Last week a young man named Onekalit[1] turned up with a nasty cough to a health center we operate in a youth prison in Gulu, Northern Uganda. The dry cough wore him down for over a month, but last week he managed to cough a bit of sputum into a small plastic container. The incredible Gates-Foundation-funded GeneXpert test confimed our fears – Tuberculosis
 

But Onekalit will be OK – after 6-9 months of gruelling treatment, the TB will be cured. He will not become one of the 1.5 million people that TB kills every year, more than double that of malaria[2]After covid subsided TB has now regained the dubious honour of the world’s deadliest infectious disease.
 

The Gates Foundation helped bring the amazing GeneXpert diagnostic test to places like rural Uganda, but Bill and co. are now going a step further making their biggest ever 400 million dollar bet on a vaccine that initial trials show may be 50% effective in stopping TB progress from latent infection to deadly lung disease. 

The first new effective TB vaccine in over 100 years.

Surprisingly this vaccine has been sitting around (in a form) doing nothing much for around 20 years. GlaxoSmithKline (GSK) bought the patent almost 20 years ago, before publishing a trial which showed it was actually quite good and could save millions of lives, then decided they couldn’t make money from the vaccine so shelved it... 

Crazy stuff.
 

Unfortunately, our economic system is not set up to bring a vaccine which could save hundreds of millions of future lives to market. Fortunately our economic system does allow people like Effective Altruists and Bill Gates to donate their own stacks of cash towards life saving endeavours that the market has failed to bring to fruition.
 

This mind bogglingly expensive 550million dollar trail is necessary because TB is a slow disease. Slow to divide, slow to spread, slow to treat. Tracking and follow up TB takes far longer than for your average infectious disease. For malaria, within a year we can start to see whether a vaccine works. For TB it will take at least 5 times as long – 5 years or more before we know whether we are onto a winner.
 

If the vaccine really is 50% effective, it could save around 10 million lives in the next 25 years, not to mention helping prevent the terrifying Antimicrobial Resistance (AMR) that TB has already partly achieved.
 

500 million died from Smallpox (“but not a single one more”) – over 1 billion have died from TB.[3] We remain far a from “not a single one more” in the case of TB – but this could be a spectacular step in the right direction.

 

  1. ^

    Not his real name

  2. ^

    https://www.who.int/news/item/27-10-2022-tuberculosis-deaths-and-disease-increase-during-the-covid-19-pandemic - Although from an effective altruism perspective the suffering caused by malaria is worse, because malaria kills mostly young children, whereas TB kills people of all ages.

  3. ^

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Very cool! 

Seems like this is an investment related to the Global Plan to End TB, 2023-2030. Over the period they call for ~250 billion USD in funding[1]. They state that in the status quo scenario we lose 234 million DALYs[2] to TB. It's a little hard to get the exact number, but looks like they aim to reduce this by around 50% over the period as a whole (?). Around 2 000 USD per DALY on average, which is a fair bit higher than what GiveWell cites for their top charities. I should note that some of the costs are in R&D which will pay dividends beyond 2030.

Given that they aim to reduce TB, cases and deaths, by 80% and 90% respectively in 2030[3], I'm guessing that some of the work should be substantially more cost-effective than the average.

I've not dug into the plan at all I only skimmed the headline numbers, but an interesting read nonetheless!

GiveWell has done some work on TB, but I'm not sure what their overall views are on the area. They recently pulled out of an RCT for a screening program (for unknown reasons?). As far as I can gather there was quite a lot of activity around 2009-2010, with Holden going so far as to personally give to Stop Tuberculosis Partnership. Seems like it was a top rated charity at the time.

If anyone has a good feel for what GiveWell thinks about the area I'd be very interested to hear about it! Or some pointers to where I can learn more.
 

  1. ^

    Page 14, under "Resource needs", The Global Plan to End TB 2023-2030 [PDF]

  2. ^

    Page 14, under "The cost of inaction", The Global Plan to End TB 2023-2030 [PDF]

  3. ^

    Page 15, under "Projected impact", The Global Plan to End TB 2023-2030 [PDF]

Just wanted to thank you and NickLaing for this exchange. I'm planning to use an adapted version of the thoughts/considerations as an example of estimating expected value in some resources I'm creating!

 

Working on a new, more effective TB vaccine: Cost per life saved?

  • About 50% of phase 3 trials are successful. So 50% chance of the rollout being possible
  • Being conservative on The Economist’s optimistic estimate of 10 million lives saved, let’s reduce it to [BLANK 1].
  • So 0.5 (probability) x [BLANK 1] (lives saved) = [BLANK 2] lives saved in expectation.
  • The trial is $550 million to open up this opportunity, then let’s estimate vaccine production and distribution costs $5 per person. 
  • There are about 7 times as many TB cases as deaths, but the vaccine is maximum about 50% effective, and they’ll have to vaccinate way more people than currently actually get TB. So let’s guess that they need to vaccinate [BLANK 3] people to save the [BLANK 1] lives
  • [BLANK 3] million x $5 = $[BLANK 4] in distribution costs.
  • $0.55 billion (trial costs) + $[BLANK 4] (distribution costs) = $[BLANK 5]
  • $[BLANK 5] (cost) / [BLANK 2] (lives saved in expectation) = $[BLANK 6] per life saved in expectation

Great comment thank you!

