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

Abstract

a b s t r a c tA resurgence of whooping cough (pertussis) has been observed in recent years in a number of developed countries, despite widespread vaccine coverage. Although the exact reasons of the recurrence of pertussis are not clear, there are a number of potential causes, like antigenic variation in the circulating strains of Bordetella pertussis, changes in surveillance and diagnostic tools, and potential differences in protection afforded by current acellular pertussis (aP) vaccines compared to more reactogenic whole cell (wP) vaccines, which they replaced. Studies in animal models have shown that induction of cellular as well as humoral immune responses are key to conferring effective and long lasting protection against B. pertussis. wP vaccines induce robust Th1/Th17 responses, which are associated with good protection against lung infection. In contrast, aP vaccines induce mixed Th2/Th17 responses. One research option is to modify current aP vaccines with the intention of inducing protective T cell responses, without compromising on their low reactogenicity profile. Here we found that formulation of an aP vaccine with a novel adjuvant based on a Toll-like receptor 7 agonist (TLR7a) adsorbed to aluminum hydroxide (alum) enhanced B. pertussis-specific Th1 and Th17 responses and serum IgG2a/b antibodies, which had greater functional capacity than those induced by aP formulated with alum alone. Furthermore, addition of a TLR7a enhanced the protective efficacy of the aP vaccine against B. pertussis aerosol challenge; protection was comparable to that of a wP vaccine. These findings suggest that alum-TLR7a is a promising adjuvant for clinical development of next generation pertussis vaccines.

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

“…on days 0 and 28 with 1/5 the human dose of Boostrix alone or mixed with 30 g BcfA and then were challenged intranasally with Bp536 on days 12 to 14 postboost. We selected this dose of aPV since it has been used by others to test vaccine-induced immune responses in mice (20)(21)(22)(23). Bacterial colonies in the lungs were enumerated on days 1, 4, 7, and 14 postchallenge.…”

Lipid conjugation of TLR7 agonist Resiquimod ensures co-delivery with the liposomal Cationic Adjuvant Formulation 01 (CAF01) but does not enhance immunopotentiation compared to non-conjugated Resiquimod+CAF01

“…Furthermore, this inclusion of a TLR7 agonist with Alum re-directed the alum-induced Th2 flavoured response towards a more Th1-biased immune profile [60][61][62]. Using anionic liposomes, Fox et al…”

DNA vaccine ROP29 from Toxoplasma gondii containing R848 enhances protective immunity in mice

“…Furthermore, previous work reported that R848 has potential as a vaccine adjuvant owing to its ability to activate the immune response. Recent studies found that R848 treatment enhanced the immune response to pathogen challenge, arousing a long‐range immune response without influencing the original immunity. Here, R848 enhanced the cellular immune response of T. gondii antigen when used as an adjuvant for the pROP29 vaccine.…”