Before the introduction of modern vaccination programs, whooping cough, caused by the bacteria Bordetella pertussis, was the primary infectious cause of infant death. B. pertussis is highly specialized to its human host and produces a number of virulence factors, with no clear correlate of protection. Despite wide-spread, aggressive vaccination, pertussis not only persists but is increasing in incidence in the US and other industrialized countries. In 2012, more pertussis cases were reported in the US since 1955. Academic, pharmaceutical and regulatory members of the pertussis community agree on the need for a more immunogenic and efficacious pertussis vaccine, but how to achieve this is not clear. Therefore, advances in the scientific basis of pertussis pathogenesis and host protective mechanisms are needed. In particular, the adenylate cyclase toxin (ACT) is the leading candidate for inclusion in future vaccines, yet there is very little data detailing the mechanisms by which ACT confers protection or its appropriateness for manufacturing and formulation as a part of a multi-component vaccine. Here, we will perform the first systematic evaluation of ACT's role in protection. This work will involve a combination of in vitro biochemical and anti-bacterial assays as well as passive and active immunization experiments using a murine model of infection which is predictive of vaccine performance in humans.
We aim to conclusively define the role of neutralizing and non-neutralizing anti-ACT antibodies in disease as well as to identify the immunological mechanisms and ACT epitopes necessary for protection.

Public Health Relevance

Once the primary infectious cause of infant death, pertussis was largely controlled by vaccination for many decades. Unfortunately, the last 10 years has seen dramatic increases disease in industrialized countries, including the US. In order to better protect infants, we need an improved vaccine. This project aims to determine whether the adenylate cyclase protein can address some of the short-comings of the current vaccine. Our ultimate goal is to contribute to the design of a better vaccine to limit pertussis morbidity and mortality in the US and world-wide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI122753-04
Application #
9605060
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
GU, Xin-Xing
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
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Acquaye-Seedah, Edith; Huang, Yimin; Sutherland, Jamie N et al. (2018) Humanised monoclonal antibodies neutralise pertussis toxin by receptor blockade and reduced retrograde trafficking. Cell Microbiol 20:e12948
Wagner, Ellen K; Maynard, Jennifer A (2018) Engineering therapeutic antibodies to combat infectious diseases. Curr Opin Chem Eng 19:131-141
Acquaye-Seedah, Edith; Reczek, Elizabeth E; Russell, Hugh H et al. (2018) Characterization of Individual Human Antibodies That Bind Pertussis Toxin Stimulated by Acellular Immunization. Infect Immun 86:
Wang, Xianzhe; Stapleton, James A; Klesmith, Justin R et al. (2017) Fine Epitope Mapping of Two Antibodies Neutralizing the Bordetella Adenylate Cyclase Toxin. Biochemistry 56:1324-1336
Nguyen, Annalee W; Wagner, Ellen K; Posada, Luciano et al. (2017) Prior exposure to Bordetella species as an exclusion criterion in the baboon model of pertussis. J Vet Med Sci 79:60-64
Wagner, Ellen K; Wang, Xianzhe; Bui, Andre et al. (2016) Synergistic Neutralization of Pertussis Toxin by a Bispecific Antibody In Vitro and In Vivo. Clin Vaccine Immunol 23:851-862