Promising Results In GSK Study Could Break Years Of TB Vaccine Deadlock

GlaxoSmithKline has published results from its latest Phase IIb trial of its investigational tuberculosis vaccine that show a subunit vaccine can reduce pulmonary TB, possibly leading the way for the first new vaccine for TB in over 90 years.

GlaxoSmithKline PLC’s tuberculosis candidate vaccine M72/AS01E, developed in alliance with non-profit organization Aeras Global TB Vaccine Foundation, has been shown to reduce pulmonary TB in HIV-negative adults with latent TB infection, in its latest Phase IIb trials.

The results published in the New England Journal of Medicine show a 54% efficacy for the vaccine, with an acceptable safety and reactogenicity profile. The study found varied response rates observed in different demographic sub-groups. In the vaccine group, 10 participants developed active pulmonary tuberculosis compared to 22 participants in the placebo group. 

"We haven’t seen a major scientific innovation in TB vaccines like this in 100 years," Emmanuel Hanon, head of R&D for GSK's Global Vaccines unit, told Scrip. "M72/AS01E is the most advanced TB vaccine in development. It has both different antigens and a different adjuvant compared to other candidates. It is the first to be evaluated in an infected adult population and, of course, it is the first subunit vaccine ever to demonstrate efficacy against TB disease in people."

The ongoing trial is conducted in tuberculosis endemic regions; Kenya, South Africa and Zambia, and involves 3,573 HIV-negative adults. Participants who received two doses of either M72/AS01E or placebo 30 days apart have been followed up for at least two years to detect evidence of pulmonary tuberculosis disease.

Jacqui Shea, CEO of Aeras, calls the study “ground-breaking”. “Given the overwhelming public health need, the importance of these promising results, which need to be confirmed through additional clinical research, cannot be overstated. An effective vaccine, able to reduce transmission, would be by far the most impactful new intervention to end the global tuberculosis epidemic,” she continued.

While both Shea and GSK's Hanon press the importance and potential of the latest results, they are also proceeding with caution. "What is clear is that these data are very encouraging, but of course there are further questions that we need to look at closely," says Hanon. "These include the efficacy of the vaccine in sub-populations, and any insights into how to use the vaccine candidate in people whose immune systems may have been compromised by HIV or other factors. Those questions might be better addressed once the final analysis is completed, after the study concludes in 2019."

The vaccine comprises an immunogenic fusion protein (M72) derived from two M. tuberculosis antigens (MTB32A and MTB39A), identified in human and animal studies over a 20-year period, and the GSK proprietary adjuvant AS01E. This candidate is unique insofar as the M72 fusion protein combined with the AS01E adjuvant induces high levels of M72 specific CD4+ T cells in humans.

Karolina Kujawa, analyst at Datamonitor Healthcare, commented that as there is no tuberculosis vaccine recommended for use in M. tuberculosis-infected adults, who represent a reservoir of potential cases of active tuberculosis if the disease reactivates, GSK’s vaccine would fill this unmet need and potentially stop, or at least minimize, further spread.

The study is still ongoing and a final analysis including all efficacy, safety, reactogenicity and immunogenicity data will be performed in 2019 after all participants have completed three years of follow up. 

Fresh Research

With the live attenuated Bacille Calmette-Guerin (BCG), discovered in 1921, still the only vaccine currently licensed to prevent TB, and with the World Health Organization (WHO) designating it as a priority infectious disease, research has seemed to gear up in the last few years, with early-stage study results now starting to be published. According to Informa's Pharmaprojects, there are 15 vaccines in active clinical development, with GSK and Johnson & Johnson the only big pharma players. The Gates Foundation injected $200m into Aeras in 2012 for the sole purpose of finding a TB vaccine. (Also see "Gates injects $200M into Aeras for TB vaccines" - Scrip, 16 Mar, 2012.)

In February, a Phase II pre-proof of concept trial conducted in South Africa that revaccinated with the BCG vaccine significantly reduced sustained TB infections in adolescents. An experimental vaccine candidate, H4:IC31, developed by Aeras and Sanofi in collaboration with the Statens Serum Institut, also reduced sustained infections, although not at statistically significant levels. However, the trend observed for H4:IC31 is the first time a subunit vaccine has shown any indication of ability to protect against TB infection or disease in humans. Sanofi announced in its Q2 2018 results that it has stopped development of its recombinant subunit vaccine; it is unclear how this may affect further studies of H4:IC31.

While there is new vigor to improve upon BCG, other vaccines have failed to make a clinical impact in recent years. A Phase IIb study of MVA85A, developed by OTEC, the Oxford-Emergent Tuberculosis Consortium, failed to replicate early promising efficacy seen in adults, in infants. (Also see "TB or not TB: Is Emergent‘s vaccine the solution?" - Scrip, 5 Feb, 2013.) 

Tuberculosis is the leading cause of death through infectious disease worldwide, with 1.6 million attributed deaths in 2017. It is estimated that one-quarter of the global population has latent tuberculosis infection. About 10% of those will develop active pulmonary tuberculosis disease.

Multi-drug resistant strains of tuberculosis are emerging globally, and the only available vaccine against tuberculosis, BCG, does not provide proven and consistent protection in adults in tuberculosis endemic countries. WHO has a target of decreasing the number of new cases by 90%, and the number of TB deaths by 95%, before 2035.