The Adjuvant Bordetella Colonization Factor A Attenuates Alum-Induced Th2 Responses and Enhances Bordetella pertussis Clearance from Mouse Lungs

Abstract

The reemergence of pertussis or whooping cough in several countries highlights the need for better vaccines. Acellular pertussis vaccines (aPV) contain alum as the adjuvant and elicit Th2 biased immune responses that are less effective in protecting against infection than the reactogenic whole cell pertussis vaccines (wPV), which elicit primarily a Th1/Th17 response. An important goal for the field is to devise aPVs that will induce immune responses similar to wPV. We show that Bordetella Colonization Factor A (BcfA), an outer membrane protein from has strong adjuvant function and elicits cellular and humoral immune responses to heterologous and antigens. Addition of BcfA to a commercial aPV resulted in greater reduction of numbers from the lungs than elicited by aPV alone. More efficient pathogen clearance was accompanied by increased IL-17 and reduced IL-5, and an increased ratio of IgG2/IgG1 antibodies. Thus our results suggest that BcfA improves aPV induced responses by modifying the alum-induced Th2-biased aPV response towards Th1/Th17. A re-designed aPV containing BcfA may allow better control of pertussis reemergence by reshaping immune responses to resemble those elicited by wPV immunization.

Bordetella Colonization Factor A (BcfA) elicits protective immunity againstBordetella bronchisepticain the absence of an additional adjuvant

“…We previously reported that immunization with BcfA/Alum protected mice against B. bronchiseptica challenge(24). BcfA also enhanced immune responses to heterologous antigens and to Bordetella vaccine antigens FHA and Prn(25). These results suggested a dual protective function of BcfA as an antigen and an adjuvant.…”

“…FHA and Prn alone or adjuvanted to alum elicit Th2-skewed antibody responses(25). To determine whether BcfA remodeled these responses towards Th1 we evaluated the systemic and mucosal IgG levels and calculated the ratio of FHA- and Prn-specific IgG2/IgG1 antibodies elicited by BcfA/FHA/Prn.…”

“…We showed that murine bone marrow dendritic cells stimulated with BcfA produced Th1/17 polarizing innate cytokines including IL-12/23. Furthermore, the addition of BcfA to aPV elicited Th1/17-polarized immune responses in C57BL/6 mice by attenuating the Th2 cytokine responses observed with alum-adjuvanted aPV(25). C57BL/6 mice have an inherently Th1-skewed immune phenotype(37).…”

“…We compared protection provided by BcfA or BcfA/FHA/Prn to that provided by Bronchicine ® , a widely used but insufficiently characterized veterinary vaccine. Mice were immunized with BcfA/FHA/Prn or BcfA as above or with 1/10 th or 1/5 th canine dose of Bronchicine ® , doses similar to those of human aPV commonly tested in mice(25, 38). Immunized and naïve mice were subsequently challenged with RB50 or with MBORD 685, a canine B. bronchiseptica strain isolated from a dog with kennel cough(3).…”

“…BcfA is also an adjuvant that elicits Th1/Th17 cytokine responses and Th1-type antibodies to protein antigens(25) potentially serving as an alternative adjuvant to alum. In the present study, we tested the efficacy of BcfA as a monovalent vaccine and combined with Bordetella virulence factors FHA and Prn.…”