Tuberculosis vaccines

Tuberculosis (TB) vaccines are vaccinations intended for the prevention of tuberculosis. Immunotherapy as a defence against TB was first proposed in 1890 by Robert Koch.[1] Today, the only effective tuberculosis vaccine in common use is the Bacillus Calmette-Guérin (BCG) vaccine, first used on humans in 1921.[2] About three out of every 10,000 people who get the vaccine experience side effects, which are usually minor except in severely immuno-depressed individuals. While BCG immunization provides fairly effective protection for infants and young children[3] (including defence against TB meningitis and miliary TB),[4][5] its efficacy in adults is variable,[6] ranging from 0% to 80%.[4][7] Several variables have been considered as responsible for the varying outcomes.[4] Demand for TB immunotherapy advancement exists because the disease has become increasingly drug-resistant.[1]

Tuberculosis vaccines
Drug class
In Wikidata

Other tuberculosis vaccines are at various stages of development, including:

New vaccines are being developed by the Tuberculosis Vaccine Initiative, including TBVI and Aeras.

Vaccine development

To promote successful and lasting management of the TB epidemic, effective vaccination is required.[9] Although the World Health Organization (WHO) endorses a single dose of BCG, revaccination with BCG has been standardized in most, but not all countries.[1][6] However, improved efficacy of multiple dosages has yet to be demonstrated.[6]

Vaccine development is proceeding along several paths:

  • Development of a new prime vaccine to replace BCG
  • Development of sub-unit or booster vaccines to supplement BCG
    • Pre-infection
    • Booster to BCG
    • Post-infection
    • Therapeutic vaccine

Since the BCG vaccine does not offer complete protection against TB, vaccines have been designed to bolster BCG's effectiveness. The industry has now transitioned from developing new alternatives, to selecting the best options currently available to advance into clinical testing.[5] MVA85A is characterized as the “most advanced ‘boost’ candidate” to date.[2]

Delivery alternatives

BCG is currently administered intradermally.[2] To improve efficacy, research approaches have been directed at modifying the delivery method of vaccinations.

Patients can receive MVA85A intradermally or as an oral aerosol.[2] This particular combination proved to be protective against mycobacterial invasion in animals, and both modes are well tolerated.[2] The design incentive behind aerosol delivery is to target the lungs rapidly, easily and painlessly[7] in contrast to intradermal immunization. In murine studies, intradermal vaccination caused localized inflammation at the site of injection whereas MVA85A did not cause unfavourable effects.[2] A correlation has been found between the mode of delivery and vaccine protection efficacy.[2] Research data suggests aerosol delivery has not only physiological and economic advantages,[7] but also the potential to supplement systemic vaccination.[2]

Obstacles in development

Treatment and prevention of TB has been delayed compared to the resources and research efforts put into other diseases. Large pharmaceutical companies do not see profitable investment because of TB's association with the developing world.[4]

Progression of vaccine designs relies heavily on outcomes in animal models. Appropriate animal models are scarce because it is difficult to imitate TB in non-human species.[3][4] It is also challenging finding a species to test on a large scale.[3] Most animal testing for TB vaccines has been conducted on murine, bovine and non-primate species.[3] Recently, a study deemed zebrafish a potentially suitable model organism for preclinical vaccine development.[3]

References
  1. Prabowo, S. et al. "Targeting multidrug-resistant tuberculosis (MDR-TB) by therapeutic vaccines." Med Microbiol Immunol 202 (2013): 95–1041. Print.
  2. White, A. et al. "Evaluation of the Safety and Immunogenicity of a Candidate Tuberculosis Vaccine, MVA85A, Delivered by Aerosol to the Lungs of Macaques." Clinical and Vaccine Immunology 20 (2013): 663–672. Print.
  3. Oksanen, K. et al. "An adult zebrafish model for preclinical tuberculosis vaccinedevelopment." Elsevier 31 (2013): 5202–5209. Print.
  4. Hussey, G, T Hawkridge, and W Hanekom. "Childhood Tuberculosis: Old And New Vaccines." Paediatric Respiratory Reviews 8.2 (2007): 148–154. Print.
  5. Verma, Indu, and Ajay Grover. "Antituberculous Vaccine Development: A Perspective For The Endemic World." Expert Review of Vaccines 8.11 (2009): 1547–1553. Print.
  6. Karonga Prevention Trial Group. "Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi." The Lancet 348 (1996): 17–24. Print.
  7. Tyne, A. et al. "TLR2-targeted secreted proteins from Mycobacterium tuberculosis areprotective as powdered pulmonary vaccines." Elsevier 31 (2013): 4322–4329. Print.
  8. Arbuesab, Ainhoa; Aguilo, Juan I.; Gonzalo-Asensio, Jesus; Marinova, Dessislava; Uranga, Santiago; Puentes, Eugenia; Fernandez, Conchita; Parra, Alberto; Cardona, Pere Joan; Vilaplana, Cristina; Ausin, Vicente; Williams, Ann; Clark, Simon; Malaga, Wladimir; Guilhoth, Christophe; Gicquel, Brigitte; Martin, Carlos (1 October 2013). "Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials". Vaccine. 31 (42): 4867–4873. doi:10.1016/j.vaccine.2013.07.051. PMID 23965219.
  9. Tameris, M. et al. "Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial." Lancet 381 (2013): 1021–1028. Print.
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