BCG, or the Bacille Calmette-Guérin vaccine, elicits a multipronged immune response that effectively fends off tuberculosis in children in developing countries, where the disease is still common. But the vaccine’s protection wanes with age, and the pathogen can infect adolescents and adults, causing a lung disease characterized by a persistent, sometimes bloody cough. Researchers aren’t sure which parts of the immune response are most critical for protection to be effective, and are taking varied approaches to improve on BCG with next-generation tuberculosis (TB) vaccines. One leading candidate shown here involves the same microbe as BCG, but with a few genetic tweaks that researchers hope will provide better protection. Another takes an entirely different approach with manipulated antigens from the BCG bacterium. Still other TB vaccines in the pipeline include live and killed whole mycobacteria of various species—including Mycobacterium tuberculosis, which causes tuberculosis—and viral delivery of the genetic recipe for mycobacterial antigens.
This 100-old vaccine is a live but weakened form of a cattle bacterium that is related to Mycobacterium tuberculosis (Mtb). Inoculation attracts frontline immune cells to the site of the injection. Dendritic cells and other antigen-presenting cells display parts of the BCG microbe on their surface to drive a response by T cells, which fight future infection with the pathogen and train B cells to produce antibodies. Both BCG and Mtb go into vesicles called phagosomes, where they interfere and stop their own destruction. BCG however is eventually degraded, whereas Mtb survives for a long period of time within cells.
VPM1002 Whole-Cell Vaccine
A genetically modified version of BCG is injected. Macrophages take up the bacterium into a phagosome, where it produces an enzyme that causes pores to form in the phagosome membrane. This allows antigens to leak out into the cytosol and trigger an inflammasome activation, in a similar way to Mtb, which BCG does not do.
M72 Protein Subunit Vaccine
Two recombinant proteins from the Mycobacterium bacteria that constitute the BCG vaccine are fused together and injected. Fusion proteins are taken up by immune cells that then display them on their surfaces to trigger an immune response against the antigens. A proprietary GlaxoSmithKline adjuvant (AS01) boosts that immune response.
In addition to the vaccines pictured above, there are several others in late-stage trials, plus additional candidates in Phase 1 and in preclinical studies (not shown).
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VPM1002: A live, attenuated BCG vaccine with a pore-forming protein from another bacterium that allows the flow of antigens and mycobacterial DNA out from the phagosome into the cytosol (see graphic)
BCG Revaccination: A booster shot of BCG
MTBVAC: A live, genetically weakened M. tuberculosis (first and only such vaccine to enter clinical trials) with mutations in virulence genes
Protein subunit vaccines
M72 + ASO1: A recombinant fusion protein consisting of two M. tuberculosis antigens and an adjuvant (see graphic above)
H56:IC31: A protein vaccine consisting of two early secretory proteins and a latency protein, together with an adjuvant
ID93/GLA-SE: Fusion of four M. tuberculosis virulence antigens, combined with an adjuvant
GamTBVac: A subunit vaccine that fuses two M. tuberculosis antigens with an adjuvant
Whole cell vaccines
DAR-901: An inactivated preparation of the related species Mycobacterium obuense, which does not cause disease (see graphic above)
MIP: An inactivated vaccine that consists of M. indicus pranii, a rapidly growing mycobacterium that does not cause disease
TB/Flu04L: A intranasally delivered live attenuated flu virus carrying two antigens from M. tuberculosis
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