TB-vaccines: Current status & challenges

Bacillus Calmette–Guérin (BCG) vaccine

The BCG vaccine, an attenuated strain of M. bovis was produced after accidental observation that M. bovis lost its virulence when grown in bile. It was assumed that exposure to a non-virulent strain will increase the resistance of the host to a fully virulent infection by similar (antigenically) organisms. It was further attenuated by 230 serial cultures in potato-glycerol-bile medium. However, the knowledge of the pathogenesis of TB and immunological processes did not exist at that point of time. Subsequently, several controlled trials in different parts of the world revealed its efficacy against pulmonary TB (PTB) varying between 0-80 per cent with lowest efficacy seen in more endemic areas^6,7. One of these was the Randomized controlled Trial (RCT) in Chengalpattu, India wherein two doses each (0.01 mg, 0.1 mg) of the Paris strain and the Danish strain and placebo were randomized to about 2.6 lakh study participants (all ages) irrespective of their reaction size to tuberculin skin test (TST) during 1968-71⁸. Follow up of study participants for 15 years revealed that BCG offered ‘NIL’ overall protection in adults and a low level of overall protection (27%; 95% CI: -8 to 50%) in children^8,9. The factors likely to be associated with variable efficacy of BCG across different geographies in the world were hypothesized as,

(i) Masking: infection with environmental mycobacteria could lead to a low-level protection against infection with tubercle bacillus and BCG does not boost such naturally acquired protection. This could mask any protection due to BCG vaccination, partially or totally¹⁰; (ii) Blocking: Pre-existing natural protection acquired by NTM infection may interfere with the ability of BCG to replicate and thereby with the development of immune response to BCG. This is supported by the fact that the prevalence of environmental Mycobacterial (EM) infection decreases and the BCG efficacy increases as we move away from the equator¹¹ and (iii) The original BCG strain has been lost and the variants (French Pasteur 1173 12, Danish 1SI 1331, Glaxo 1077, Tokyo 172) maintained by different laboratories using different methods are not the same. India uses the Danish strain in its Universal Immunization Programme (UIP)¹².

However, trials conducted across the world have shown efficacy of BCG 60-80 per cent against childhood TB meningitis and miliary TB¹³. Thus, under the immunization programme in India, 0.05 ml of the reconstituted vaccine is given intradermally at birth. It is contraindicated in HIV infected infants due to a poorer immune response observed in small number of studies and a higher incidence of disseminated BCG disease when given at birth. Hence, in infants born to HIV infected mothers, administration of BCG vaccination, should be delayed until HIV infection has been excluded (preferably by viral amplification test/other tests after the window period). Till date, BCG remains the only vaccine licensed for use against TB.

Newer vaccines

Since BCG induced cell mediated immune response was not enough to protect against PTB, subsequent efforts at vaccine development focused on boosting immune response primed by BCG. A major part of these efforts focused on designing subunit vaccines that deliver immune-dominant Mycobacterium tuberculosis (MTB) antigens using viral/protein adjuvants.

After 1968, the first vaccine to enter efficacy trial was MVA85A which expresses MTB antigen 85A considered among the most important MTB antigens required for cell wall synthesis on an attenuated vaccinia Ankara viral vector. This antigen is conserved across different mycobacterial species including, BCG, MTB and EM. Animal studies, phase 1 and 2a clinical trials among infants showed that even though it induced strong T-cell mediated immunogenicity as elicited by Ag85A specific CD4+ and CD8+ counts, interferon gamma release assay (IGRA) and other cytokine assays, no protection against clinical TB was seen on three-year follow up¹⁷. Another study among HIV reactive adults revealed a mono-functional immune response and nil protection against TB¹⁸. Two important learnings from these findings were that antigen 85A on Ankara viral vector and a mono-functional (single cytokine production) immune response might be insufficient to mount an effective immune response. Therefore, subsequent efforts at vaccine development were to use newer technologies to develop vaccines that could deliver 85A using modified approaches, viz. on a different viral vector, through aerosol route, in combination with other antigens.

