Advancing Immunotherapeutic Vaccine Strategies Against Pulmonary Tuberculosis

Abstract

Chemotherapeutic intervention remains the primary strategy in treating and controlling tuberculosis (TB). However, a complex interplay between therapeutic and patientrelated factors leads to poor treatment adherence. This in turn continues to give rise to unacceptably high rates of disease relapse and the growing emergence of drug-resistant forms of TB. As such, there is considerable interest in strategies that simultaneously improve treatment outcome and shorten chemotherapy duration. Therapeutic vaccines represent one such approach which aims to accomplish this through boosting and/or priming novel anti-TB immune responses to accelerate disease resolution, shorten treatment duration, and enhance treatment success rates. Numerous therapeutic vaccine candidates are currently undergoing pre-clinical and clinical assessment, showing varying degrees of efficacy. By dissecting the underlying mechanisms/correlates of their successes and/or shortcomings, strategies can be identified to improve existing and future vaccine candidates. This mini-review will discuss the current understanding of therapeutic TB vaccine candidates, and discuss major strategies that can be implemented in advancing their development.

Intramuscular Boosting with hIFN-Alpha 2b Enhances BCGphipps-Induced Protection in a Murine Model of Leprosy

“…These data suggest that the type of BCG strain used to formulate the vaccine could influence the outcome of the humoral immune response against MLM or M. leprae [51]. Furthermore, several studies in tuberculosis have shown the potential and beneficial effects of the heterologous prime-boost strategy in the induction of protective immune responses [68][69][70]. Moreover, it is well known that the type and the route of immunization influence the magnitude of the antibody and cellular immune responses.…”

An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis

“…The development of novel immunotherapeutic regimens that synergize with antibiotics to accelerate curative TB treatment is an attractive strategy for improving medical adherence and treatment completion rates, and for reducing costs (24). In the current study, we show that MIP-3α fusion and the IN route of delivery individually enhance the therapeutic adjunctive activity of a DNA vaccine targeting an Mtb persistence antigen in a murine model of chronic TB.…”

“…Of note, only a small minority of DCs are attracted to sites of immunization (32), and, in the case of HIV and TB infections, a proportion of the attracted DCs may be dysfunctional (33). Fusion of the antigen of interest to the chemokine MIP-3α (or CCL20) targets the antigen to immature DCs (24). It has been shown that following naked DNA vaccination, epidermal cells secrete the antigen of interest-chemokine MIP-3α fusion construct (20, 34).…”

“…Compelling evidence suggests that protection against respiratory pathogens, such as Mtb , is dependent on the presence of pathogen-specific immune cells at the primary site of infection (24, 36, 37). Pre-clinical studies have shown that parenteral immunization with TB vaccines can drive robust antigen-specific T-cell responses in the periphery, but these cells are unable to rapidly enter the restricted lung mucosal compartments and largely fail to restrict Mtb replication (38).…”

“…Of note, only a small minority of DCs are attracted to sites of immunization (32), and, in the case of HIV and TB infections, a proportion of the attracted DCs may be dysfunctional (33). Fusion of the antigen of interest to the chemokine MIP-3α (or CCL20) targets the antigen to immature DCs (24).…”