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.

Public Health Relevance

Bordetella pertussis causes pertussis (whooping cough), a severe respiratory syndrome that is a reemerging global public health threat. Due to side effects attributed to the 1940?s whole cell vaccine, a new acellular vaccine was developed and introduced in the US and other parts of the world in the 1990s. Although the acellular pertussis (aP) vaccine has few side effects, its protective efficacy is lower than that of the whole cell vaccine. Furthermore, it has been demonstrated that, unlike the whole cell vaccine, the aP vaccine fails to prevent nasopharyngeal colonization and transmission of B. pertussis. We hypothesize that our new protein subunit vaccine containing 22BF, admixed with a mucosal adjuvant, will elicit an immune response that protects against B. bronchiseptica and B. pertussis by preventing colonization of the respiratory tract, thereby promoting host protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI136525-02
Application #
9613783
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
GU, Xin-Xing
Project Start
2017-12-15
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045