Vaccine strategies for the Mtb/HIV copandemic

Abstract

One-third of world's population is predicted to be infected with tuberculosis (TB). The resurgence of this deadly disease has been inflamed by comorbidity with human immunodeficiency virus (HIV). The risk of TB in people living with HIV (PLWH) is 15-22 times higher than people without HIV. Development of a single vaccine to combat both diseases is an ardent but tenable ambition. Studies have focused on the induction of specific humoral and cellular immune responses against HIV-1 following recombinant BCG (rBCG) expressing HIV-1 antigens. Recent advances in the TB vaccines led to the development of promising candidates such as MTBVAC, the BCG revaccination approach, H4:IC31, H56:IC31, M72/AS01 and more recently, intravenous (IV) BCG. Modification of these vaccine candidates against TB/HIV coinfection could reveal key correlates of protection in a representative animal model. This review discusses the (i) potential TB vaccine candidates that can be exploited for use as a dual vaccine against TB/HIV copandemic (ii) progress made in the realm of TB/HIV dual vaccine candidates in small animal model, NHP model, and human clinical trials (iii) the failures and promising targets for a successful vaccine strategy while delineating the correlates of vaccine-induced protection.

Keywords: Diseases; Immunology; Microbiology; Pathogenesis.

Fig. 1. Potential vaccine candidates for TB/HIV copandemic.

The figure illustrates the preclinical and clinical development of existing TB and TB/HIV vaccine candidates including small animal (mouse), NHP model, and human clinical trials.

Fig. 2. LTBI correlates in mouse and NHP model of TB/HIV coinfection.

The figure outlines the immune correlates of latent TB infection that can be utilized as biomarkers in vaccine design against TB/HIV copandemic to prevent infection and reactivation. It also compares and contrast the mouse and NHP model in terms of mimicking human infection and immune response in TB/HIV coinfection.

Fig. 3. Mechanism of action of the key vaccine candidates with a potential to combat TB/HIV copandemic.

Aerosol delivery of a leading TB vaccine candidate, modified vaccinia virus Ankara expressing antigen 85 A (MVA85A) in rhesus macaques produced a higher immune response compared to intradermal injection highlighting an immunization strategy that limits systemic immunity. Novel TB vaccine candidate, pho P mutant SO2 was unable to induce apoptotic events during lung infection in vivo. H56 fusion protein (Ag85B-ESAT6-Rv2660c) has been developed as a BCG booster in cynomolgus macaques. In addition to delaying the clinical disease manifestation post Mtb infection, H56 booster was able to prevent anti-TNF triggered reactivation of latent TB infection. As observed with H56:IC31, ID93/GLA-SE elicited a significant T_H1 immune response, comprising of multifunctional IFN-γ, TNF-α, and IL-2 CD4⁺ T cells. The induction of a dominant T_H1 response was associated with reduced TB burden in cynomolgus macaques and MDR-TB control in the lungs of vaccinated mice.