Abstract
Tuberculosis places a staggering burden on human health globally. The new World Health Organisation End-TB Strategy has highlighted the urgent need for more effective TB vaccines to improve control of the disease. Protein-based subunit vaccines offer potential as safe and effective generators of protective immunity, and the use of particulate vaccine formulation and delivery by the pulmonary route may enhance local immunogenicity. In this study, novel particulate subunit vaccines were developed utilising biodegradable poly(lactic-co-glycolic acid) (PLGA) slow-release particles as carriers for the Mycobacterium tuberculosis lipoprotein MPT83, together with the adjuvants trehalose-dibehenate (TDB) or Monophosphoryl lipid A (MPL). Following delivery by the pulmonary or subcutaneous routes, the immunogenicity and protective efficacy of these vaccines were assessed in a murine model of M. tuberculosis infection. When delivered peripherally, these vaccines induced modest, antigen-specific Th1 and Th17 responses, but strong anti-MPT83 antibody responses. Mucosal delivery of the PLGA(MPT83) vaccine, with or without TDB, increased antigen-specific Th17 responses in the lungs, however, PLGA-encapsulated vaccines did not provide protection against M. tuberculosis challenge. By contrast, peripheral delivery of DDA liposomes containing MPT83 and TDB or MPL, stimulated both Th1 and Th17 responses and generated protection against M. tuberculosis challenge. Therefore, PLGA-formulated vaccines primarily stimulate strong humoral immunity, or Th17 responses if used mucosally, and may be a suitable carrier for vaccines against extracellular pathogens. This study emphasises the critical nature of the vaccine carrier, adjuvant and route of delivery for optimising vaccine efficacy against TB.
Highlights
Despite considerable research efforts, tuberculosis (TB) remains a staggering burden on global health with 10.4 million new cases and 1.7 million deaths in 2016 [1]
It was verified that mice left unimmunised or vaccinated with poly(lacticco-glycolic acid) (PLGA) alone did not generate immune responses to MPT83
The immunogenicity of PLGA (MPT83) in combination with Monophosphoryl lipid A (MPL) encapsulated within the same particle, in a separate PLGA particle, or external to the particle in soluble form, were compared after peripheral immunisation
Summary
Tuberculosis (TB) remains a staggering burden on global health with 10.4 million new cases and 1.7 million deaths in 2016 [1]. Of the estimated two billion individuals infected, 90% effectively control the infection via the host immune response but do not eliminate it, providing a reservoir for reactivation and subsequent transmission. No new vaccines have been approved for human use since the development of the live attenuated M. bovis bacille Calmette-Guerin (BCG). BCG has been widely used since 1921, but has highly variable efficacy, does not prevent transmission and possesses significant safety concerns for immunocompromised individuals [2, 3]. The 2015 World Health Organisation End-TB Strategy identifies the urgent need for more effective and administrable vaccines, as the optimum tool for controlling TB. Exploring alternative routes of vaccine delivery, antigens and adjuvant formulations may aid this development
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