IL-17-dependent SIgA-mediated protection against nasal Bordetella pertussis infection by live attenuated BPZE1 vaccine

Abstract

BPZE1 is a live attenuated Bordetella pertussis vaccine for nasal administration to mimic the natural route of infection. Here, we studied the mechanism of BPZE1-induced immunity in the murine nasal cavity in contrast to acellular vaccine (aPV), although both vaccines protected against lung colonization. Transfer of splenocytes or serum from BPZE1-vaccinated or aPV-vaccinated mice protected naïve mice against lung colonization but not against nasal colonization. However, transfer of nasal washes from BPZE1-vaccinated mice resulted in protection against nasal colonization, which was lost in IgA-deficient or poly-Ig receptor-deficient mice, indicating that it depends on secretory IgA (SIgA) induction induced in the nose. BPZE1-induced protection against nasal colonization was long-lived despite the relatively rapid decay of SIgA, indicating a potent BPZE1-induced local memory response, likely due to CD4 tissue-resident memory T cells induced in the nose by BPZE1. These cells produced interleukin-17 (IL-17), known to be important for SIgA secretion. Furthermore, BPZE1 failed to protect Il17 mice against nasal colonization by B. pertussis and induced only background levels of nasal SIgA. Thus, our results show important differences in the protective mechanism between the upper and the lower murine respiratory tract and demonstrate an IL-17-dependent SIgA-mediated mechanism of BPZE1-induced protection against B. pertussis nasopharyngeal colonization.

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

“…Live vaccines have the potential to induce strong mucosal protection, but suffer from concern about their risk. An exciting new vaccine candidate against B. pertussis is the live attenuated vaccine, BPZE1, which has been shown to induce a robust local B and T cell response despite genetically engineered mutations that render it relatively safe (283,284). Excitingly, phase I trials demonstrate that the intranasal formulation of the vaccine transiently colonizes the nasal cavity, leading to the generation of stronger immunity (264,268).…”

Development of Improved Acellular Pertussis Vaccines Through Inclusion of the RTX Antigen or Induction of Mucosal Immunity

“…A parallel study also, found that after the fifth dose of DTaP the odds of acquiring pertussis increased on average 42% each year 35 . This trend continued as the same group compared pertussis rates among adolescents who received the Tdap booster, which consists of a lower concentration of vaccine antigens with the addition of Fim antigen.…”

“…Vaccine potency was assessed as international units, determined by comparing mouse survival following different lots of wPs compared to survival following a standard vaccine. The problem was that DTaP vaccine-induced protection could not be fully validated using Kendrick's mouse potency test, as DTaP immunizations did not protect against lethality in the intracerebral challenge 25 . To address this, a modified Kendrick test was developed to assess vaccine potency of DTaP immunizations 26 .…”

“…As a result, Guiso et al developed an intranasal mouse challenge model, where B. pertussis was capable of colonizing the lung. This protocol led to the validity of DTaP vaccines based on serological titers and clearance of the pathogen from the lower-respiratory system of mice 25 .…”

“…Subsequent studies have determined that neutrophil depletion prior to B. pertussis infection in naïve mice does not increase bacterial burden. However, when immunized mice are challenged with B. pertussis following depletion of neutrophils the B. pertussis bacterial burden increase, demonstrating a protective role of neutrophils in immunized mice 25 . As previously mentioned, B. pertussis toxins PT and ACT both affect neutrophils and their recruitment 6,[26][27][28] .…”