Streptococcus pneumoniae is an important human pathogen, causing many severe diseases such as meningitis, pneumonia, bacteremia and sepsis. The vaccines currently available are based on the induction of antibodies against the capsular polysaccharide, but they present some disadvantages, such as high cost and coverage restricted to serotypes included in the formulations. The use of the 7-valent polysaccharide conjugated vaccine resulted in a drastic reduction of invasive disease caused by vaccine serotypes, but there was also a fast replacement by disease caused by non-vaccine serotypes. Furthermore, these vaccines have a much lower efficiency against non-invasive diseases, including pneumonia. Thereby, the development of new vaccines against pneumococcus remains a priority and alternative strategies are being tested, such as the use of protein antigens. Many recombinant proteins expressed in Escherichia coli are being studied, including PspA (Pneumococcal surface protein A). PspA shows variability in different isolates and our group has shown that some variants of PspA are able of inducing antibodies with broader cross-reactivity with different strains. We have also demonstrated that these variants of PspA induce protection against a lethal intranasal challenge and against colonization of the nasopharynx in mice. We propose now to test the effectiveness of a formulation based on PspA nanoparticles against pneumococcal pneumonia. The vaccine will be administered as a powder directly into the lungs of mice through use of a pulmonary insufflator. The use of the formulation as a powder will greatly reduce costs, allowing transport at room temperature without need of a cold chain. PspA adsorbed to nanoparticles based on PGA-co-PDL (poli(glicerol adipato-co-É-pentadecalactona), a biodegradable polyester, will be tested. The nanoparticles have been formulated in nanocomposite microparticle carriers, which are adequate for pulmonary inoculation with an insufflator. It is expected that the nanoparticles will efficiently present the antigen to lung dendritic cells, conferring protection against pneumonia. The induction of immune responses will be evaluated through dosage of antibodies in the serum and lungs. Cytokine production by lung cells and splenocytes of immunized animals will be evaluated in vitro after stimulation with PspA. The effectiveness of immunization in the protection against pneumonia will be evaluated using two models of intranasal challenge: the first one causes non-invasive pneumonia and the second one causes pneumonia followed by invasion and death.
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