A new vaccine against tuberculosis

Some 1.7 billion people are infected with tuberculosis (TB), and it remains the world’s leading cause of death from a single pathogen. Every year, there are some 10 million new cases of active TB, and of the 1.6 million annual TB-related deaths, 95% are in low and middle income countries. In 2015, the World Health Organisation (WHO) published the End TB strategy, aiming for a 2035 target of a 90% drop in new TB cases and a 95% drop in deaths from TB. However, to achieve this, a successful vaccine that provides sterilising immunity or prevents lung disease is critical.

Live attenuated BCG (Mycobacterium bovis bacillus Calmette-Guérin) is the only licensed TB vaccine to date and is given to infants intradermally shortly after birth. However, it offers only partial and variable protection against pulmonary TB. Since the BCG’s introduction a century ago, remarkably little progress has been made toward an effective TB vaccine.

Robert Wilkinson combines his life as a Crick/Imperial joint group leader with his role as Director of the Cape Town-based Wellcome Centre for Infectious Diseases Research in Africa, and he has recently co-led a seminal study in humans showing that a new protein-adjuvant TB vaccine can significantly and durably protect individuals with latent TB from developing pulmonary TB disease (Tait et al, 2019). This work has huge significance, demonstrating for the first time that highly effective vaccine-based protection is both biologically feasible and achievable.

The M72/AS01_E vaccine (made by GlaxoSmith-Kline) contains a recombinant fusion protein derived from two M. tuberculosis antigens (Mtb32A and Mtb39A), discovered by serological profiling of TB patients nearly 20 years ago. The recombinant antigen is slightly unusual in that the Mtb39A sequences are embedded inside the Mtb32A sequences. The protein is combined with AS01_E, a liposome-based adjuvant composed of the saponin QS-21 and the TLR4 agonist monophosphoryl lipid A. AS01_E is already used successfully in GlaxoSmith-Kline’s commercial anti-shingles vaccine Shingrix.

Tait el al. report the final analysis of a randomised, double-blind, placebo-controlled, phase 2b trial of M72/AS01_E (clinicaltrials.gov number NCT01755598). Between 2014 and 2015, the study enrolled a total of 3,575 latently M. tuberculosis-infected, HIV-negative subjects aged 18 to 50 in South Africa, Kenya and Zambia. After randomisation, M72/AS01_E or placebo was delivered intramuscularly in two doses one month apart (but for 243 participants, who received only one dose), and individuals were monitored for development of active pulmonary TB disease over the next three years.

Remarkably, at three years post-vaccination, M72/AS01_E was shown to be roughly 50% effective in preventing bacteriologically confirmed TB: at this timepoint there were 26 cases of pulmonary TB in the placebo arm, and 13 in the vaccine arm of the trial. Serious adverse events, potential immune-mediated diseases and deaths occurred with similar frequencies in both the vaccine and placebo groups.

To assess immunogenicity, humoral and cell-mediated immune responses were measured in blood samples taken from a subgroup of 244 participants enrolled in Kenya and South Africa. Vaccinated individuals developed anti-M72 IgG antibodies by month two following vaccination, and numbers of antigen-specific polypositive CD4⁺ T cells producing IFN-γ, IL-2, and TNF-α increased substantially and stayed elevated for three years after vaccination in 53.7% of those tested. These responses were not detected in the placebo group, suggesting that durable humoral and CD4⁺ T cell responses to the vaccine afford partial protection in latently infected individuals.

These data do not address the important issue of whether M72/AS01_E will work in individuals previously unexposed to TB, or if protection is based on the boosting of pre-existing responses in latently infected people; further studies are in hand to establish this. The results will also need confirmation in larger and longer studies conducted in a broader range of populations. These caveats aside, this work strongly supports further evaluation of M72/AS01_E as a tool for global TB control, and importantly, represents the most promising progress to date towards a vaccine to eliminate the global scourge of TB.