New Tuberculosis Vaccines (2022)

Tuberculosis is a communicable infection caused by the bacteria “Mycobacterium tuberculosis” which latches onto the lungs following inhalation of aerosolized bacteria (emitted by an infected individual).

In the 19th and 20th centuries, tuberculosis killed over 1 billion people – and it continues to kill in excess of 1 million people each year, inflict permanent lung damage in a significant number, and antibiotic treatment causes disability in others (e.g. blindness, hearing loss, kidney damage, etc.).

Although a vaccine for TB exists called the “BCG vaccine” – this vaccine’s efficacy is considered controversial, questionable, and suboptimal for the prevention of tuberculosis infection and disease.

Related: New tuberculosis drugs & regimens

New tuberculosis vaccines

To prevent further death and disability associated with tuberculosis, it is imperative that we develop new safe and effective vaccines.

Included below are tuberculosis vaccines based on stage of clinical trial/development.

Keep in mind that while vaccines are sorted by phase of development, there was no intra-phase sorting (such that one vaccine listed ahead of another within a specific phase of trials may not necessarily be further along in development).

For reference…

  • Prevention of disease: Preventing “disease” of tuberculosis within the body (e.g. lung damage, continued spread, flu-like symptoms, etc.).
  • Prevention of infection: Preventing tuberculosis from infecting the body (happens before disease).
  • Prevention of recurrence: Preventing subsequent tuberculosis infection after fully recovering from an infection.

M. vaccae (“Vaccae”)

  • Developers: Anhui Zhifei Longcom
  • Indication: Treatment of TB
  • Type: Inactivated bacteria

Whole-cell heat-inactivated M. vaccae (Mycobacterium vaccae) is under investigation by Anhui Zhifei Longcom as an immunotherapeutic agent for the treatment of tuberculosis.

Because M. vaccae is closely related to M. tuberculosis – it is thought that training one’s immune system to eliminate an inactive M. vaccae should confer some degree of cross-immunity against M. tuberculosis (thus making MTB easier to eradicate).

A study in mice (2020) found that M. vaccae vaccine provided good protection in mice against MTB infection via a highly complex set of molecular changes (2326 upregulated & 2221 downregulated genes via 123 signaling pathways). (R)

Evidence suggests that M. vaccae is safe, tolerable, and immunogenic in HIV-positive adults – and appeared to induce CD4+ T-cell responses with IFN-gamma and IL-10 in cultures from M. vaccae treated mice.

A study by Weng et al. (2016) reported that M. vaccae vaccine has a significant effect as an adjunctive therapy in the treatment of MDR (multidrug-resistant) TB. (R)

A study by Yang et al. (2011) found that M. vaccae vaccine is helpful in never-treated TB patients when added to conventional antibiotics – for improving sputum conversion and X-ray appearances. (R)

In China M. vaccae vaccine has been approved to prevent disease among individuals with preexisting TB infection.

M. indicus pranii (MIP) (Immuvac)

  • Developers: ICMR & Cadila Pharmaceuticals
  • Indications: Prevention of disease (POD) & Treatment of TB
  • Type: Inactivated mycobacteria

Whole-cell M. indicus pranii (MIP) a.k.a. Immuvac is a vaccine in development by ICMR & Cadila Pharmaceuticals for the prevention and treatment of tuberculosis disease.

Mycobacterium indicus pranii (M. indicus pranii) is a bacterial species that’s closely related to Mycobacterium tuberculosis (M. tuberculosis) – such that training the immune system to fight off MIP could generate cross-immunity such as to prevent MTB disease.

A study found that MIP (M. indicus pranii) immunotherapy: accelerated bacterial eradication of M. tuberculosis; improved organ pathology; increased activated antigen-presenting cells and lymphocytes in lungs; and modulated granulomatous response – in animal models of MTB. (R)

Another study showed that intranasal MIP (M. indicus pranii) administration to mice induced significant recruitment of CD4+ and CD8+ T-cells expressing activation markers in the lung airway lumen – and strong memory T-cell responses. (R)

A 2017 study by Sharma et al. found that MIP as an adjunct to antitubercular treatment led to a significantly higher rate of sputum culture conversion after 4 weeks (67.1%) relative to a placebo (57%). (R)

MIP is currently undergoing a Phase 3 trial evaluating its safety, efficacy, and immunogenicity vs. a placebo in the prevention of TB disease among 12,721 household contacts (6+ years of age & HIV-negative) of TB-infected persons in India.

VPM1002 (Live rBCG)

  • Developers: Serum Institute of India (SII)
  • Indications: Prevention of disease (POD); prevention of infection (POI); prevention of recurrence (POR)
  • Type: Live recombinant BCG

VPM1002 is a live recombinant Bacille Calmette-Guerin (rBCG) vaccine under development by the Serum Institute of India (SII).

