It is little wonder that some TB vaccine researchers suffer from a rare syndrome that understandably threatens their mental health. Symptoms include frustration, impatience, irritability, seemingly inexplicable rage, and in the least resilient, despair.
It is called VJS or vaccine jealousy syndrome** - in 99% of cases associated with the sudden appearance and out of kilter funding of, (in an astoundingly short 12 months), COVID-19 vaccines.
Never ones to miss an opportunity, even though they carry the research begging bowl, the TB crew have started leveraging the remarkable scientific advances that produce vaccines with up to 95% efficacy against COVID-19. Even so, researchers say that based on current information, it will take up to five years for the top TB vaccine candidate, M72, to complete sufficiently large Phase III trials.
'No contest' comparison
A snapshot comparison: StatsSA's 2020 report on mortality in South Africa puts the TB death toll for 2017 at around 29 000 while the WHO estimates around 58 000 in 2019 (it is not unusual for model-based estimates such as those produced by the WHO to be much higher than comparatively "raw" counts such as those produced by StatsSA). Professor Keertan Dheda, a globally recognised authority on respiratory medicine and multi-drug resistant TB, says it's currently closer to 70 000 (his estimate for 2020).
On 5 March 2020, COVID-19 landed on our shores. Some 15 months later, to be exact by 11 May 2021, a total of 54 896 people in South Africa had succumbed to the coronavirus, according to the official count, although the South African Medical Research Council (SAMRC) estimates that the real tally from COVID-19 could be well over double that.
Either way, as COVID-19 deaths hopefully subside in the coming years, they should again drop below TB deaths - and when one takes the long view, the accumulated death toll from TB over recent decades far exceeds that of COVID-19. Globally, it is the biggest and most chronic killer of human beings outside of two world wars, costing African countries up to 3% of their GDPs annually yet it receives comparatively little attention or funding.
Dheda stresses, "It's important to say this is not a death competition. We're not negating COVID-19 deaths, just highlighting how TB has been neglected."
He says COVID has cumulatively reduced TB case detection in SA by 30-40% over the course of 2020, resulting in tens of thousands of premature deaths.
"It's taken TB control backward by about five to 10 years," he adds.
TB is curable and preventable - the vast majority of people who develop it can be successfully treated with a 6-month drug regimen. Yet, according to the WHO, it remains one of the top 10 causes of death worldwide, killed 1.4 million people in 2019 (280 000 people with HIV), and caused 10 million people to fall ill. Also in 2019, just 30 high TB burden countries accounted for 87% of new TB cases. Eight accounted for two-thirds of the total, with India leading the count, followed by Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and South Africa.
Needless to say, it is a disease of poverty.
Multidrug-resistant TB, (MDR-TB), is a public health crisis and an increasing health security threat. A global total of 206 030 people with multidrug- or rifampicin-resistant TB (MDR/RR-TB) were detected and notified in 2019 (though the total burden was closer to 500 000 cases), a 10% increase from 186 883 in 2018.
Globally, TB incidence is falling at just 2% per year and between 2015 and 2019 the cumulative reduction was 9%. That is less than halfway to the End TB Strategy milestone of a 20% reduction between 2015 and 2020.
MDR-TB a major danger
Dheda says MDR-TB remains a massive challenge particularly in South Africa and BRICS countries, aggravating existing TB containment.
A vaccine would change the entire game.
One explanation, (besides global health economics), for the outlandishly different responses to the two disease crises, is TB's slow, insidious development compared to the dramatically fast spread of COVID-19. People respond more quickly to an immediate threat, although the tardy leadership of the WHO got everyone out of the COVID-19 starting blocks a month too late, according to the body's own Independent Panel for Pandemic Preparedness and Response.
Leading vaccinologist and Director of the Africa Health Research Institute, Professor Willem Hanekom, asks, "Why are we not seeing this (TB) as a crisis? I realise that the developed world probably won't because it doesn't affect them directly, but for us in South Africa, India, and Indonesia, for example, we certainly do."
Hanekom helped set up SA's COVID-19 variant research consortium. He wants to know why the same was not done for TB many years ago.
TB the funding "orphan"
"Clearly we need to recognise TB as an incredible crisis, similar to COVID, and then start mobilising resources to deal with it," he adds, citing figures of over $78 billion spent on COVID-19 globally so far in the public sector alone. This soars when private-sector spending is factored in. TB spending is a minuscule fraction of this.
