Developing New Anti-Tuberculosis Vaccines: Focus on Adjuvants

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that sits in the top 10 leading causes of death in the world today and is the current leading cause of death among infectious diseases. Although there is a licensed vaccine against TB, the Mycobacterium bovis bacilli Calmette-Guérin (BCG) vaccine, it has several limitations, namely its high variability of efficacy in the population and low protection against pulmonary tuberculosis. New vaccines for TB are needed. The World Health Organization (WHO) considers the development and implementation of new TB vaccines to be a priority. Subunit vaccines are promising candidates since they can overcome safety concerns and optimize antigen targeting. Nevertheless, these vaccines need adjuvants in their formulation in order to increase immunogenicity, decrease the needed antigen dose, ensure a targeted delivery and optimize the antigens delivery and interaction with the immune cells. This review aims to focus on adjuvants being used in new formulations of TB vaccines, namely candidates already in clinical trials and others in preclinical development. Although no correlates of protection are defined, most research lines in the field of TB vaccination focus on T-helper 1 (Th1) type of response, namely polyfunctional CD4+ cells expressing simultaneously IFN-γ, TNF-α, and IL-2 cytokines, and also Th17 responses. Accordingly, most of the adjuvants reviewed here are able to promote such responses. In the future, it might be advantageous to consider a wider array of immune parameters to better understand the role of adjuvants in TB immunity and establish correlates of protection.

Keywords: adjuvants; infectious diseases; tuberculosis; vaccines.

Figure 1

O verview of Proposed Mechanisms of Action of Adjuvants in vaccines. (A) Receptors and Molecule Activation of adjuvants. The active principle of GLA-SE and AS0, the MPLA, activates TLR4 and downstream pathways, namely MyD88 and, after internalization of the CD14/TLR4/MD-2 complex, the “late” TRAM-TRIF pathway. Starch interacts with C-type DC-SIGN receptor. IC31, more specifically, CpG motifs, as well as pDNA present in TMC microparticles activate TLR9 inside the endosome. AS01 and Chitosan activate the inflammasome and promote the subsequent release of pro-inflammatory cytokines. CDNs activate STING receptors in the endoplasmic reticulum. (B) IC31′s KLK peptide increases the permeability of the adjuvant system in the membrane to deliver the antigen and CpG motifs. (C) Cationic Liposome adjuvants, such as CAF01, promote a depot effect on the injection site and release the antigen in a controlled way, stimulating innate immunity.