VPM1002 is a recombinant version of BCG in which the urease C gene has been replaced by listeriolysin O (LLO) encoding gene (hly) from Listeria monocytogenes. (R)

  • Urease C neutralizes phagosomes containing mycobacteria by generating ammonia which inhibits phagolysosomal maturation and enhances mycobacteria survival within macrophages.
  • Depletion of urease C allows for rapid phagosome acidification which promotes phagolysosome fusion and provides optimal pH for LLO stability.
  • LLO is a cholesterol-dependent cytolysin that forms transmembrane beta-barrel pores in the phagolysosomal membrane – enabling escape of L. monocytogenes into the cytosol.
  • Expression of LLO in VPM1002 facilitates the release of antigens and bacterial DNA into the cytosol which triggers autophagy, inflammasome activation, and apoptosis.

In other words, VPM1002 contains a strategically modified version of BCG bacteria (M. bovis) in a way that makes it easier for immune cells to recognize and respond.

Preliminary research suggests that VPM1002 is safe and adequately immunogenic in healthy young adults.

VPM1002 is currently undergoing a Phase 3 clinical trial to evaluate its safety, efficacy, and immunogenicity vs. placebo in preventing TB disease among 12,721 household contacts (6+ years of age & HIV-negative) of MTB-infected persons in India.

It is also undergoing a Phase 3 clinical trial involving 6,940 newborn infants (HIV-exposed and MTB-uninfected eligible) in Gabon, Kenya, South Africa, Tanzania, and Uganda – and a Phase 2/3 trial evaluating

Undergoing a Phase 2/3 trial evaluating safety, efficacy, immunogenicity vs. placebo in preventing TB disease recurrence in 2000 HIV-negative adults (18-65 years old).

M72/AS01E (Protein/adjuvant subunit vaccine)

  • Developers: GMRI & GSK Biologicals
  • Indications: Prevention of disease (POD) & Prevention of infection (POI)
  • Type: Protein/adjuvant subunit

M72/AS01E is a vaccine under investigation by GMRI & GSK Biologicals primarily for the prevention of tuberculosis disease and secondarily for the prevention of infection among TB-uninfected persons.

Specifically, M72/AS01E contains a recombinant fusion protein derived from 2 M. tuberculosis antigens (Mtb32A & Mtb39A) combined with the AS01E adjuvant system.

A proof-of-concept Phase 2 clinical trial found that M72/AS01E prevented bacteriologically-confirmed pulmonary TB in HIV-negative adults with latent MTB infection within a 2-year period. (R)

A different study involving 3,575 participants found that M72/AS01E significantly increased concentrations of M72-specific CD4+ T-cells and provided protection against TB disease for at least 3-years post-injection in ~49.7% of recipients. (R)

A Phase 3 clinical trial will evaluate the safety, efficacy, and immunogenicity of M72/AS01E in 20,000 persons (ages 16-34) with and without TB infection.

Phase 3 clinical trial to evaluate safety, efficacy, and immunogenicity in 20,000 individuals ages 16-34 with and without tuberculosis infection.

MTBVAC (Live-attenuated MTB)

  • Developers: Biofabri & EDCTP
  • Indications: Prevention of disease (POD)
  • Type: Live-attenuated MTB

MTBVAC is a live-attenuated form of Mycobacterium tuberculosis weakened by the strategic deletion of 2 virulence genes (phoP & fadD26).

It was created by the biotech company Biofabri in collaboration with EDCTP – and the specific strain of M. tuberculosis included in MTBVAC has been researched for over 25 years.

MTBVAC was developed after an outbreak of multidrug-resistant M. bovis that killed more than 100 people with HIV in Spain in the early 1990s – whereafter researchers identified the phoP gene as critical to the virulence of MTB.

Preliminary research involving animal models of TB suggests that MTBVAC-vaccinated mice exhibit enhanced immunogenicity and better protection against MTB challenge relative to BCG-vaccinated mice. (R)

Evidence from early human trials suggests that MTBVAC vaccination appears to be safe, tolerable, and immunogenic.

MTBVAC seems to function by eliciting polyfunctional T-helper type 17 cells; interleukin-10; and immunoglobulins in the airway. (R)

It is currently undergoing Phase 3 clinical trials to evaluate safety, efficacy, and immunogenicity relative to BCG vaccine in 6,960 HIV-unexposed and HIV-exposed infants in South Africa, Senegal, and Madagascar.

BCG (whole-cell M. bovis)

  • Developers: Henry M. Jackson Foundation
  • Indications: Prevention of infection (POI)
  • Type: Live bacteria

The old “BCG” vaccine (first tested in 1921) is being evaluated by the Henry M. Jackson Foundation for the Advancement of Military Medicine.

Although the BCG vaccine is thought to function by inducing cross-immunity (immune response to M. bovis overlaps with M. tuberculosis) – its efficacy in large-scale, high-quality trials necessitates additional evaluation.

Researchers will determine the safety, efficacy, and immunogenicity of BCG revaccination among 2,150 BCG-vaccinated and MTB-uninfected adolescents in South Africa – relative to a placebo – for the prevention of MTB infection.