Another strategy was to develop adjuvanted protein subunit vaccines in which one component is a protein-based antigen(s) and the other is an adjuvant- an antigen delivery system that also might have immune stimulating properties.

However, all the subunit and adjuvant vaccines altogether included only 12 of 4500 targetable MTB antigens. Therefore, whole-cell mycobacterial vaccines that contain a broader range of immunogenic molecules are expected to induce a more diverse immune response to a range of protein and lipid antigens.

The properties of various candidate vaccines that have been developed over the period are summarized in Table I^19-37 and the candidates currently in different phases of clinical trials are depicted in Table II^38,39. These trials are being conducted in diverse groups of study participants, viz. infants, HIV reactive/non-reactive adults, BCG naïve/vaccinated individuals, purified protein derivative positive/negative individuals; mostly for prevention of disease and a few for prevention of infection and as adjunctive immunotherapy to patients on anti-TB treatment. Besides, there are other candidates still in the pre-clinical stage.

While Mw/MIP (Mycobacterium indicus pranii vaccine) a killed vaccine was demonstrated to have significant efficacy against leprosy during a placebo controlled randomized trial among household contacts of 1226 multibacillary (MB) and 3757 paucibacillary (PB) cases of leprosy⁴⁰, its potential for protection against TB has been demonstrated in experimental animals as well as in human studies⁴¹. The ongoing VPM1002 and Immuvac vaccine trial in India is expected to provide further insights. MIP and M. vaccae are also being evaluated as therapeutic vaccines with the aim to compliment therapeutic effect of chemotherapy by increasing treatment success rate and to decrease the required duration of treatment. Efficacy of MIP as an adjunct to anti-TB drug therapy was demonstrated among erstwhile so classified category-II (CAT-II) pulmonary TB cases (unfavorable treatment outcome after treatment as a new TB patient and re-treated with a streptomycin containing re-treatment regimen of first line anti-TB drugs)⁴². However, further studies are warranted to understand its role in enhancing bacillary clearance amongst drug resistant TB patients as well as new drug sensitive cases and those co-infected with HIV especially as the earlier CAT-II treatment is no longer in vogue. Similarly, M. vaccae has beneficial value in bacillary clearance⁴³. 

The Phase III POD (prevention of disease) trial of VPM and MIP is currently in progress in India¹⁶. In this multi-centric double blind randomized trial, 12000 household contacts of bacteriologically confirmed index TB patients were randomized into three arms-VPM1002, MIP and placebo during 2019-2021 and followed up for three years for incident TB. While the results are expected in the near future, there is a likelihood that the true efficacy of the vaccines if any might be masked because of telephonic follow up for a significant proportions of study participants for presumptive TB rather than physical follow up by the clinician due to restrictions as well as inhibitions posed during the COVID epidemic.

The M72/ASO1E adjuvanted vaccine trial conducted among adults with latent TB at centers located in South Africa, Kenya and Zambia elicited an immune response and provided protection against the pulmonary TB disease for at least three years⁴⁴.

The newer RNA-based vaccine platform has shown that repRNA systems are a promising option for tuberculosis vaccines and should be prioritized, particularly those containing CD4+ and CD8+ T-cell epitopes from MTB antigens⁴⁵.

Challenges in vaccine development

Our understanding of the pathogens host interactions remains incomplete despite the progress we have made in science.

There is a lack of a validated animal model that can predict vaccine efficacy in humans with certainty. Guinea pigs are commonly used for vaccine efficacy studies because of their high susceptibility to low dose infection, besides the mice, rabbits, non-human primates and cattle. Most of these animal models do not use the aerosol route for infection which is the primary route for humans and look only for primary progression and dissemination with bacterial load as end-points; none mimics the range of outcome of exposure in humans, viz. latency, progression from latency to disease. Also, the role of unconventional T-cells located in mucosal lining and unique to primates has also been overlooked.

