Alum is the most widely used adjuvant in acellular vaccines for bacterial pathogens including Bordetella pertussis, the causative agent of pertussis or whooping cough. However, it may not be the most effective adjuvant to elicit long-term protection when the mechanism involves Th1-type immune responses, since it skews antibody and T cell responses towards Th2. Since alum activates strong antigen-specific responses and provides protection in the short term, leveraging these properties with an adjuvant that shapes the immune repertoire towards a Th1/Th17-type response may elicit a more protective response that confers life-long immunity. Despite high vaccine coverage, the incidence of pertussis is increasing in the USA, Europe and other countries. The current acellular pertussis vaccines (aPV) are only partly effective, compared with whole cell vaccines (wPV). However, the reactogenicity of wPV limits its use. We identified an outer membrane protein, Bordetella Colonization Factor A (BcfA), and show that it has adjuvant activity and enhances antibody responses to protein antigens. In an intranasal murine model of B. pertussis infection, we show that addition of BcfA to the aPV induces Th1-skewed antibody responses and provides better protection against infection. We hypothesize that the combined activity of alum and BcfA will result in synergistic enhancement of protective immune responses in mice against B. pertussis.
In Specific Aim 1, we will test the signaling pathways activated by BcfA, alone and together with alum. We hypothesize that combination treatment with these adjuvants will reshape the profile of activated cytokines produced by inflammatory cells.
In Specific Aim 2, we will determine how combined immunization with BcfA and alum alters the phenotype of antibody and T cell responses to B. pertussis antigens.
In Specific Aim 3, we hypothesize that the Th1/Th17 skewed immune responses induced by the combination of alum and BcfA will result in better clearance of a B. pertussis challenge, and long-lived immunologic memory. This hypothesis will be tested by determining the effect of combined alum/BcfA immunization on B. pertussis clearance from the murine respiratory tract. IMPACT: We have identified a novel adjuvant, BcfA, and hypothesize that the potent responses induced by alum will be shaped to a Th1 type response by BcfA thereby providing better protection against B. pertussis infection. This adjuvant combination may be applicable to other diseases where Th1 type immunity is important for protection.

Public Health Relevance

We identified a novel adjuvant BcfA, which enhances protection against a Bordetella pertussis infection in mice, by a current aPV. We will investigate BcfA's mechanism of action. This research will result in a more effective pertussis vaccine which will have significant and wide-spread public health impact world-wide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI125560-02
Application #
9283339
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Lu, Kristina
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$391,067
Indirect Cost
$136,759
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Cattelan, Natalia; Jennings-Gee, Jamie; Dubey, Purnima et al. (2017) Hyperbiofilm Formation by Bordetella pertussis Strains Correlates with Enhanced Virulence Traits. Infect Immun 85:
Nicholson, Tracy L; Brockmeier, Susan L; Sukumar, Neelima et al. (2017) The Bordetella Bps Polysaccharide Is Required for Biofilm Formation and Enhances Survival in the Lower Respiratory Tract of Swine. Infect Immun 85:
Carbonetti, Nicholas H; Wirsing von König, Carl Heinz; Lan, Ruiting et al. (2017) Erratum for Carbonetti et al., ""Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development"". Clin Vaccine Immunol 24:
Carbonetti, Nicholas H; Wirsing von König, Carl Heinz; Lan, Ruiting et al. (2016) Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development. Clin Vaccine Immunol 23:842-850