“You get a big company to take [a new TB vaccine} forward?... BULLSHIT…”

The above quote comes from Steven Reed, the co-inventor of a ‘new’ TB vaccine that's been seriously hampered in its development by one of the biggest of Big Pharma. The shameful story of its (lack of) development sadly shines a terrible light on how our biomedical system works with such casual indifference to the plight of those most threatened by tuberculosis (while it works so very efficiently for the profit of the pharma companies themselves and so and for the benefit of their shareholders, and so deprives those most in need of its immense and impressive technical expertise).

The Background

1. The ineffective BCG vaccine

The only approved vaccine for TB (BCG) is now over a hundred years old – and it’s been well known that it’s meaningfully ineffective (except for use in super-vulnerable infants) for half of this period. The proof’s in the pudding: around ten million new active cases are still emerging each year, and a quarter of mankind is currently reckoned to be latently infected with this lethal pathogen. If the vaccine were anywhere near effective these numbers logically would be minimal by now.

So no-one can deny that a new vaccine is desperately needed to staunch the annual death toll – because still today (with vaccine and drugs) one-in-six of those with active disease are dying from it.

2. Adjuvants

But vaccines are tricky beasts. You don’t just need an antigen in the vaccine itself, you also need the help of so-called ‘adjuvants’ – additional ingredients that enhance the host response to the vaccine making the protection stronger and more long-lasting.

Most vaccines today either only incorporate a significantly weakened version of the pathogen, or otherwise only contain small components of the pathogen (often specific proteins), so this is where adjuvants come in – they beef up the response to enhance a vaccine’s protection. The problem is that developing and incorporating them can be tricky (as anyone well-versed in recent vaccine history will tell you).

Developing adjuvants which are generally both effective and safe in humans is challenging – maybe explaining why it’s been described as ‘one of the slowest processes in the history of medicine’. One important adjuvant (MPL) was developed in the 1980s and was found to be helpful, but not as much as intended so researchers began experimenting with combinations of adjuvants.

Enter Glaxo-Smith Kline

At that time GSK scientists recognised the limitations of ‘single’ adjuvants, and quickly began doing active research in this field with a particularly powerful candidate combination emerging - using MPL plus components synthesised from the bark of a fairly rare tree that grows wild in Chilean forests, and it quickly became clear to them that there were enormous potentials for blockbuster vaccines and treatments using this combination.

For commercial reasons, however, Glaxo-Smith Kline cynically didn’t just pursue this technical research with vigour - they also moved in to take control of the supply chain. First, they bought up the company with the rights to manufacture MPL in 2005, and then in 2012, they struck a deal for the rights to a lion’s share of the supply of the Chilean tree bark extract.

And at this same time GSK were testing this combination on a number of diseases including Lyme Disease, HIV, hepatitis and ‘flu.

Enter Steven Reed and TB vaccine research

At this point Steven Reed (who offered us the devastating ‘bullshit’ quote that heads this particular blog) entered the story. He is an immunologist with key expertise in adjuvants, but more importantly, he had (and still has) a key interest in TB, running a nonprofit research organization that worked on infectious diseases and co-founding a biotech company to create and market products.

As such, he pitched the idea to GSK executives in 1994 that it was especially worth their while looking to develop a new TB vaccine, one that could be a game changer for TB control – in fact to finally develop a TB vaccine that could really do what vaccination implies - protect against TB. It’s relevant to mention that, at this point (1994), TB was running out of control, stoked by HIV/AIDS and had been officially identified as a ‘Global Emergency’ just the year before by the World Health Assembly. There was, therefore, every reason for this work to be developed on an urgent humanitarian basis.

Well, the GSK executives led Reed to believe that they agreed, asking him to look over their adjuvants with TB in mind, and so Reed and his colleagues, using significant public funding (and also some from GSK it should be said), worked on this potential new TB vaccine for a decade between 1995 and 2005. As the vaccine progressed into testing, the Bill & Melinda Gates Foundation also pitched in to fund the research, as did the governments of the United Kingdom, the Netherlands and Australia, among others. In other words, this GSK research was significantly capitalising off of public funds.

Introducing shingles into the mix

Amid this apparent interest in TB, however, GSK also started testing Reed’s adjuvant mixture in its shingles vaccine, but very significantly did so at a much faster speed than with TB.

With TB, for example, it performed a small proof-of-concept study to justify moving to a larger one, finally reporting it positively in 2018. There’s no evidence at all, however, that it went through the same painstaking process with shingles because By 2010 (eight years earlier than TB’s proof-of-concept report), GSK’s shingles vaccine had already overtaken the TB vaccine and was being entered into its final trials, and in 2017 the FDA actually approved the shingles vaccine for use while the TB research was essentially languishing in a lay-by still awaiting a proper Phase 3 trial.

Here's the technical blurb on the adjuvant mix for Shingrix, the shingles vaccine: ‘Monophosphoryl lipid A (MPL) and QS-21, a natural compound extracted from the Chilean soapbark tree, combined in a liposomal formulation’. It’s the self-same mixture as was intended for the TB vaccine.

It’s worth adding that this crucial QS-21saponins are only found in Quillaja saponaria soap bark trees, in the bark of trees that are more than 10 years old which helps partly explain its sky-high price. 1 gram costs over 100,000 US dollars. And this price is unlikely to reduce any time soon, not just because of rising demand, but because the trees themselves have been negatively affected by drought in Chile said to be caused by climate change.

