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Pneumococcal protein vaccines, evaluation of immune responses under different presentations

Grant number: 09/17030-4
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2010
Effective date (End): February 28, 2015
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal Investigator:Luciana Cezar de Cerqueira Leite
Grantee:Cibelly Goulart
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:08/05207-4 - Pneumococcal conjugate vaccine: capsular polysaccharide - pneumococcal surface protein A, AP.TEM

Abstract

Streptococcus pneumoniae is a serious public health problem worldwide, causing more than 4 millions deaths every year mainly in developing countries. The currently available vaccines are based on capsular polysaccharides, and have high cost and limited coverage, reinforcing the need of research for alternative vaccine strategies. The use of conserved pneumococcal proteins has shown promising results in several animal models, and some of these proteins underwent phase 1 clinical trials with success. Among the most studied pneumococcal proteins are PspA and pneumolysin. PspA is an exposed virulence factor present in all pneumococcal strains, able to protect mice against invasive challenge with virulent pneumococci. The N-terminal domain of PspA displays serologic diversity, being clades 1 to 4 worldwide prevalent. However, there are variable levels of cross-reactivity between clades and within PspAs of the same clade, which influence the size and type of PspA to be used as vaccine. Pneumolysin (Ply) is a conserved protein with inflammatory properties; it has also been shown to interact with TLR-4, being directly involved in the innate immune response triggered by pneumococcus. Since the ability to activate innate immunity is characteristic of molecules with adjuvant properties, we postulate that Ply and/or PDT (its mutated non-toxic form) may have an adjuvant effect when used in conjunction with PspA, providing a strong immune response against both proteins. The aim of this project to evaluate, from a panel of brazilian pneumococcal isolates, which family 1 PspA molecule was able to induce greater reactivity/cross-protection in this family. In order to increase the vaccine immunogenicity, we propose to fuse the PspA to detoxified Ply, whose adjuvant effects could enhance the antigenic properties of that protein. We also want to evaluate the potential of these proteins as carriers for PS, as well as the combined effect of PS-PspA/PS-PspA-PDT on the immune response induced to each component. We believe that the combination of different pneumococcal antigens with potential protective role is a promising vaccine strategy, capable of promoting a strong immunity with broad protection against several pneumococcal serotypes, and it is also an economic strategy, because it reduces the number of antigens included in the current formulations. (AU)