Development of a next generation vaccine to prevent pertussis

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SUMMARY Bordetella pertussis causes pertussis (whooping cough), which is a reemerging global public health threat. In the 1940s an inactivated, whole-cell pertussis vaccine was introduced that dramatically reduced the mortality caused by pertussis. A new, potentially less toxic acellular vaccine was developed and introduced in the United States and other parts of the world in the 1990s. Although the acellular pertussis (aP) vaccine has fewer side effects, its protective efficacy is lower than that of the whole cell vaccine potentially due to the inability of aP to prevent nasopharyngeal colonization leading to transmission of B. pertussis. Like many Gram-negative pathogens, Bordetella spp. possess a type III secretion apparatus (T3SA). It resembles a molecular syringe and needle and two protein complexes localize atop the needle: a tip protein and the first translocator protein. These proteins are required for pathogenesis of Bordetella spp. and are 95-98% conserved among Bordetella spp. We have previously fused the Shigella spp. T3SA tip and translocator proteins to create DBF, which was used to successfully develop a novel subunit vaccine antigen against Shigella spp. When administered intranasally (IN) or parenterally (IM), DBF, admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from Enterotoxigenic E. coli, protects mice against a lethal challenge by S. flexneri and the heterologous pathogens S. sonnei and S. dysenteriae. We have similarly produced a fusion for Bordetella. In the initial mouse experiment the fusion protected 100% of the mice from a lethal pulmonary challenge with B. bronchiseptica, the causative agent of canine kennel cough. Furthermore, 38% sterilizing immunity was observed in the lungs despite the high bacterial load administered in the challenge. Thus, we hypothesize that our fusion will elicit a robust immune response that protects against B. bronchiseptica and B. pertussis infection. Additionally, we hypothesize that the fusion will elicit sterilizing immunity in the respiratory tract to break the transmission chain. Thus, the specific aims of this investigation are: 1) Assess the respective humoral and cell-mediated immune responses elicited by the fusion delivered IN and IM and 2) Determine the protective efficacy of the fusion against B. bronchiseptica and B. pertussis challenge.