Somehow all of the efforts that had begun with the crucial TB vaccination research had switched to shingles, but to make matters worse, GSK finally appeared to be pulling back from TB entirely.

It doesn’t sound that surprising that Reed has called out Pharma’s interest in TB vaccines as ‘bullshit’, does it? It’s because he feels he was betrayed by the company, we can assume.

Questions were being asked about this elsewhere, though, with GSK explaining to the WHO in 2019 that they were quite willing to hand over the TB vaccine to an organization or company for further research, but that company would need to cover the cost of future development, licensing, manufacturing and liability.

Furthermore, if this development went well, this organisation could then sell the vaccine in the “developing world,” but with GSK still retaining the (profitable) sales rights in wealthier countries by controlling the price.

Hmmm – already sounds unreasonable, but turn over a stone or two and maybe it’s even worse…

GSK’s hidden terms and conditions

Maybe this even sounds reasonable given market forces, but it really wasn’t because GSK still held on to the critical controlling factor – the crucial supply of the precious Chilean bark for the adjuvant, and they weren’t going to give that near-monopoly up to help the untold millions at most risk of TB when there was a pretty penny to be made from using it in their shingles vaccine in the richer world.

It's important to appreciate that GSK actually only has enough tree bark for its other vaccines, so whoever might take over the TB vaccine’s development would essentially need to pay GSK a price inflated by demand to ramp up production (if it could be done at all – because a LOT of bark would be needed for the necessary quantity needed for a scaled up TB vaccine roll-out). Great news for GSK shareholders, but very bad news indeed for those most at risk from TB.

It's worth adding that the Chilean tree bark adjuvant was also used in the Novavax SARS-CoV-2 vaccine (which is sold at high price), and GSK also uses it (at least as far as we can determine) in its ‘mosquivix’ malaria vaccine too. It’s a product in increasingly high demand.

Fast forward (perhaps a poor turn of phrase to employ given the sluggish progress of this story that has been unravelling so far for so many years) to June of this year (five years after that TB vaccine proof-of-concept report), and the Gates Foundation and the Wellcome Trust got around to pledging US$550 million to fund the phase 3 trial that is necessary to finally show whether the TB vaccine really works as hoped.

Assuming that it does, neither Gates nor GSK yet appear to be willing to say who will finally have the rights to sell the vaccine in which countries, but Gates MRI has said it will “work with partners to ensure the vaccine is accessible for people living in high TB-burden lower- and middle-income countries” which at least sounds vaguely promising. Meanwhile, GSK has been acknowledging that its rights still extend to South America and Eastern Europe, two regions with significant incidence of TB where it will be able to sell the vaccine (developed by ‘others’) at a price that they can control.

The Chilean tree bark issue

Meanwhile Gates MRI and anyone else involved will still be dependent on GSK to supply much of the adjuvant which is now being hoovered up in their shingles blockbuster vaccine Shingrix.

In May, meanwhile, the FDA also approved a GSK vaccine for the respiratory virus known as RSV with analysts projecting that this one will bring in $4 billion annually at its peak. And this one also uses the critical adjuvant. Meanwhile, GSK continues to study the adjuvant in additional vaccines – which begs the question - exactly how much tree bark will be available to produce adjuvant for a TB vaccine if the research proves successful?

The TB vaccine phase 3 trial itself is now finally set to begin early next year. It’s been reckoned that in the time between 2018 (the proof-of-concept report) and 2024 (when the Phase 3 trial should start) at least 9 million people will have died from TB. And since the results of this new crucial phase of research aren’t expected until 2028, another 9 million (or more given current TB trends) will have died from this ancient disease before there’s any significant roll-out.

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So, yes - this is a story coated in bullshit which exemplifies EXACTLY why TB control has been so poorly expedited and explains one of the reasons why TB thus remains humanity’s most significantly lethal infectious enemy, as well as being the only anti-microbial resistant infection that is infectious by being airborne. From any decent humanitarian perspective, it really shouldn’t be like this,

Throughout this story, moreover, it’s beyond doubt that the search for a new TB vaccine has remained terrifyingly underfunded anyway, but worse still its progress it looks like it has actually been deliberately corrupted by Big Pharma for the benefit of its shareholders.

This cruel and iniquitous phenomenon adds extra insight into the dubious outcomes of last month’s High Level Meeting on TB at the UN (following through on the one five years earlier in which all of the nearly 200 national delegates UNANIMOUSLY agreed to a set of targets for TB which were up for review in 2023). This recent meeting reported in a particularly mealy-mouthed way how those targets set in 2018 had been badly missed (some truly appallingly) but without accounting much blame beyond passing it on to COVID-19. But then those present agreed to generally reset the same targets but did so with an accompanying Political Declaration that actually watered down those original political commitments, essentially watering down both responsibilities and accountabilities (which of course are those signatories).

What does this mean? It means that they KNOW that they won’t be meeting these targets even at the same time they were resetting them.

And along the way, in a particularly tragic and ironic way, those most active in the world of TB are actually being encouraged to be grateful for what was achieved in this Declaration – because it could have been much worse…

George Orwell (a victim of TB himself) must be rolling in his grave at the double-speak on such show.