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Abstract
An estimated 10 million people developed tuberculosis (TB) disease in 2019 which underscores the need for a vaccine that prevents disease and reduces transmission. The aim of our current studies is to characterize and test a prophylactic tuberculosis vaccine comprised of ID93, a polyprotein fusion antigen, and a liposomal formulation [including a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant, GLA) and QS-21] in a preclinical mouse model of TB disease. Comparisons of the ID93+GLA-LSQ vaccines are also made to the highly characterized ID93+GLA-SE oil-in-water emulsion adjuvant, which are also included these studies. The recent success of vaccine candidate M72 combined with adjuvant AS01E (GlaxoSmithKline Biologicals) in reducing progression to active disease is promising and has renewed excitement for experimental vaccines currently in the TB vaccine pipeline. The AS01E adjuvant contains monophosphoryl lipid A (MPL) and QS-21 (a saponin) in a liposomal formulation. While AS01E has demonstrated potent adjuvant activity as a component of both approved and experimental vaccines, developing alternatives to this adjuvant system will become important to fill the high demand envisioned for future vaccine needs. Furthermore, replacement sources of potent adjuvants will help to supply the demand of a TB vaccine [almost one-quarter of the world’s population are estimated to have latent Mycobacterium tuberculosis (Mtb) according to the WHO 2019 global TB report], addressing (a) cost of goods, (b) supply of goods, and (c) improved efficacy of subunit vaccines against Mtb. We show that both ID93+GLA-SE (containing an emulsion adjuvant) and ID93+GLA-LSQ (containing a liposomal adjuvant) induce ID93-specific TH1 cellular immunity including CD4+CD44+ T cells expressing IFNγ, TNF, and IL-2 (using flow cytometry and intracellular cytokine staining) and vaccine-specific IgG2 antibody responses (using an ELISA). In addition, both ID93+GLA-SE and ID93+GLA-LSQ effectively decrease the bacterial load within the lungs of mice infected with Mtb. Formulations based on this liposomal adjuvant formulation may provide an alternative to AS01 adjuvant systems.
Highlights
The only vaccine currently available for use against Mycobacterium tuberculosis (Mtb) is the attenuated live vaccine, bacille Calmette-Guerin (BCG), which is known to reduce childhood TB but wanes with time, giving variable efficacy against adult TB [1]
We evaluated two different formulations of glucopyranosyl lipid adjuvant (GLA), GLA-liposomes + QS-21 (LSQ) (QS-21+neutral liposomes) and GLA-stable emulsion (SE), for innate responses following their addition to human whole blood (WB) (Fig 1) and human dendritic cells (DC) (Fig 2)
We predominantly show an ID93-specific T helper 1 (TH1) cellular immune response, including CD4+ T cell production of IFNγ, TNF, and IL-2 in mice immunized with both ID93+GLA-SE and GLA-LSQ, in addition to vaccine-specific IgG2 humoral responses
Summary
The only vaccine currently available for use against Mtb is the attenuated live vaccine, bacille Calmette-Guerin (BCG), which is known to reduce childhood TB (disseminated extrapulmonary Mtb) but wanes with time, giving variable efficacy against adult TB (pulmonary Mtb) [1]. The recent clinical prevention of disease (POD) trial for TB with the M72 subunit vaccine candidate adjuvanted with a liposomal formulation including monophosphoryl lipid A (MPL) and QS-21 (M72/AS01E, GlaxoSmithKline Vaccines) has shown promise [4]. The phase 2b clinical results of the M72/AS01E vaccine showed 54% protective efficacy against active pulmonary TB disease [4] and remains nearly 50% effective (49.7%) for at least 3-years after the final boost immunization [5]. These results have generated immense enthusiasm for the feasibility of additional subunit vaccines and adjuvants that could prove to be effective
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