Researchers will also evaluate the safety, efficacy, and immunogenicity of primary BCG vaccination in 2,000 BCG-native and MTB-uninfected long-term travelers preparing to work outside the United States – relative to placebo – for the prevention of MTB infection.

GamTBvac

  • Developers: Ministry of Health of the Russian Federation
  • Indications: Prevention of disease (POD)
  • Type: Protein/adjuvant subunit

GamTBvac is a protein-adjuvant subunit vaccine developed by the Ministry of Health of the Russian Federation for the prevention of MTB disease.

GamTBvac is thought to protect against TB disease by significantly inducing both humoral (IgG antibody levels) and cellular immunity (expressed in IFN-gamma increase) – and a number of whole-blood lymphocyte-produced cytokine increases. (R)

A recent Phase 2 study found that 2 doses of GamTBvac were safe and well-tolerated in 180 adults and capable of eliciting antigen-specific CD4+ T-cell and antibody (IgG) responses. (R)

The Gamaleya Research institute of Epidemiology & Microbiology in Russia announced a Phase 3 trial of GamTBvac to evaluate safety, efficacy, and immunogenicity for the prevention of MTB disease in 7,180 HIV-negative and MTB-uninfected adults (ages 18-45).

DAR-901 (Inactivated M. obuense)

  • Developers: Dartmouth College & GHIT Fund
  • Indications: Prevention of infection (POI)
  • Type: Inactivated bacteria

DAR-901 is a booster vaccine under co-development by Dartmouth College and the GHIT (Global Health Innovative Technology) Fund for the prevention of tuberculosis infection.

DAR-901 is a vaccine derived from the master cell bank of SRL172 which was shown to prevent MTB infection. Unlike SRL172 which is agar-grown and difficult to scale production, DAR-901 is broth grown and its production is highly scalable.

It is thought that administering DAR-901 to BCG-vaccinated individuals as a “booster” will enhance protection against MTB relative to standalone BCG vaccination.

This vaccine is hypothesized to provide protection against MTB infection by training the immune system to fight off a deactivated strain of whole-cell M. obuense (Mycobacterium obuense).

Because M. obuense is closely related to M. tuberculosis – this should generate some degree of cross-immunity such that one’s immune system will be primed to efficiently neutralize M. tuberculosis following exposure.

Evidence from animal models indicates that DAR-901 induces cellular and humoral immunity – and provides greater protection against MTB infection relative to BCG vaccination. (R)

Preliminary research in humans suggests that a 3-injection series of DAR-901 is well-tolerated, safe, and induces cellular and humoral immune responses to mycobacterial antigens. (R)

It appears as though DAR-901 induces low-magnitude polyfunctional effector memory CD4+ T-cell responses – which is likely how it helps prevent MTB infection. (R)

H56:IC31

  • Developers: Statens Serum Institute, IAVI, EDCTP, Valneva
  • Indications: Prevention of recurrence (POR)
  • Type: Protein/adjuvant subunit

H56:IC31 is a vaccine under investigation by the Statens Serum Institute of Denmark in conjunction with IAVI, EDCTP, and Valneva.

H56:IC31 is comprised of a fusion protein of Ag85B, ESAT-6, and Rv2660c – formulated in an IC31 adjuvant.

A study from 2015 testing H56:IC31 found that it appeared safe, tolerable, and immunogenic in 25 humans. (R)

Research from 2019 found that H56:IC31 vaccinations at the lowest dose induced durable antigen-specific CD4+ T-cell responses with acceptable safety and tolerability profiles in both MTB-infected and MTB-uninfected adults – over a span of 292 days. (R)

A study from 2021 showed that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients – supporting additional studies of H56:IC31 as a host-directed therapy strategy. (R)

Interestingly, immunization with H56:IC31 led to vaccine-specific cellular immune responses significantly above the levels observed with conventional TB treatment – indicating that preexisting immune reactions during active TB do not interfere with vaccine-related enhancement of cellular immunity.

ID93/GLA-SE (QTP101)

  • Developers: Quratis, ACTG, HVTN
  • Indications: Prevention of disease (POD); Prevention of reinfection (POR)
  • Type: Protein/adjuvant subunit

ID93/GLA-SE (QTP101) is a vaccine under investigation by Quratis in conjunction with ACTG (AIDS Clinical Trials Group) and HVTN (HIV Vaccine Trials Network) for the prevention of tuberculosis disease.