I would say this vaccine work could be far more cost-effective than the average spending on the global plan to end TB. Because of the nature of the disease (long follow up, long expensive treatment), TB costs so much money to treat and follow up compared with other diseases. Lets have a go at some Napkin calculations for potential vaccine cost-effectiveness?!

About 50% of phase 3 trials are successful, so that's easy to adjust for. So 50% chance of the rollout being possible

Being conservative on their optimistic estimate of 10 million lives saved, lets reduce that by 80% to 2 million. Each life saved could be equivalent to 20 DALYs averted, given TB kills a lot of older people as well. 

Remember here though we haven't included DALYs of those who were saved from suffering but wouldn't have died from TB so I think that makes this quite conservative. TB is unlike malaria in that because its a long and hard to cure disease suffering is a huge factor - I would imagine average suffering for the average person who doesn't die TB might well be over 1 DALY (it has probably been calculated somewhere)

So 0.5 (probability of trial success at current 50% prevention rate) x 20 (DALYs averted per life saved) x 2,000,000 (Lives saved) = 20,000,000 DALYs

20 million DALYS averted in the next 25 years (Not before 2030 mind you).

The trial is 550 million dollars to open up this opportunity, then I'm going to pretty randomly estimate vaccine ends up costing $5 per person (not sure how many doses are needed or production) to produce in the Indian factory like they have planned and distribute. If they vaccinate 500 million people that's estimated 2.5 billion in distribution costs. I could have massively over/underestimated the cost here. So 3 billion dollars all up, to prevent 20 million DALYs

$3,000,000,000 (cost) / 20,000,000 DALYs

That's an EV of about $150 a DALY, closer to GiveWell. And this might look much better value after suffering for non-deaths is factored in. 

Obviously this is a 10 minute calculation with ludicrous error and probably large mistakes, but I think its still useful to have a go!

Indeed, inspiring stuff!

I have no idea what's needed in terms of production costs, distribution costs etc. but it's an interesting back of the envelope calculation nevertheless. 

In the report I've referenced they project around 12-14 billion USD for vaccinations from 2027 to and including 2030, summing to around 50 billion. And this is assuming the vaccine has been developed. They put another 10 billion on top for vaccine R&D.

This is what they write in the report:

Adequate funding must be mobilized to support the manufacturing, procurement and distribution of vaccines, especially in high-burden settings.

This ist he first Global Plan to estimate the costs for rolling out new TB vaccines. Global costs to implement a new vaccine are projected to average US$ 13.15 billion annually from 2027 through 2030, totalling US$ 52.6 billion. Modelled cost estimates include costs to scale up the use of a two-dose TB vaccine, reaching at least 60% of adults and adolescents by 2028, and to maintain 60% coverage or more after that. The cost of vaccine dose units and the operational cost for vaccine delivery have been informed by the experience of rolling out COVID-19 vaccines.

- Page 71, under "Invest adequate resources in vaccine roll- out and scale-up", The Global Plan to End TB 2023-2030 [PDF]


I did read parts of chapter 9 on costs to try to get a better picture of what goes into these estimates, but didn't find anything very detailed in my quick scan. So I'm not sure exactly how they come up with these numbers. 

It does seem that this is assuming world-wide distribution, and that the costs vary quite a bit depending on the particulars of any specific region. See f.ex. Table 19 on page 145 in the report.

Thanks you've put some effort into reading that article nice one.

From what I could see it lookked to me like they were looking at the total cost of developing and rolling out a new vaccine.

"In the report I've referenced they project around 12-14 billion USD for vaccinations from 2027 to and including 2030, summing to around 50 billion. And this is assuming the vaccine has been developed. They put another 10 billion on top for vaccine R&D." 

- Where did you get that from?" I couldn't find the 10 billion figure for R&D I thought that was part of their total.

I don't think they had this far cheaper situation mind which has already been developed and now "just" needs phase 3 tryial and manufacture/distribution. Also plans are already underway to minimise costs in an Indian factory. Costs vary wildly with vaccines - for example the covax vaccine was more like 5 dollars a dose (which I used as my figure here), wheras Moderna and other RNA vaccines were closer to 20. That's a factor of 4 already. I'd imagine the Gates foundation will do a decent job of keeping prices down, who knows maybe even by a factor of 5-10x compared with if it was manfactured commercially in say America.

The article doesn't talk much at all about they get their numbers which is a little annoying.

I did a little more digging, and through a WHO report referenced by the Gates Foundation in their article, I think I've found something that could be the source of the claims in the report I skimmed.

