CyaA-PspA: towards the development of a protein-based vaccine against Streptococcus pneumoniae infections

• Grant number: 24/01950-7
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2024
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Maria Leonor Sarno de Oliveira
• Grantee: Maria Leonor Sarno de Oliveira
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Eliane Namie Miyaji ; Rosa Maria Chura Chambi

Abstract

Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium of great importance in public health. The bacterium colonizes the upper respiratory tract of healthy individuals, with higher colonization rates in children attending daycare centers and schools. Transmission between individuals occurs via aerosol. In situations of low immunity or that favor the bacterial colonization, such as viral infections and inflammations, pneumococcus can reach the lungs, causing pneumonia, and the bloodstream, causing septicemia and meningitis. The occurrence of otitis media is also quite common. The available vaccines are composed of capsular polysaccharides and provide effective protection, however restricted to the serotypes included in the formulations. This characteristic, added to the high diversity of pneumococcus, means that this pathogen continues to have a major impact on human health, despite the available vaccines. The induction of serotype-independent immunity is the target of several current studies. Our group, in collaboration with the group of Dr. Daniel Ladant from the Pasteur Institute in Paris, developed experimental formulations based on the antigen presentation system of the adenylate cyclase toxin (CyaA) of Bordetella pertussis and the PspA antigen (Pneumococcal Surface Protein A). Several CyaA-PspA proteins containing fragments of the N-terminal region of PspA from different clades have been constructed and tested in animal models over the past few years. The results indicated the best candidates, with broad reactivity against pneumococcal isolates, composed of fragments of the final region of the N-terminal portion of PspAs from clades 1, 2, 3, and 4 carried in CyaA. In this project, we propose to advance the study of these vaccine candidates with the objective of developing effective and viable formulations, aiming for future production on large scale, through: I. evaluation of the use of adjuvants; II. evaluation of the induction of immune response in the respiratory tract through nasal inoculation, III. protection studies against pneumococcal isolates of current clinical importance and IV. studies of optimization protocols for obtaining recombinant CyaA-PspA in soluble form. The results are expected to contribute to the development of alternative vaccines that can complement the immunity induced by currently available vaccines. (AU)