  • ID93 is a fusion protein that incorporates 3 proteins which comprise ID83 (Rv1813, Rv2620, Rv2608) – plus an additional Mtb protein (Rv3619). (R)
  • GLA-SE (EM005) is an adjuvant stable oil-in-water emulsion formulated with synthetic monophosphoryl lipid A that appears to enhance the magnitude and polyfunctional cytokine profile of CD4+ T-cells with ID93 administration. (R)

Preliminary research in animals suggest that ID93/GLA-SE immunization generates a Th1-biased response with antigen-specific polyfunctional CD4+ T-cells and protects mice against a multidrug-resistant (MDR) strain of tuberculosis. (R)

It also appears as though ID93/GLA-SE effectively “boosts” BCG-vaccinated guinea pigs – by providing additional protection against MTB post-BCG vaccination. (R)

ID93/GLA-SE appears to effectively “boost” the BCG vaccine to provide protection against the hypervirulent M. tuberculosis “Beijing” genotype in mice. (R)

A randomized, double-blind, placebo-controlled Phase 1 trial found that escalating doses of ID93 + GLE-SE induced antigen-specific CD4+ T-cell and humoral responses with an acceptable safety profile in BCG-vaccinated adults. (R)

A randomized, double-blind, placebo-controlled Phase 2 trial found that ID93 + GLA-SE was safe and immunogenic – as evidenced by robust/durable antibody responses and specific polyfunctional CD4+ T-cell responses to vaccine antigens. (R)

RUTI

  • Developer: Archivel Farma
  • Indications: TB treatment (adjunct)
  • Type: Fragmented MTB

RUTI is a vaccine under investigation by Archivel Farma – a R&D biotech company that specializes in developing immunotherapies for unmet medical needs – for the adjunct treatment of active M. tuberculosis infection.

RUTI is composed of purified and liposomal cellular fragments of Mycobacterium tuberculosis (MTB) bacilli cultured under stress (to mimic intra-granulomatous conditions) to induce latency antigens which would typically be hidden from the immune system.

The immune response to RUTI has been evaluated in animal models since the early 2000s and clinical studies and is characterized by a poly-antigenic response. (R)

The primary immunotherapeutic effect elicited by RUTI occurs via induction of T helper-1 (Th1) response against both growth-related antigens and structural antigens.

A 2010 double-blind, randomized, controlled trial found that RUTI was safe and immunogenic when administered to healthy volunteers. (R)

A 2014 Phase 2 clinical trial demonstrated reasonable tolerability to RUTI in HIV-negative and HIV-positive patients with latent tuberculosis infection. (R)

A 2019 study found that RUTI induces a balanced immune response (M1/M2 monocytes) in mice – promoting an effective cell-mediated response while simultaneously limiting excessive inflammation. (R)

ChAdOx1 85A + MVA85A

  • Developer: Oxford University
  • Indications: Prevention of disease (POD)
  • Type: Viral vector

ChAdOx1 85A + MVA85A is a combination vaccine under investigation by Oxford University for the prevention of tuberculosis disease.

  • ChAdOx1 85A is a novel chimpanzee adenoviral vectored vaccine expressing Ag85A (Mycobacterial antigen 85A) – which is advantageous over human adenoviral vectors due to low prevalence of preexisting anti-vector antibodies in humans (a factor limiting the use of adenoviruses thus far).
  • MVA85A is a vaccine with modified Vaccinia Ankara (MVA) virus expressing antigen 85A that is thought to enhance the protective efficacy associated with BCG vaccine against TB. (R)

For reference, MVA85A appears safe but ineffective as a standalone in reducing risk of developing tuberculosis. (R)

However, the combination of MVA85A with ChAdOx1 is thought to be more effective.

ChAdOx1 expresses 2 Influenza-A antigens NP (nucleoprotein) and M1 (matrix protein 1) – and has been shown to be safe and immunogenic in humans in a dose-escalation study. (R)

A Phase 1 clinical trial involving 42 healthy BCG-vaccinated adults found that ChAdOx1 85A + MVA85A was well-tolerated and immunogenic in 42 healthy UK adults. (R)

ChAdOx1 85A in isolation induces Ag85A-specific ELISpot and intracellular cytokine CD4+ & CD8+ T-cell responses – which are NOT boosted by a second dose (of ChAdOx1 85A) but are boosted with MVA85A.

BCG (aerosolized)

  • Developer: University of Oxford
  • Indication: Prevention of infection (POI); prevention of disease (POD)
  • Type: Live bacteria

Aerosolized BCG (bacillus Calmette-Guerin) is under investigation by the University of Oxford for the prevention of tuberculosis infection/disease.

The BCG vaccine was first administered to humans in 1921 – and it remains the only TB vaccine approved for medical use worldwide.

It is thought to prevent TB infection by training the immune system to overcome a live-attenuated version of M. bovis (a bacterial species closely related to M. tuberculosis) – such that cross-immunity is developed to M. tuberculosis.

BCG vaccination is typically performed via subcutaneous injection (under the skin) – but its efficacy via this mode of administration is considered controversial/suboptimal.

As a result, researchers such as those at the University of Oxford are examining alternative modes of BCG administration – one of which involves intranasal aerosolization.

A primary reason to explore aerosolized BCG is that aerosolized delivery mimics natural tuberculosis transmission, incubation, and infection – and this might increase its protective efficacy.

