News from vaccine development against tuberculosis

In the Sars-CoV-2 pandemic, several effective vaccines were developed, produced and approved within a year of the novel coronavirus appearing. In contrast, vaccine development for tuberculosis (TB) paints a sobering picture. The result: since the discovery of the tuberculosis pathogens in 1882, only one vaccine, the BCG vaccine, has been approved to date^.1,2

The BCG vaccine (short for Bacille Calmette Guérin) is based on an attenuated strain of the human pathogenic TB pathogen M. bovis and was developed in 1921. The BCG vaccine reliably protects against the development of severe courses of TB disease such as miliary TB or TB meningitis in children. However, the vaccine does not offer sufficient protection against the most common manifestation by far, pulmonary TB. In addition, there are sometimes considerable side effects: in addition to frequent scarring at the injection site, cases of tuberculous osteomyelitis and even disseminated courses can be triggered. The risk of this is greater with concomitant immunosuppression, e.g. due to an HIV infection. As the risk of side effects exceeds the risk of a severe course in Germany as a low-incidence country for tuberculosis, the BCG vaccine has no longer been recommended in Germany since 1998. This also follows the recommendation of the WHO, which only recommends BCG vaccination for high-incidence countries in which children are exposed to a high risk of TB disease and therefore severe courses. It is also assumed that the BCG vaccine has a positive influence on the sometimes high child mortality rate in the Global South. This is attributed to non-specific effects, in that general immune stimulation also improves the response to other infectious diseases^.3

Various new vaccine candidates against TB are currently in development, based on viral vectors, vaccine adjuvants and attenuated live or inactivated vaccines. As in therapy, the special properties of mycobacteria pose a major challenge. Unlike many other vaccines, there is no clearly identifiable immunodominant antigen, meaning that an effective vaccination cannot be based on neutralizing antibodies alone, but requires an efficient T-cell response. A sufficient immune response is particularly complex in immunocompromised patients.

A multicenter, double-blind, randomized Phase 2 study published with an editorial in The Lancet Infectious Diseases on June 27, 2022, evaluated the safety and immunogenicity of the vaccine candidate VPM1002 in South African newborns^.4,5 VPM1002 is a recombinant BCG strain developed at the Max Planck Institute for Infection Biology in Berlin that has shown an immune response equivalent to BCG in immunocompetent patients including neonates in previous phase 1 and 2 studies. In the current non-inferiority trial, 416 HIV-exposed and non-exposed neonates were vaccinated with VPM1002 (n=312) or BCG (n=104) within the first 12 days of life and followed up for one year. The follow-up consisted of immunological examinations, screening for adverse events and a tuberculin skin test in the 12th month after vaccination.

Insgesamt zeigte sich in Bezug auf die Impfstoff-Sicherheit eine Nicht-Unterlegenheit von VPM1002 gegenüber BCG: Sowohl das Auftreten schwerwiegender unerwünschter Ereignisse als auch die Rate an lokalen Reaktionen wie Vernarbungen und Abszessbildung waren bei VPM1002 über die Kohorten im Vergleich zu BCG weniger ausgeprägt (p<0.0001). Im sekundären Endpunkt der erzielten Immunantwort schnitt der neue Kandidat im Vergleich etwas schwächer ab, bei insgesamt vorhandener Immunogenität. Die Impfstoffwirksamkeit von VPM1002 wird aktuell in einer weiterführenden Phase-3-Studie untersucht. Ein wichtiger logistischer Vorteil dieses Impfstoffes besteht in der Möglichkeit der Großproduktion, die die weltweiten Versorgungsengpässe wie beim BCG-Impfstoff zukünftig abfangen und damit Probleme der globalen Verfügbarkeit adressieren könnte.

In addition to VPM1002, several candidates from different vaccine classes are currently in development or already undergoing clinical testing. The website of the Tuberculosis Vaccine Initiative(https://www.tbvi.eu/what-we-do/pipeline-of-vaccines/) provides an overview. In the search for a TB vaccine that combines effective protection against pulmonary TB with safe use even in immunocompromised patients, which has been ongoing for over 100 years, the news from vaccine development is very positive.

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Literature

1. Lange C, Aaby P, Behr MA, et al. 100 years of Mycobacterium bovis Bacille Calmette-Guérin. Lancet Infect Dis 2022; 22: e2-12.
2. Kaufmann SHE. Vaccine development against tuberculosis over the last 140 years: failure as part of success. Front Microbiol 2021; 12:
3. Benn CS, Roth A, Garly ML, et al. BCG scarring and improved child survival: a combined analysis of studies of BCG scarring. J Intern Med 2020; 288: 614-24.
4. Cotton MF, Madhi SA, Luabeya AK, Tameris M, Hesseling AC, Shenje J, Schoeman E, Hatherill M, Desai S, Kapse D, Brückner S, Koen A, Jose L, Moultrie A, Bhikha S, Walzl G, Gutschmidt A, Kotze LA, Allies DL, Loxton AG, Shaligram U, Abraham M, Johnstone H, Grode L, Kaufmann SHE, Kulkarni PS. Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies: a randomized, phase 2 non-inferiority double-blind controlled trial. Lancet Infect Dis. 2022.
5. Dockrell HM. A next generation BCG vaccine moves forward. Lancet Infect Dis. 2022 Jun 27:S1473-3099(22)00287-0. doi: 10.1016/S1473-3099(22)00287-0. Epub ahead of print. PMID: 35772448.