A study on non-human primates (Macaca mulatta) has shown that intravenous administration of BCG profoundly limits the MTB infection and it challenges the current concept of vaccine delivery through intradermal or aerosol route⁴⁶.

Studies on T cell receptor repertoires have provided valuable insights into how different types and responses of T cells, based on their receptors, influence whether an individual can effectively control tuberculosis infection or it would progress to active TB disease. These findings suggest that antigens recognized by T cell groups linked to infection control should be prioritized as targets for future vaccine development⁴⁷.

Many of the newer vaccines found highly immunogenic turned out to be ineffective in preventing clinical TB implying that the currently known immunological markers do not correlate with clinical efficacy. Lack of reliable biomarkers impedes rational decision making for proceeding to the next stage/phase of vaccine development pathway.

TB vaccine development pathway-identification of potential molecules, pre-clinical development and evaluation, animal model studies, initial stage clinical trials for safety, immunogenicity and proof of concept, clinical trials requiring long follow up of thousands of participants and the regulatory approvals thereof require huge monetary resources spanning over 10-15 yr with an added risk of failure making it unattractive to industry.

Exploring new ideas in TB vaccine design

A better understanding is required regarding the factors important in the virulence of MTB, its ability to escape the immune mechanism of the host and discover antigenic epitopes that may normally be hidden from immune response. In this context, identification of the bacterial components involved in this receptor-mediated entrance into macrophages may offer new insights.

We also need to find factors associated with establishment of latency and a better understanding of the biomarkers that correlate with protection. A deeper understanding of the immune responses in the sub-set of individuals who after sustained exposure and tuberculin/IGRA positivity revert to negativity might give a clue to vaccine development.

Approaches primarily based on inducing CD4+ and CD8+ cell responses have limitations. Thus, attempts are being made to develop new TB vaccines which can enhance other aspects of the immune response. A study in South Africa revealed that MTB specific IgG is capable of recruiting other immune cells like macrophages and NK cells⁴⁸.

An epitope is that specific piece of the antigen to which antibody binds. Ability of such sub-dominant epitopes induced protection has been demonstrated previously in mouse model. Thus, there is a scope of redirecting the host immune responses towards an epitope within an antigen⁴⁹.

A group of pumps known as ESX systems on the surface of the mycobacteria play a key role in its survival and ability to infect macrophages. But these systems are so small that our immune system may not include them in its defense. Danish scientists have fused six such tiny proteins to design a new vaccine that our immune system might be able to recognize and build immunity against these pumps⁵⁰.

Research on human challenge models for TB has made gradual progress, though significant challenges remain. Unlike diseases with shorter courses, TB’s complexity, prolonged infection, and potential severity make it difficult to safely develop such models. Researchers are exploring the use of low-dose or attenuated strains of MTB to minimize risks, or even employing M. bovis BCG strain as a safer alternative for study. Human challenge models hold the potential to transform TB vaccine research with a future aim to offer controlled conditions to observe early immune responses, which could accelerate vaccine development by allowing for quicker testing and refinement before larger trials⁵¹.

What the future holds

Several collaborative efforts are underway for TB vaccine development. Efforts to find risk of progression to disease correlates are currently under progress in several African countries by the South African TB vaccine initiative (SATVI) among HIV negative adult household contacts of people with TB. Tuberculosis Vaccine Initiative (TBVI), a non-profit foundation supports partnership in research and innovation for development of new, safe, effective and affordable TB vaccines and resource mobilization in partnership with the Global TB Vaccine Partnership (GTBVP). International AIDS vaccine initiative is another non-profit organization that supports vaccine development for HIV, TB and emerging infectious diseases with partners from discovery through clinical trials to post-licensure access. It is desirable that the medical community, civil society, and funding consortia lend extended support to fulfil the promise of newer vaccine(s) to End the TB epidemic⁵².

It brings us a ray of hope if one or more of the candidate vaccines currently under advance stages of trials will be able to replace or offer better protection than the currently available.