Systemic priming and intranasal booster with a BcfA-adjuvanted acellular pertussis vaccine generates CD4+ IL-17+ nasal tissue resident T cells and reduces B. pertussis nasal colonization

Abstract

IntroductionResurgence of pertussis, caused by Bordetella pertussis, necessitates novel vaccines and vaccination strategies to combat this disease. Alum-adjuvanted acellular pertussis vaccines (aPV) delivered intramuscularly reduce bacterial numbers in the lungs of immunized animals and humans, but do not reduce nasal colonization. Thus, aPV-immunized individuals are sources of community transmission. We showed previously that modification of a commercial aPV (Boostrix) by addition of the Th1/17 polarizing adjuvant Bordetella Colonization Factor A (BcfA) attenuated Th2 responses elicited by alum and accelerated clearance of B. pertussis from mouse lungs. Here we tested whether a heterologous immunization strategy with systemic priming and mucosal booster (prime-pull) would reduce nasal colonization.MethodsAdult male and female mice were immunized intramuscularly (i.m.) with aPV or aPV/BcfA and boosted either i.m. or intranasally (i.n.) with the same formulation. Tissue-resident memory (TRM) responses in the respiratory tract were quantified by flow cytometry, and mucosal and systemic antibodies were quantified by ELISA. Immunized and naïve mice were challenged i.n. with Bordetella pertussis and bacterial load in the nose and lungs enumerated at days 1-14 post-challenge.ResultsWe show that prime-pull immunization with Boostrix plus BcfA (aPV/BcfA) generated IFNγ+ and IL-17+ CD4+ lung resident memory T cells (TRM), and CD4+IL-17+ TRM in the nose. In contrast, aPV alone delivered by the same route generated IL-5+ CD4+ resident memory T cells in the lungs and nose. Importantly, nasal colonization was only reduced in mice immunized with aPV/BcfA by the prime-pull regimen.ConclusionsThese results suggest that TH17 polarized TRM generated by aPV/BcfA may reduce nasal colonization thereby preventing pertussis transmission and subsequent resurgence.

Opposing effects of acellular and whole cell pertussis vaccines onBordetella pertussisbiofilm formation, Siglec-F+ neutrophil recruitment and bacterial clearance in mouse nasal tissues

“…Most animal studies have evaluated bacterial burden in the nose by washing the airway and collecting the nasal lavage (NL) (6, 7, 13, 14) while we enumerate bacterial load in the nasal tissues, which includes the septum, turbinates, and nasal epithelial cells (15). Here, we hypothesized that enumeration of bacterial burden in the NL alone vastly underrepresents the true Bp burden in the nose.…”

“…CD4+ T cells were increased in the NT following bacterial challenge of wPV immunized mice, while challenged aPV immunized mice did not have significant numbers of CD4+ T cells in the NT. aPV immunization elicits TH2 polarized systemic T cells specific for the aPV antigens, FHA, Prn and PT (15,(37)(38)(39)(40)(41). However, these may not be the immunodominant Bp antigens presented following infection [Shamseldin, Hall, Hernandez et al, submitted], and thus the aPV antigen specific T cells may not be mobilized to respond to the infection (42,43).…”

A novel “prime and pull” strategy mediated by the combination of two dendritic cell-targeting designs induced protective lung tissue-resident memory T cells against H1N1 influenza virus challenge

“…In detail, CXCR3 is upregulated on T cells upon activation and remains high through the effector and memory stages [ 45 ], and the application of chemokines CXCL9 and CXCL10 was sufficient to selectively recruit effector CD8 + T cells to the vagina through interaction with surface-displayed CXCR3, bypassing the requirement for CD4 + T-cell help. A similar “prime and pull” strategy was also reported in which the mice were immunized intramuscularly with Boostrix plus BcfA and boosted intranasally with the same formulation to generate IFN-gamma + and IL-17 + CD4 + T RM cells and significantly reduced B. pertussis colonization of the nose [ 46 ]. Other inflammatory agents [ 47 ] or the chemokine CCR5 [ 48 ] have also been found to sufficiently generate CD8 + T RM cells in the skin or gut.…”

Understanding the impact of adult pertussis and current approaches to vaccination: A narrative review and expert panel recommendations

“…The panel acknowledged emerging approaches to inducing potent cellular immune responses in the respiratory mucosa, with potential to improve protective local pertussis immunity in humans. These strategies include novel vaccine delivery methods, such as vaccine antigens entrapped in biodegradable microparticles, 83 and investigational vaccine candidates, including ap vaccines formulated with novel Th17/Th1-skewing adjuvants, 84 outer membrane vesicle (OMV) vaccines, 85 and live attenuated vaccines. 86 Among all candidates to date, only BPZE1, a nasally administered live attenuated pertussis vaccine, has advanced into clinical development.…”