming several shortcomings of current vaccines and taking a vertical step forward in the field. The streamlined workflow of developing a novel vaccine using reverse vaccinology and biomedical technologies will engage undergraduate and graduate students from across Mississippi, a traditionally underrepresented state, in the advancement of biomedical research, thereby fulfilling the goals of the AREA grant program and also contributing to the mission of the NIH by of applying knowledge to enhance human health.

Despite the implementation of polysaccharide-based pneumococcal vaccines, Streptococcus pneumonia still remains a major socioeconomic burden on public health. The proposed study will identify novel protein-based vaccine candidates essential for colonization, but refractory to naturally acquired immunity. Vaccination with these novel candidates will synergistically fill a critical gap in current pneumococcal vaccines (protection against colonization), and provide more complete protection from pneumococcal infection.