Portnoy, A., et al. (2022). The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study. medRxiv, 2022.05.04.22274654. doi: https://doi.org/10.1101/2022.05.04.22274654

Interestingly, the baseline scenario assumes a vaccine price similar to you, around 5 USD per dose in a 2-dose regiment, which in my naive reading seems to confirm that the bulk of the costs are in fact in logistics. Of course, the headline is that even if the costs here are higher than one would like, it's still hugely cost-effective in terms of return on investment, and great news for the world as a whole!

Even if (on an extremely shallow read) it seems like it doesn't quite cross GiveWell's bar for cost-effectiveness. Unless I am confused about something. Again, if anyone knows if GiveWell has a take on this, I'd be very happy to see :)

"In the report I've referenced they project around 12-14 billion USD for vaccinations from 2027 to and including 2030, summing to around 50 billion. And this is assuming the vaccine has been developed. They put another 10 billion on top for vaccine R&D." 

- Where did you get that from?" I couldn't find the 10 billion figure for R&D I thought that was part of their total.

 

Thanks for pointing out I forgot to mention where I got that from! It's from Table B. Resources needed to accelerate R&D of new TB tools, 2023–2030, page 15 in the report.

I'm sure gates foundation are working very hard on keeping costs down, and let's hope they succeed! I do have a feeling that the bulk of the costs for vaccinations come from the distribution and logistics rather than the production costs, but this is just my vague intuition.

New Incentives, a GiveWell recommended charity, uses roughly 100 USD per vaccination.

I'm not sure how this new trial impacts Stop TB Partnership's expectations for development costs, but hopefully  it turns out to be much cheaper than their expert group estimated at the time of the report being written :)

If you have the time I'm sure they'd be happy to answer an email!

Hi, Hakon,

We were very excited to learn of this trial, a much-needed step toward reducing deaths from tuberculosis. We applaud Gates and Wellcome for this sizable commitment of resources, which is, as Nick points out, necessary to gain adequate information about the vaccine's efficacy, but beyond the reach of most funders.

We have investigated TB-related funding opportunities, and we remain very open to funding either programs or research. However, we have several significant uncertainties about the programs we've explored so far and have not yet funded any at scale.

We are working on a report summarizing the evidence for mass TB screen-and-treat programs, which will provide more detail on our views specific to that type of program.

Best, Miranda

Fantastic, thanks for the update Miranda!

The bit about the vaccine sitting on the shelf for 20 years makes me think: what other potential treatments are available but not researched/deployed due to lack of commercial incentive? I wonder if there's a systematic research to identify the most promising interventions in this category.

That's a great comment Eli - I'm not sure there is!

Probably the most shocking story of shelved innovations (not much talked about) is the discovery of the best malaria treatment we have in 1972, which took over 25 years to become the treatment of choice. A combination of China hiding the discovery and western mistrust, how many lives could have been saved if it had come into use 20 years earlier?

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966551/

I found the opening paragraph a bit confusing. Suggested edits:

  • Last week a young man named Onekalit turned up 
  • The dry cough wore him down for over a month, but last week he finally managed to cough a bit of sputum
    • Why 'finally'? This makes it sound like the dry cough was preventing the collection of sputum.
  • The incredible Gates-Foundation-funded GeneXpert test [add hyphens]

Thanks so much appreciate it, have made the edits!

Yes though, the dry cough was the thing preventing the collection of sputum.

This would be massive if successful, and one of the few ways around XDRTB (and should contribute to slowing drug resistance more generally).

Yep for sure - and with something like a 50% chance of success in phase 3 trials, the chance of it working are pretty good!

Those looking through an AMR lens could even argue that slowing down the proliferation of MDR/XDR TB could be the most important outcome from a vaccine like this - potentially more than direct lives saved through preventing the disease directly.

XDRTB has been an interesting one, obviously its a terrifying prospect, but it hasn't proliferated as much as I think we expected 10-15 years ago. When I did my tropical med diploma it was all the buzz, we feared it would spread from Russian prisons around the world within 10 years and leave millions with no options for treatment. Although it continues to spread, fortunately the proportion of patients with XDR hasn't increased as we thought it might, and in many cases has even reduced due to better treatment programs. 

For example here showed a massive reduction in Southern India https://www.nature.com/articles/s41598-020-74432-y

Saving someone a google search hopefully:
XDRTB = Extensively drug-resistant tuberculosis
MDRTB = Multi drug-resistant tuberculosis

Seems like it's my week of learning a bit about tuberculosis! What's up with the acronyms in the tuberculosis-space anyways? TB isn't that much shorter than tuberculosis.

The Global TB Dictionary has been released ahead of World TB Day 2024: https://tbdictionary.org/

The search function could be a little more sensitive, but otherwise it's a good resource. I also wish I knew the reasoning behind using all these acronyms. Maybe it's just by virtue of its age, being isolated in 1882 -- 142 years is a lot of time to accrue terminology...

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