Progress in tuberculosis vaccine research
Authors: Priya Venkatesan
Journal: The Lancet Microbe (2021)

Tuberculosis is thought of as an ancient disease by many high-income, low-burden countries, yet it is still the leading infectious cause of death in the world, causing 1·4 million deaths globally in 2019 alone, according to WHO. Most cases of tuberculosis occur in low-income, resource-poor regions such as southeast Asia and Africa. Although the tuberculosis incidence is gradually falling, more preventive interventions are needed to reduce its burden. One such intervention would of course be highly effective tuberculosis vaccines to lower the risk of infection or prevent the progression of infection to tuberculosis disease. The only currently deployed vaccine—BCG—in use since 1921, is effective when given to infants and children and protects against severe childhood tuberculosis but provides little protection against the disease in adults. Thus, development of new, effective tuberculosis vaccine approaches is crucial. Part of the challenge in advancing research into tuberculosis vaccines is the tricky nature of the bacterial pathogen causing the disease, Mycobacterium tuberculosis, which seems to have developed many mechanisms to survive within human cells and evade the human immune response. Despite this fact, as noted by Toyin Togun (The TB Centre, London School of Hygiene and Tropical Medicine, London, UK) and Thomas Scriba (South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa), huge progress has been made in understanding tuberculosis immunology and researching new candidate vaccines. The Treatment Action Group (TAG) 2020 pipeline report on tuberculosis vaccines is also optimistic on the whole, and discusses the promising efficacy shown in two recent trials of tuberculosis vaccination. In the first, a phase 2a trial of the candidate vaccine H4:IC31 versus BCG revaccination in 990 adolescents aged 12–17 years in a high-transmission setting in South Africa who had previously received neonatal BCG vaccination, BCG revaccinaton was effective in preventing sustained M tuberculosis infection (efficacy 45·5%, 95% CI 6·4–68·1). In the second, a phase 3 trial of the M72/AS01E candidate vaccine versus placebo in 3575 adults aged 18–50 years with confirmed M tuberculosis infection but without disease, the vaccine seemed to protect against progression to pulmonary tuberculosis disease for at least 36 months (efficacy 49·7%, 90% CI 12·1–71·2). Additionally, the TAG report notes 16 further vaccine candidates that are at different stages of development. According to Scriba, the results of the proof-of-concept efficacy trials seem to suggest that deployment of a highly effective tuberculosis vaccine is likely within the next 10 years. But perhaps the timeframe does not need to be that long. We have seen this year the breath-taking rapidity with which the COVID-19 vaccines have been developed—within 12 months of genomic sequencing of the SARS-CoV-2 virus. The process has never before advanced so swiftly. As Scriba comments, “The remarkable ‘warp-speed' at which COVID-19 vaccines are being developed demonstrates what real urgency can achieve and serves as a benchmark”. Togun agreed, adding “The incredible energy, resources, advocacy and global [collaboration] that have made possible the tremendous progress achieved in development of COVID-19 vaccines are important lessons that could help with advancing the progress in [tuberculosis] vaccines development”. However, a major obstacle for tuberculosis vaccine research and development is a lack of funding and resources. The TAG report shows that funding for tuberculosis research is still only halfway to the US$2 billion per year required according to 2018 UN figures. This is in stark contrast to the huge amounts of funding for the COVID-19 vaccines that readily poured in from private reserves and the governments of high-income nations such as the UK and the USA who pre-bought the vaccines, alleviating the usual financial concerns faced by pharmaceutical companies when developing a vaccine. Togun comments, “If the same amount of resources, energy, and active global cooperation ploughed into [the] COVID[-19] response had been directed into tuberculosis research, remarkable progress would have been made towards elimination of [the disease].” The COVID-19 pandemic has not only stalled research efforts in other diseases but additionally, ongoing developments in vaccine construct technologies, such as gene insertion from a pathogen into a weakened adenovirus (vector-based vaccines), were pivoted away from other diseases including tuberculosis towards the COVID-19 vaccines and enabled their rapid development. Scriba notes, “It will be critical that these technologies are reverted back to advance efforts for diseases such as tuberculosis”. The TAG report also highlights other ways that tuberculosis research directly contributed to providing tools for COVID-19 research; for example, with regards to non-specific effects of the BCG vaccine, the ongoing global BRACE trial is investigating whether BCG reduces the incidence of COVID-19 compared with placebo, which may be a useful weapon in blunting the effects of the pandemic. Scriba comments “Given the morbidity and mortality globally due to tuberculosis, it is time to accelerate commitment and investment to stop [this] infectious disease that has killed the most human beings”.