Live nasal recombinant B. pertussis vaccine against tuberculosis

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ABSTRACT: Live nasal recombinant B. pertussis vaccine against tuberculosis An effective TB vaccine that blocks infection and interrupts transmission of TB from infected adolescents and adults is urgently needed as a complement to the worldwide use of BCG in infants. Although BCG is moderately effective in preventing disseminated forms of TB, new vaccine strategies are necessary for improved control and prevention of TB which infects over 10 million people annually. True correlates of protective immunity have not been identified. However, local, lung-resident memory T cells have been implicated in protection against pulmonary forms of TB in many prior animal model studies. Furthermore, recent evidence shows that IL-17 secreting T cells that are enriched in the lung tissue of infected humans are likely involved with immunological control of pulmonary infections. New vaccine strategies are needed that can induce mucosal response and better induce protective T cells in the lungs. Our vaccine strategy will advance a live vaccine platform based on B-Tech, an attenuated strain of Bordetella pertussis, which has already completed Phase 2 clinical trials and has demonstrated ability to induce durable and specific mucosal and systemic immune responses. We propose to develop the platform bacterial vector (called B-Tech-Mtb) for intranasal vaccination. B-Tech strains transiently colonize the nasopharyngeal mucosa in animal models and humans and induce mucosal (including secretory IgA and resident memory T cells) and systemic (including serum antibodies and circulating T cells) responses against pertussis antigens. In addition, B-Tech vaccines are lyophilized, have >2-year stability at 25°C, and can be produced by most if not all developing countries at low cost. In murine studies, transient colonization induces a resident memory T cell response that is associated with protection against B. pertussis infection. Indeed, transient colonization of the nasopharyngeal mucosa by B. pertussis results in targeting of mucosal dendritic cells, the induction of Th17 T cell responses, and high expression of IL-17 that is associated with the development of robust secretory IgA and resident T cell memory in the lungs. We propose to engineer genetically modified bacterial systems developed in our labs for expression and secretion of several Mtb hybrid antigens that have been tested clinically as parenteral vaccines. We will construct and test B-Tech- Mtb vaccine candidates after intranasal administration in mice and non-human primate models, secreting selected M. tuberculosis antigens continuously in the vicinity of mucosal inductive sites. By developing B. pertussis strains secreting one or more Mtb antigens, we anticipate that Th1/Th17 skewed T cell responses will be more robust than observed in prior vaccine studies with other mucosally or parenterally administered TB vaccine candidates. With success, this program will enable production of enhanced Mtb- specific mucosal immune responses, including resident memory T cell responses, leading to protection in TB challenge models.