A Pertussis Outer Membrane Vesicle-Based Vaccine Induces Lung-Resident Memory CD4 T Cells and Protection Against Bordetella pertussis, Including Pertactin Deficient Strains

Abstract

Pertussis is a respiratory infectious disease that has been resurged during the last decades. The change from the traditional multi-antigen whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines that consist of a few antigens formulated with alum, appears to be a key factor in the resurgence of pertussis in many countries. Though current aP vaccines have helped to reduce the morbidity and mortality associated with pertussis, they do not provide durable immunity or adequate protection against the disease caused by the current circulating strains of Bordetella pertussis , which have evolved in the face of the selection pressure induced by the vaccines. Based on the hypothesis that a new vaccine containing multiple antigens could overcome deficiencies in the current aP vaccines, we have designed and characterized a vaccine candidate based on outer membrane vesicle (OMVs). Here we show that the OMVs vaccine, but not an aP vaccine, protected mice against lung infection with a circulating pertactin (PRN)-deficient isolate. Using isogenic bacteria that in principle only differ in PRN expression, we found that deficiency in PRN appears to be largely responsible for the failure of the aP vaccine to protect against this circulating clinical isolates. Regarding the durability of induced immunity, we have already reported that the OMV vaccine is able to induce long-lasting immune responses that effectively prevent infection with B. pertussis . Consistent with this, here we found that CD4 T cells with a tissue-resident memory (T RM ) cell phenotype (CD44 + CD62L low CD69 + and/or CD103 + ) accumulated in the lungs of mice 14 days after immunization with 2 doses of the OMVs vaccine. CD4 T RM cells, which have previously been shown to play a critical role sustained protective immunity against B. pertussis , were also detected in mice immunized with wP vaccine, but not in the animals immunized with a commercial aP vaccine. The CD4 T RM cells secreted IFN-γ and IL-17 and were significantly expanded through local proliferation following respiratory challenge of mice with B. pertussis . Our findings that the OMVs vaccine induce respiratory CD4 T RM cells may explain the ability of this vaccine to induce long-term protection and is therefore an ideal candidate for a third generation vaccine against B. pertussis .

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

“…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. These studies found that Tdap effectiveness dropped from 69% the first year after vaccination to an alarming 9% after 4 years 36 . Predictably, a study found that individuals who only received DTaP immunizations compared to those who received the wP vaccine schedule were at greater risk of contracting pertussis 37 .…”

“…Current and past B. pertussis immune response studies have focused on a limited set of known immunological responses to B. pertussis challenge such as: bacterial burden, antibody response, recruitment of phagocytes, cytokine profiles, and others 35,36 .…”

“…ACT plays a key role in the pathogenesis of B. pertussis and many studies have shown that both native and recombinant ACTs can be adjuvants and/or antigens for protection against pertussis in murine challenge studies [17][18][19][20][35][36][37][38][39] . In this study, we aimed to systematically evaluate the RTX antigen (toxoid version of ACT) for inclusion into the acellular pertussis vaccine.…”

“…In the murine model, recent data has pointed to the importance of IgA and a local mucosal immune response in the lung and nasal cavity. [32][33][34][35][36] We aimed to measure the presence of IgA antibodies in the murine respiratory tissue due to IN immunization.…”

“…Data from orally administered vaccines demonstrates that gut-associated lymphoid tissue promotes tolerance over immunogenicity 35 . We reasoned that because the alum adjuvant is not optimal for mucosal vaccination, that IN administered DTaP may not induce enough inflammation to induce a protective immune response 36 . It may be that in order to induce a systemic response, the vaccine would have to stimulate a pro-inflammatory response upon vacation, as was the case in the BPZE1 vaccine discussed above.…”