Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

Abstract

Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells.

Addition of a TLR7 agonist to an acellular pertussis vaccine enhances Th1 and Th17 responses and protective immunity in a mouse model

“…Control mice immunized with PBS developed a persistent infection, characteristic of that previously observed in naive mice [5]. Mice immunized with wP or aP+alum-TLR7a had cleared the infection by day 3 post challenge (Fig.3C).…”

“…Studies in mice have shown that wP vaccines protect through induction of a mixed Th1/Th17 response, while the aP vaccine promotes Th2/Th17 polarized responses [5,7], with Th2 responses being dispensable for protection. Developed countries are not likely to revert to wP vaccines due to their higher reactogenicity.…”

“…Studies using this model have demonstrated that B. pertussisspecific T cells, as well as antibodies, mediate natural and vaccine-induced protective immunity [4]. Experiments in knockout mice showed that IFN-c and IL-17, secreted by Th1 and Th17 cells respectively, contribute to protection, and vaccines that induce both of these T cell subtypes are most effective [5]. While natural infection and wP vaccination induce a mixed Th1/Th17 response in mice [5,6], a more Th2-polarized response is induced by immunization with conventional aP vaccines [5].…”

“…Experiments in knockout mice showed that IFN-c and IL-17, secreted by Th1 and Th17 cells respectively, contribute to protection, and vaccines that induce both of these T cell subtypes are most effective [5]. While natural infection and wP vaccination induce a mixed Th1/Th17 response in mice [5,6], a more Th2-polarized response is induced by immunization with conventional aP vaccines [5]. Importantly, the immune responses induced by infection or vaccination in baboons are similar to those in mice, further validating the mouse model; infection induces long-lived Th1/Th17 responses, wP vaccination induces more Th17-dominated responses, whereas aP vaccines induce Th2-polarised responses [2,7].…”

The role ofB. pertussisvaccine antigen gene variants in pertussis resurgence and possible consequences for vaccine development

“…[3][4][5] It has been long recognized that while WCVs induce a mainly Th1 biased response, the response to ACVs has a distinct Th2 bias. 6 Using an infant baboon model of pertussis, there are clear differences between WCV-and ACV-induced immunity. Both types of vaccines protect the individual against disease but animals vaccinated with ACV were colonized to a higher level and for longer when subsequently challenged with B. pertussis, compared to animals vaccinated with WCV.…”