Rational design of an adhesin-based pneumococcal vaccine targeting colonization

Mississippi State University, Mississippi State MS

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Abstract

Currently licensed pneumococcal conjugate vaccines have been successful in preventing invasive disease; however, overall colonization rates have remained constant and serotype replacement by non-vaccine serotypes is now common. This suggests that most highly antigenic pneumococcal proteins may elicit strong, yet insufficiently protective immune responses against colonization. The long-term goal of this research is to identify novel vaccine candidates which can synergize with immunity induced by natural pneumococcal infections to provide universal serotype-independent protection against S. pneumoniae. The objective of this R15 renewal is to identify key pneumococcal surface protein (PSP) adhesins which are critical for colonization but fail to induce effective responses in the majority of the population, thereby contributing to stable colonization rates. The central hypothesis is that non-conventional PSP adhesins eliciting IgA response in human sera capable of inhibiting pneumococcal attachment, are ideal vaccine targets providing protective immunity against invasive pneumococcal infection. This hypothesis is based on strong preliminary evidence that demonstrates a low number of individuals develop antibodies that significantly inhibit pneumococcal attachment to respiratory epithelial cells while others do not. Identifying key colonization factors recognized by IgA responses in human sera capable of blocking adherence to host cells will help lead to new targets for serotype-independent protection against pneumococcal colonization. To accomplish this the following three specific aims will be pursued: 1) Identify PSPs eliciting IgA that inhibit pneumococcal adherence to host respiratory epithelial cells; 2) Determine the PSPs which play a critical role in pneumococcal adherence to host respiratory epithelial cells and their mechanism of attachment; 3) Determine protective effect of PSPs vaccine targets in a mouse model of pneumococcal infection. This approach is innovative because it will identify previously unknown non-traditional PSP adhesins critical for colonization, the prerequisite step to invasive disease, while also identifying their cognate receptors on host cells, thereby clarifying the mechanisms of attachment. This work is significant because it will provide new vaccine candidates to limit the large population of humans colonized with pneumococcus, thus overcoming the shortcomings of current vaccines. The streamlined workflow for developing a novel vaccine, which incorporates basic and advanced techniques in microbiology, molecular biology, biochemistry, immunology, and reverse vaccinology, will engage undergraduate and graduate students from across Mississippi in the advancement of biomedical research. This effort fulfills the goals of the AREA grant program and contributes to the mission of the NIH by applying scientific knowledge to enhance human health.