Bordetella pertussis is a Gram-negative pathogen that is the primary cause of the disease whooping cough (pertussis). Whole cell pertussis vaccines (wPs: DTP; Diphtheria, Tetanus, Pertussis) were developed in the 1940s. In the 1990's, however, the whole cell vaccines, which had undesirable side effects, were replaced with acellular vaccines (aPs: infant dose-DTaP and booster dose-Tdap), containing three to five virulence-associated proteins (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae) adsorbed to aluminum adjuvant. Since the 1990s, there has been a resurgence in pertussis cases in the US and world which has augmented the need for new and more efficacious vaccines. This proposal seeks to utilize the murine and baboon models to develop an intranasal booster vaccine by building upon how the current acellular vaccines are formulated. We have demonstrated that intranasal immunization with acellular vaccine in mice can protect against B. pertussis challenge. The proposed vaccine utilizes curdlan (linear beta-1,3-glucan) as the adjuvant and includes a new toxoid antigen that will direct humoral responses that will neutralize the adenylate cyclase toxin. In this project, we will optimize the adjuvant / antigen composition of Intranasal curdlan acellular Pertussis vaccine (IN-caP) to protect against B. pertussis challenge in the pre-clinical murine model (aim 1). Once we have established the optimized IN-caP vaccine we will also evaluate the protective capacity in the baboon model of pertussis.
In aim 2, we will characterize the IN-caP cell mediated responses in comparison to IP-aP immunized mice. In the third aim, we will examine IN-caP boost as a mechanism to synergistically improve sub-optimal IP- aP vaccination. At the completion of the project, we expect to have formulated a new class of acellular pertussis vaccine that can be further developed towards clinical trials. It is also likely that the methodologies established will be applicable to develop of vaccines against other bacterial pathogens.
The proposed research is relevant to public health because Bordetella pertussis causes potentially deadly respiratory infections (whooping cough) in children and significant respiratory distress in adults. The re- emergence of whooping cough indicates a critical need to develop new vaccines and strategies. The proposed research is relevant to NIH's mission regarding enhancing health, lengthening life, and reducing illness.