Maclouf published multiple articles discussing aerosol administration of BCG in 1951 & 1952 – but I’m unable to access the contents… nonetheless, this shows that BCG aerosolization was historically considered. (R1, R2)

One study reported that intranasal BCG administration in mice provides: (1) superior short-term protection in the lung from MTB infection (relative to subcutaneous BCG) and (2) potent/persistent splenic protective responses for 10+ months. (R)

Another study found that pulmonary (i.e. aerosolized) BCG vaccination of mice provides superior protection against M. tuberculosis relative to subcutaneous BCG vaccination. (R)

Aerosol vaccination with BCG was reported to be a potentially useful immunomodulatory strategy to reduce disease burden in juvenile food animals before the adaptive immune system has fully matured. (R)

A study from 2020 found that inhaled BCG vaccination (delivered by portable vibrating mesh nebulizer) in Rhesus Macaques monkeys – conferred a significant level of protection that was equivalent and by some measures superior to intradermal BCG vaccination. (R)

Other research from 2019 showed that inhalable vaccines with BCG encapsulated in alginate particles (BEAP) are more immunogenic than standard aerosolization of bacilli – and that they provide better protection in mice when exposed to MTB (H37Rv). (R)

AdHu5Ag85A

  • Developers: McMaster University & CanSino
  • Indication: Prevention of infection (POI); prevention of disease (POD)
  • Type: Viral vector

AdHu5Ag85A is a vaccine under investigation by McMaster University and CanSino for the prevention of tuberculosis infection/disease.

AdHu5Ag85A is an acronym for adenovirus (Ad) human serotype-5 (Hu5) mycobacterial antigen 85A (Ag85A) – and it’s a recombinant human type 5 adenovirus-based TB vaccine with preliminary efficacy in numerous animal species.

A Phase 1 clinical trial (2013) found that intramuscular administration of AdHu5Ag85A was safe, well-tolerated, and immunogenic in both BCG-naïve and BCG-immunized adults. (R)

Immunogenicity of AdHu5Ag85A was more significant in BCG-immunized adults than BCG-naïve adults – as evidenced by marked increases in polyfunctional CD4+ and CD8+ T-cell immunity.

A study (2015) involving BCG-vaccinated nonhuman primates (rhesus macaques) found that a single AdHu5Ag85A immunization via respiratory mucosal delivery was safe, tolerable, and significantly enhanced antigen-specific T-cell responses. (R)

Inhaled delivery of AdHu5Ag85A appears safe and superior to other modes of administration for the elicitation of respiratory mucosal immunity against TB. (R)

AEC/BC02

  • Developer: Anhui Zhifei Longcom
  • Indication: TB treatment
  • Type: Protein/adjuvant subunit

AEC/BC02 is a vaccine under investigation by Anhui Zhifei Longcom for the treatment of TB disease.

AEC/BC02 is a recombinant vaccine in which Ag85b (mycobacterial antigen 85b) and fusion protein ESAT6-CFP10 are combined with BCG CpG in an aluminum salt-based adjuvant system.

A study (2015) found that AEC/BC02 administered to mice induced strong cellular immune responses characterized by a high frequency of antigen-specific interferon-gamma-secreting T-cells at different time points after the last vaccination. (R)

In the aforementioned study, AEC/BC02 did not protect against M. tuberculosis as a pre-exposure vaccine in guinea pigs – but it effectively controlled the reactivation of M. tuberculosis in a latent infection model suggestive of a therapeutic effect.

A study (2022) suggested that AEC/BC02: (1) induced a significant Th1-biased response and (2) immunotherapy may shorten future TB treatment – in rodent models of latent TB infection. (R)

TB/FLU-04L

  • Developers: RIBSP, RII, Russian Federation
  • Indication: Prevention of infection (POI); prevention of disease (POD)
  • Type: Viral vector

TB/FLU-04L is an intranasally-administered vector vaccine under investigation by the Research Institute for Biological Safety Problems (Kazakhstan), Research Institute of Influenza (RII), and the Russian Federation for the prevention of tuberculosis infection/disease.

TB/FLU-04L is based on a specific attenuated Influenza-A strain (Flu NS106/ESAT-6-Ag85A) expressing mycobacterial antigens ESAT-6 and Ag85A.

Preliminary research of TB/FLU-04L in ferrets, monkeys, and rabbits suggests that it’s safe when administered intranasally. (R)

A toxicity study in mice and rats showed that TB/FLU-04L had no toxic effect. (R)

Note: There’s also a similar vaccine candidate called “TB/FLU-01L” being investigated by the same developers associated with TB/FLU-04L.

AERAS-402/Ad35

  • Developers: Aeras Global TB Vaccination Foundation & Crucell
  • Indication: Prevention of infection (POI); prevention of disease (POD)
  • Type: Recombinant

AERAS-402/Ad35 is a recombinant fusion protein vaccine under co-development by Aeras Global TB Vaccination Foundation (AERAS-402) and Crucell (Ad35).