Another example is given by Dheda, who is also Director of the Lung Infection and Immunity Unit and Head of the Division of Pulmonology in the Department of Medicine at UCT.
He says just one speculative COVID vaccine development contract cost the US over $1 billion.
"That exceeds the funding for the entire TB vaccine field globally for the past 10 years," he says.
TB researchers have been hard at it for 20 years, (a century if you count the very first BCG human trials) and have only recently identified a vaccine candidate with 50% efficacy in adults in a Phase II trial - wide confidence intervals means the efficacy of this vaccine might be substantially higher or lower than this mark.
Given the strictures of regulating authorities (which proved somewhat flexible for COVID-19), it will probably take another five years before we see any TB vaccine relief, predicts Hanekom.
Asked whether the rules were bent for COVID-19 vaccines, Dheda pauses, then replies, "I won't say bent. Everything was massively accelerated. It just shows that if you have enough money and resources, things can move along very quickly. If the TB field had that, plus the political will, we'd have the same results."
A slow-motion vaccine race
One reason for TB's slow-motion vaccine race is we are almost completely inured to it. It's been in South Africa since 1860 (probably even earlier), when the first minor outbreaks were recorded in Butterworth and Queenstown in the Eastern Cape - or whatever military, trading or missionary outposts existed then. Today, Hanekom estimates that 70% of the population is infected but asymptomatic, with about 10% of those ever developing full-blown TB.
Until now, vaccines typically took up to 15 years to develop, test and manufacture. Both the chickenpox vaccine and FluMist, which protects against several strains of the influenza virus, took 28 years to develop. It took 15 years to develop a vaccine for the human papillomavirus, which can cause various types of cancer. It also took 15 years to develop a vaccine for rotavirus, which commonly causes severe, watery diarrhoea. It took Jonas Salk six years to develop and test the first polio vaccine, starting with the isolation of the virus.
Yet the Pfizer-BioNTech and the Moderna COVID-19 messenger RNA vaccines, by contrast, were developed in less than a year - although the underlying technologies have been years in the making. Even so, that's warp speed.
Future TB vaccine options
Hanekom says the only existing TB vaccine, BCG, is given to children where it provides good protection against severe lung and disseminated forms of TB, including meningitis, for the first ten years of life. It's the most widely used of all current vaccines and reaches more than 80% of all children, newborns, and infants in countries where it is part of the national childhood immunisation programme. However, the protection it provides against pulmonary TB in adults is highly variable and unproven.
"The TB we want to prevent is in adolescents and adults. They have a lot of bugs - they cough up bacterium and so they spread it. Children don't - this is the dilemma in the TB vaccine world," explains Hanekom.
Enter the far newer M72 TB vaccine, which after 20 years of work has been found to provide 50% efficacy in a Phase II trial, but with confidence intervals of between 10% and 86%. This means that without confirmation in a large Phase III trial no regulatory authority will allow it to be rolled out, even though at a 40% efficacy it would have, in Hanekom's words, "a massive impact".
"We've tested the waters with regulatory authorities. It's completely safe, but we have to do a Phase III trial asap. That will take four to five years and we need huge numbers of people," he said.
Dheda added that despite the Phase II results being announced in 2018, the Phase III study had yet to start," asking; "would this be acceptable for COVID-19?"
Until early 2020 the M72 vaccine was being developed by the pharmaceutical company GSK, after which they licensed it to the Bill & Melinda Gates Medical Research Institute for its further development.
But while it is the front-runner, M72 is not the only prospect.
"Technology transfer could be taken advantage of and vaccine approaches developed could be applied to TB. We'll be able to leverage all we've learnt from C-19 vaccine development and repurpose that to accelerate TB vaccine development," Dheda asked.
Hanekom says there is another TB vaccine candidate in a Phase 3 efficacy trial in India, called VPM 100, being worked on by that country's Serum Institute (which supplied SA with the controversially abandoned AstraZeneca COVID-19 vaccines).
Besides this, there was 'a whole raft' of vaccines in phase 2B efficacy trials, most in preliminary, not definitive testing - the main reason being a lack of resources.
*See Treatment Action Group's excellent 2020 Pipeline Report chapter on TB vaccines for more on the landscape of vaccines in development.
**Not a real condition
Note: The Bill & Melinda Gates Medical Research Institute is mentioned in this article. Spotlight receives funding from the Bill & Melinda Gates Foundation. Spotlight is editorially independent and a member of the South African Press Council.