Vaccine pipeline for TB

We’ve just come across this: the Treatment Action Group’s ‘Tuberculosis Vaccines – Pipeline Report 2022’.

It's a terrific analysis of where we are today with new vaccine development for TB. If you're at all interested in global health and equity of provision, we really encourage you to read it (it's not too long), but we hope that TAG won’t mind our extracting some of their excellent text and adding some contextual commentary of our own to it.

We’re certainly sure they won’t mind us identifying that the need for new TB vaccine is urgent and what's more isn’t new. The first official target of a new vaccine (once the world started waking up to the disaster that is global TB control in the 1990s) anticipated a five-year development programme from proof-of concept to approval (much as is the norm) and so the world expected a new vaccine by 2015. In other words, this Pipeline Report is looking at something that is already officially 7 years overdue and counting. Given the huge rolling annual estimated deathtoll from TB (that's due for an update in a few days, incidentally) this is a very serious issue.

(In case you don’t know of the Treatment Action Group, they are a valiant/heroic group of likeminded souls who, year on year, fight tooth and nail for better treatments for HIV, TB and Hep C. We in Moxafrica don’t always see things exactly the same way as they do, but we do nevertheless have infinite respect for their integrity and authenticity. The report itself was written by TAG’s TB Project co-director Mike Frick who (again) we hold extremely high in our esteem.)

On this occasion, however, having read through his Report and what's more being super-impressed by its thoroughness, we can’t help but wonder whether he was being a little too charitable in one of his comments. ”Comparisons between research and development (R&D) timelines for COVID-19 and tuberculosis (TB) vaccines, while inevitable, are also more than a little unfair”, he cautions at the outset of this Report. What troubles us about this viewpoint is that he then delivers a summary of facts that very strongly demand that comparisons really should be made because they are so extraordinarily stark and their implications so dire and unfair in themselves. Furthermore, given how explicitly he describes the spped of development of the mRNA vaccines for COVID-19 from Pfizer/BioNTech and the U.S. government/Moderna as a "lightning-fast quest” which was furthermore completed “in record time” then surely comparisons are compelling.

Isn’t it fair and reasonable to ask, for instance, why the development of new TB vaccines remains so unbelievably slow given the ongoing human misery and trail of death that this ancient disease delivers year-on- year? It’s a hundred-and-one years now, after all, since the BCG vaccine (which we think is the most widely used vaccine in the history of medicine, incidentally) was originally launched, and it remains the only vaccine that is currently (or has ever been) approved for this disease. But it's still little appreciated as to how generally ineffective it is. In August 2022, for instance, Lancet Global Health published a meta-analysis of BCG effectiveness analyzing patient data from over 68 thousand TB contacts (all studies reviewed having been published within the last 20 years). The conclusion they drew was that the overall effectiveness of BCG against all forms of TB runs at just 18%. (This deficiency isn’t new, by the way: its ineffectiveness has been known about since at least the 1970s). But BCG does still offer significant protection against TB in children younger than age 5 (at a fairly mediocre 37%) but significantly offers a very striking >80% protection against death for infants, an effect that lasts right through to age 14 – so this old vaccine does still have some legs. Nevertheless, neglect still rules even with the provision of this old warrior of a vaccine, because supplies have been haphazard for years meaning that many, many thousands of children have died unnecessarily. And, of course, while it may still have protected a lot of kids from early death, it’s still done little to dent the immense rolling global pandemic of infectious tuberculosis in the last century.

But try this. One of the more promising ‘new’ vaccines in the pipeline that Mike Frick identifies in TAG's Report is as simple as ‘BCG (re)vaccination’ (i.e.re-vaccinating with BCG in children at adolescence). The tone pitched regarding this innovation is relatively hopeful (in the sense that there is some hope of a new TB vaccine emerging from it in this current decade). What's more, three BCG re-vaccination studies are underway and are based on preliminary data that are encouraging too (with a possible protection of as much as 45%). But here’s the kicker – none of these studies have yet progressed beyond Phase II stage – so the critical Phase III research (the vital big studies that are normally necessary before approval of any new vaccine regimen) haven’t even been begun yet. As such, valid question surely emerges from this: how on earth has it taken a full century for enough imagination to materialise within the TB vaccine research community to consider repeat-dosing the BCG vaccine given its rubbish record pf protection beyond infancy that itself is over half a century old?

Sadly, reviewing some of the other most promising studies currently in the pipeline, more discomforting questions arise.

One relates to the MTBVAC vaccine, this one with an ongoing Phase III trial anticipated to complete in 2027. Why so long (compared to the development of the coronavirus vaccines for instance)? It's an obvious question, but Mike identifies another even more discoincertyaing one for us: how in earth has it taken a full 25 years for this vaccine candidate to travel from discovery work to phase III trials, given that its prime movers first started developing MTBVAC at the University of Zaragoza in the 1990s?

Or try this question, this time quoting directly from Mike’s Report: why has it taken “four years and counting to begin a phase III trial of TB vaccine candidate M72/AS01E [another promising cadidate] following publication of positive results from the primary analysis of its phase IIb trial in 2018”? The TAG Pipeline Report further reckons that the Phase III research hasn’t started yet “but… hopes to enroll all 26,000 participants in 2.5 years and expects to the first efficacy analysis to occur approximately two years after completion of enrollment.” That means that analysed results could be available “as early as 2028”.

Seriously?

Operation Warpspeed? Operation No-speed more like.

One further question: why is the world investing only a twelfth of what the Stop TB Partnership (hosted by the UN) reckons is needed to develop a new TB vaccine by 2025?!! (a date which the Report suggests is highly unlikely anyway given the available evidence).

Comparisons surely are fair and in order here and we don’t see it as unfair to identify them.

Here's an interesting comparison, for instance: Spend-through-the-roof for a vaccine for a SARS-CoV-2 infection with a case fatality ratio of around 1% maximum (even without any good treatment available); or starve researchers of universally pledged funding (despite commitment to do the opposite at the UN in 2018) for an infection with a case fatality ratio of around 15% even with effective drugs (and a 50-70% CFR if drugs aren’t working).

TAG’s Report exposes a global TB response that is currently in tatters, but the sorry fact is that it’s been that way for a long time. Ten years ago (i.e. in 2012), Dr Peter Small who was then a deputy director of the Gates Foundation summed up the situation as it was then, welcoming how much had changed in the previous ten years with vaccine research for TB. “Ten years ago [i.e. back in 2002]” he wrote, “all the TB vaccine researchers in the world would have fit into a minivan.” When he said this in 2012, he reckoned that as many as 500 researchers were now working in the same field.

We wonder how many may be working in it now, and end by asking if it’s unfair for this number (whatever it is) to be compared to the number of minivans full of researchers who have been working globally over the last three years on candidate vaccines for SARS-CoV-2.

A hundred times as many? Probably much more than this. Surely there's something appallingly unfair revealed in such a comparison, and we don't think it's unfair to identify this.