It is a replication-deficient, adenovirus serotype 35 (Ad35) containing DNA that encodes a fusion protein (AERAS-402) of 3 major MTB antigens (Ags) with both CD4+ and CD8+ T-cell epitopes (Ag85A, Ag85B, TB10.4).

Evidence suggests that AERAS-402 is safe and immunogenic (predominantly polyfunctional CD8+ T-cells) in Indian males. (R)

A study (2015) found that AERAS-402/Ad35 is well-tolerated, safe, and induced predominantly polyfunctional CD4+ & CD8+ T-cell responses in HIV-infected, BCG-vaccinated adults. (R)

Mtb72F (GSK-692342)

  • Developers: GlaxoSmithKline (GSK)
  • Indication: Prevention of infection (POI); prevention of disease (POD)
  • Type: DNA vaccine

Mtb72F (GSK-692342) is an optimized DNA vaccine under investigation by GlaxoSmithKline for the prevention of tuberculosis infection/disease.

Research suggests that PLGA-nanoparticles loaded with Mtb72F DNA-based vaccine with TB10.4 could be a promising vaccine candidate against TB. (R)

It was scheduled to start Phase 2 clinical trials in Kenya and Zambia as of September 2021 – but it’s unclear as to whether these trials started.

H4:IC31

  • Developers: Statens Serum Institute (SSI); Aeras; AJ Vaccines; NIAID; Sanofi
  • Indications: Prevention of disease (POD); prevention of infection (POI)
  • Type: Recombinant subunit

H4:IC31 is a recombinant subunit vaccine under development by SSI, Aeras; AJ Vaccines; NIAD; and Sanofi for the prevention of tuberculosis infection/disease.

H4:IC31 is comprised of a fusion protein of immunodominant antigens TB10.4 and Ag85B (H4) formulated in a novel adjuvant (IC31).

Preliminary research suggests that H4:IC31 is safe and immunogenic in South African adults – with 15 mcg dose being optimal for immune response. (R)

A study (2018) comparing H4:IC31 and BCG vaccination found that BCG vaccination was more effective than H4:IC31 in adolescents for prevention of tuberculosis disease. (R)

Other potential TB vaccines (status unknown)

Included below are TB vaccines of unknown clinical status. Some clinical trials/investigations involving these substances may have been discontinued for various reasons (e.g. lack of financial investment, lack of trial participants, COVID-19 pandemic, etc.).

  • phlei: Heat-inactivated Mycobacterium phlei (M. phlei) is under investigation as a potential vaccine for tuberculosis.
  • smegmatis: Heat-inactivated M. smegmatis (Mycobacterium smegmatis) is under investigation as a potential vaccine for tuberculosis.
  • rBCG30: Developed at UCLA. Began Phase 1 clinical trials in 2004 – but no development was reported by 2007. A study from 2014 reports rBCG30 induces improved protection against MTB and cross-protection against M. leprae relative to BCG. (R) (That said, there is potential danger from antibiotic resistance gene).
  • AERAS-422: Developed by Aeras Global TB Vaccine Foundation. No reports of development have been identified for Phase 1 clinical trials as of 2016. Unexpected VZV reactivation (varicella zoster virus) occurred in 2/8 volunteers.
  • BCG-PSN: This is the polysaccharide nucleic acid fraction of bacillus Calmette-Guerin which likely has immunomodulatory properties. It appears useful for the treatment of various dermatologic conditions (e.g. lichen planus, urticaria, etc.) – but its status as a TB prophylactic remains unknown.
  • H1:CAF01: A combination of Ag85B-ESAT-6 (H1) with CAF01 (novel liposome adjuvant). Evidence suggests that the combination is safe in humans and immunogenic (evidenced by antigen-specific T-cell responses which persisted 150+ weeks and long-lasting memory response). (R)
  • H56:CAF01: A combination of MTB antigens Ag85B, ESAT-6, and Rv2660 (H56) and CAF01 (novel liposome adjuvant). H56/CAF01 vaccination promotes protective CD4+ T-cell responses and provides prolonged control of infection in mice and enhances BCG-mediated protection in non-human primates. (R)
  • H1:LTK63: A combination of MTB antigen Ag85B-ESAT-6 (H1) and a non-toxic mutant of heat-labile Escherichia coli enterotoxin (LTK63). It appears as though LTK63 is a safe mucosal vaccine adjuvant in animals. However, 2/9 volunteers in a human study experienced transient peripheral facial nerve palsies.
  • HBHA: Heparin-binding hemagglutinin adhesin (HBHA) is an important virulence factor for MTB and helps generate intracystolic lipid inclusions – and was investigated as a possible subunit vaccine. (R) HBHA significantly increases Th1 response (characterized by high IFN-gamma levels) but no significant IL-17 production in mice – such that protection against MTB may be suboptimal.
  • H64:CAF01: A subunit adjuvant vaccine under investigation for the prevention of MTB infection/disease. Combines ESX-1-associated antigens (H64) specific for MTB and a liposomal adjuvant (CAF01). (R)
  • MVA-TG: A viral vector vaccine that combines a modified Vaccinia Ankara virus expressing MTB 10 Ag. There doesn’t seem to be much information on this specific vaccine candidate in medical journals – other than it was being developed by Transgene and TBVI.
  • rhCMV-6Ag: This is a viral vector vaccine utilizing Rhesus cytomegalovirus coding for 6 specific MTB antigens (Ag85A, ESAT-6, Rv3407, Rv2626, Rpf A, Rpf D). It was being developed by Vir Biotechnology, Oregon Health & Science University, and AERAS.
  • CysVac2/Advax: This is a polysaccharide-adjuvanted vaccine that aims to elicit resident pulmonary T-cells to protect against aerosolized MTB infection. It appears capable of eliciting Th17 lung-resident memory T cells and is a candidate for human trials. The University of Sydney and TBVI are its developers. (R)
  • ChAd3/MVA-5Ag: A viral vector vaccine with chimpanzee-derived adenovirus serotype-3 (ChAd3) and modified Vaccinia virus Ankara (MVA) expressing the same 5 antigens as MTB (Ag85B, ESAT-6, Rv2626, Rv1733, RpfD). Under investigation by the University of Oxford.
  • BCG (ZMP1 deletion): A live-attenuated, recombinant vaccine containing BCG with a deleted ais/zmp1 gene is under investigation by the University of Zurich & TBVI. Evidence from animal models suggests that deleting zmp1 gene from BCG improves BCG-mediated vaccine protection against MTB. (R)

