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Obtention of detoxified pneumolisin for inclusion in a quimeric PspA-Ply anti-pneumococcal vaccine

Grant number: 10/00744-1
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2010
Effective date (End): September 30, 2012
Field of knowledge:Health Sciences - Collective Health - Preventive Medicine
Principal Investigator:Michelle Darrieux Sampaio Bertoncini
Grantee:Thais Raquel da Silva
Home Institution: Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil

Abstract

Streptococcus pneumoniae is an important cause of pneumonia, meningitis and sepsis. It is an encapsulated gram-positive bacterium, and the polisaccharide capsule is the main virulence factor and the basis of the current vaccines. Free PS, however, is a T-independent antigen, not immunogenic in young children. A conjugated PS-protein vaccine has been used to immunize children, but its high production costs limit its use in developing countries. Several pneumococcal proteins have been tested as vaccine candidates, since they-re able to induce T mediate response and broad coverage against diverse pneumococcal serotypes. Among those, PspA and Pneumolysin (Ply) have shown the most promising results in animal models. PspA is an important surface exposed virulence factor, while Ply is a toxin able to bind TLR4 with many biological proprerties. The combination of these 2 proteins has presented the highest protection rates aginst pneumococal sepsis in mice. However, Ply is vey toxic, and it is necessary to use detoxified forms of this protein. This project aims at producing detoxified forms of ply through site directed mutagenesis. These mutants will be tested for their immunogenic portential and their ability to interact with complement system; those with best results will be genetically fused to the N-terminus of PspA family 1 molecules in order to produce a quimeric vaccine. The combination of 2 penumococcal proteins, uniting the high immunogenicity of PspA with the adjuvanticity of Ply is a promising vaccine strategy, capable of inducing broad prtection.