Note: There may be additional tuberculosis vaccines that I missed – such as to not be included in this article. If you know of any additional vaccines for TB under investigation, be sure to share in the comments.

First TB vaccine (BCG) development & history (R)

In 1900, Albert Calmette (physician & bacteriologist) and Camille Guerin (veterinarian) began research for development of a tuberculosis vaccine at the Pasture Institute in Lille, France.

The researchers began with a virulent bovine strain of tubercle bacillus (Mycobacterium bovis) that was isolated from the udder of an infected cow – and cultured it on a bile-glycerin-potato medium.

They then subcultured the bacteria at 3 week intervals in hopes of finding a less virulent strain of the tubercle bacillus that could be utilized for vaccine development.

After ~230 subcultures over an 11-year span, researchers isolated a tubercle bacillus which failed to produce progressive tuberculosis after injection into animals (guinea pigs, rabbits, cattle, horses, etc.).

Researchers named the strain Bacille Calmette-Guerin (BCG) – this was the exact strain that went on to become known as the first tuberculosis vaccine a.k.a. the “BCG vaccine.”

The BCG vaccine was first used in an infant in 1921 without complications. By 1924 664 oral BCG vaccinations had been administered to infants – and between 1924-1928 about 114,000 infants were vaccinated without adverse events.

How the BCG vaccine works (in theory)

The BCG vaccine contains a specific, live-attenuated (i.e. weakened) strain of the bacterial species “Mycobacterium bovis” (M. bovis) – a bacterium that causes tuberculosis in cattle (i.e. bovine tuberculosis).

M. bovis is NOT the same as M. tuberculosis, but it’s closely related such that it is believed to generate an analogous immune response in humans.

Injecting humans subcutaneously with the specific weakened strain of M. bovis called “BCG” is thought to train the immune system to fight off M. bovis.

Once the immune system has learned to effectively eradicate M. bovis, it theoretically will have built some degree of cross-immunity to the related bacterial species M. tuberculosis – thus potentially protecting against TB infection and/or disease.

Problems with the BCG vaccine

Questionable efficacy

The main problem with the BCG vaccine is its efficacy.

A Bacillus Calmette-Guerin (BCG) vaccine report by Okafor et al. (2022) states that in healthcare workers, the efficacy of BCG vaccination is not definite. (R)

A systematic review by Brett & Severn (2020) reports that there’s evidence to suggest that the BCG vaccine protects against drug-susceptible TB infection and death in immunocompetent persons. (R)

However, evidence supporting the efficacy of BCG vaccination is considered outdated (from studies in the 1930s-1980s) and low-to-moderate quality (as a result of significant limitations).

What’s more, Brett & Severn state that it remains unclear as to whether the BCG vaccine protects against drug-resistant (DR) forms of tuberculosis – as this hasn’t been specifically tested/evaluated.

Other research states that the BCG vaccine likely protects ~20% (1/5) of vaccinated children but is less effective in adults (the primary transmitters of TB). (R)

Certain people may respond better to the BCG than others based on age, immune profile, genetics, and environment (e.g. exposure to mycobacteria vs. no exposure).

There’s also controversy as to whether specific BCG vaccines (strains & manufacturers or producers) are more effective than others.

Some also believe that the BCG vaccine may have become less effective over time due to the way tuberculosis continues to evolve. (In other words – tuberculosis evolved considerably but the BCG has remained stagnant in its design.)

Complications

Although the BCG vaccine is considered relatively safe for immunocompetent individuals, it can cause adverse events/complications – some of which could be serious.

Risk of complications/adverse reactions significantly increases when the BCG vaccine is administered to immunocompromised individuals.

  • Injection site reaction: This is the most common complication of the BCG vaccine. Signs of this include: granulomatous lesions or nodules/ulcers at the vaccination site.
  • Lymphadenitis: Swelling or enlargement of the lymph nodes.
  • Osteomyelitis: Inflammation or swelling that occurs within bones.
  • Disseminated infection: Wherein M. bovis within the BCG vaccine spreads to many areas of the body and causes infection.

Tuberculosis remains underfunded relative to other conditions

Global funding for tuberculosis (TB) research reached $915M in 2020 – but still accounts for less than 50% of the annual $2B budget set by member states at the United Nations (UN) High-Level Meeting on the Fight to End TB in 2018.

A 2021 report released by the Treatment Action Group (TAG) and Stop TB Partnership revealed that coronavirus disease (COVID-19/SARS-CoV-2) thankfully hasn’t affected TB research funding – despite local TB programs struggling in various ways as a result of the coronavirus pandemic.

Investments from governments, philanthropy, and pharmaceutical companies in the fight against TB have remained somewhat flat/stagnant since 2018 – which is in stark contrast to the meteoric funding and sense of urgency in neutralizing COVID-19.

Which TB vaccines are most promising?

Obviously those that are furthest along in clinical trials.

Many vaccines seem promising conceptually in early phases of trials, but unless they pass safety, efficacy, and immunogenicity evaluations – they’re completely useless regardless of whether they have a unique design.

Examples of TB vaccines with significant promise include:

  • Vaccae (M. vaccae)
  • M. indicus pranii (MIP)
  • VPM1002 (Live rBCG)
  • M72/AS01E
  • MTBVAC
  • GamTBvac
  • BCG (alternate modes of admin)

Challenges in TB vaccine development

There are a variety of challenges associated with developing vaccines for tuberculosis including (but not limited to) what’s listed below.

Valley of death: The phase between research and successful innovation (laboratory to clinical trial-enabling activities) – where most vaccines end up abandoned (i.e. dead).  Reasons vaccines end up in the valley of death include:

  • Complexity of development of manufacturing process, formulation, analytical assays.
  • Optimization of clinical laboratory assays to measure the immune response induced by the vaccine.

Financial investment: It is estimated that the average vaccine costs between $200-500M from research/discovery to registration. TB vaccines in particular are even more expensive (costing well over $500M) as a result of technical complexity and requirement of large clinical trials.

Manufacturing process: Inherently involves growth and modification of live organisms or their components or recombinant protein expression in a live cell line. Biological entities are highly variable and the process needs to be optimized to make vaccines consistently with pre-specified characteristics, purity, and commercially-viable yields.

Immunological assays: Analytical assays are needed to characterize the vaccine and measure/validate its potency and the dosing threshold at which immunologically-active components elicit a sufficient immune response.

Clinical trials: Innovative large-scale clinical trials are needed to evaluate the safety, tolerability, and efficacy of all prospective TB vaccines. Suboptimally designed or insufficiently populated clinical trials make it difficult to know the actual efficacy of TB vaccines.

Complexity of TB: If it were easy to create an effective vaccine for TB – we’d have likely done it by now. Mycobacterium tuberculosis is an extremely difficult bacterium to effectively eradicate with chemotherapy (i.e. antibiotics) and vaccination due to various resistance genes and ability to evade certain aspects of immunological responses.

My thoughts on TB vaccine development…

It seems as though there are a variety of vaccines in the developmental pipeline for tuberculosis (TB) – including: inactivated vaccines; recombinant vaccines; live vaccines; live-attenuated vaccines; TB subunit vaccines; and DNA vaccines.

The presently-available BCG (subcutaneous injection) containing a live-attenuated version of M. bovis is probably better than no vaccine – if you are currently living in an area where TB is endemic or traveling to a TB-endemic location and are immunocompetent.

It’s obvious that curing TB has not been a significant global priority – or we’d likely have more effective vaccine options… (we created a relatively effective vaccine for the early strains of COVID-19 in ~1-2 years).

I’m extremely interested in therapeutic vaccines such as to help treat latent tuberculosis infections via an immunotherapeutic effect – as well as vaccines that generate a robust immune response within the lungs (the organ most affected by TB).

I do think that researchers should examine the effect of intravenous (IV) BCG vaccination in immunocompetent humans on the basis that it was safe and extremely immunogenic in nonhuman primates (far more immunogenic than subcutaneous injection).

Have any thoughts on TB vaccines in development?

If you have any specific thoughts on current tuberculosis vaccines in development – feel free to leave a comment below.

  • Which TB vaccines do you think have the most promise? (Why?)
  • Have you been vaccinated with BCG? (If so, did you ever catch TB?)
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