Why 1Day Sooner Needs EAs to Sign Up for Hep C Challenge Studies

This post makes an argument that EAs should consider signing up for upcoming hepatitis C human challenge studies. If you want to express interest and/or learn more, click here. Our FAQ document covers basic details and questions on early hep C challenge study participation (e.g.  “Why use a challenge model? Could I transmit it through sex? What are the health risks?”). 

We’re very open to constructive criticism and skepticism of our arguments in the comments. 

Overview & Introduction

The movement for COVID challenge studies was launched by effective altruists. Nir Eyal, an EA bioethicist, co-wrote the first academic piece calling for them. That pre-print was sent to one of 1Day Sooner’s founders by a program officer at Open Philanthropy on March 24, which prompted work on the project to begin. Within a week we had our first sign-up form online. A week after that we had 470 people signed up, driven largely by our first two public mentions, in the 80K Hours Facebook page and the Future Perfect newsletter. 

Now 1Day needs EAs to help launch a movement for a hepatitis C vaccine. Hepatitis C is a blood-borne infection spread largely by needles that may kill as many as 542,000 people per year (15.3M DALYs).^[1] Although an effective treatment exists, disease burden is forecast to rise to 20M DALYs by 2040.^[2] By comparison, GiveWell’s interventions last year targeted an impact of (very roughly) 4.1 million DALYs.^[3]

Human challenge studies are likely the only way to achieve a vaccine in the foreseeable future. The impracticality of vaccine development outside of challenge studies was described in an open letter we organized, which was published in The Lancet Gastroenterology & Hepatology last month. Among its 121 signatories are two of the Nobel Laureates who discovered the hepatitis C virus. 

A successful vaccine would not eliminate 100% of disease burden, but per a peer-reviewed paper we commissioned, the conservative estimate of expected value from testing three vaccines with challenge studies would be to avert 185K infections, saving approximately 370K years of life.^[4] If those trials required 300 participants total, it would imply roughly 1,000 years of life saved per person in the study. There is never a guaranteed outcome of medical research, however, and this model represents an estimate. It is possible, for example, that vaccines for hepatitis C prove extremely difficult, like HIV (see “Arguments against” section).

Quantitative estimates can provide false certainty, but qualitatively speaking, tackling hep C creates excellent opportunities to advance challenge studies and vaccinology more broadly. 

The Qualitative Case for Hep C Challenge

Buy-in from Stakeholders: Expert Consensus Views Challenge Model as Critical for Hep C Vaccine

A major obstacle to adopting the COVID-19 challenge model quickly was opposition from some experts and governments. Support for hepatitis C challenge studies is far greater. All three of the winners of the Nobel Prize for discovering hepatitis C have authored articles proposing and planning the challenge model. The last traditional hep C vaccine study took from 2013-2019 to observe 28 cases, and its corresponding author has argued that challenge studies are needed. Many experts who opposed challenge studies for COVID support them here.

1Day Sooner has been accelerating the existing movement towards hepatitis C challenge studies, beginning with a symposium we sponsored among experts in June 2022. Teams at various major research institutions in the US, Canada, and UK are pursuing their development.  We predict Open Philanthropy will commit funding within the next twelve months to support hepatitis C vaccine development. They have taken a generally favorable stance towards the idea of HCV challenge models.

Validating Challenge Studies as a Viable Way to Accelerate Vaccine Development

It’s possible a vaccine for hepatitis C could be authorized on the basis of challenge studies alone. While so far this has only happened for one vaccine — Vaxchora, for cholera — the method of hep C challenge (with a needle/injection) is highly similar to natural infection, which is not true for most challenge models. There may be a compelling case to license directly from challenge studies for highly impacted demographics (i.e. people who inject drugs, PWIDs) in industrialized countries.^[5] This would entail confirmatory post-market study to generate the type of “real-world evidence” that is a priority of US FDA Commissioner Robert Califf.

Establishing a pathway for vaccine authorization on the basis of challenge study efficacy results would help with vaccine development across a wide range of diseases including influenza, tuberculosis, group A strep, Zika, and COVID. With the exception of Zika, each of those diseases costs more than 10 million DALYs in annual disease burden.

Use Case for “Warp Speed 2.0” 

Vaccines take on average ten years from the start of human testing until regulatory approval.^[6] The COVID mRNA vaccines took about nine months. In the United States, Operation Warp Speed — a concentrated government effort that streamlined regulatory processes and made significant fiscal and logistical resources available to developers — showed that in an emergency a faster timeline is possible.

Enabling technologies such as mRNA vaccine platforms, gene sequencing, and rational drug design^[7] create the opportunity for a permanently faster cadence for vaccine development.^[8] 

If a robust hep C challenge model can be developed quickly, it could support a “Warp Speed” for hep C vaccine development that would validate the Warp 2 model during peacetime and could advance a permanently faster cadence for vaccine development globally.

Why Are EA Volunteers Needed? 

To reach their full potential, we believe these studies need a critical mass of participants motivated by effective altruism. Beyond enabling the studies to occur, EAs who participate could help mold the design of the studies to improve their impact. Given the role EA played in the campaigns for COVID-19 challenge studies, we believe this community is well positioned for advocacy related to hepatitis C.^[9]

The initial challenge studies will be used to establish the challenge model. “Establishing a challenge model” means infecting participants to find the proper infectious dose, characterize infections with the pathogen, and isolate the samples of the pathogen (inocula) for future use. No vaccines are used. Subsequent challenge studies anywhere in the world can use these standardized samples to test hepatitis C vaccines. 

These initial characterization challenge studies are slated to begin in Canada and the UK, likely in the first half of 2024, and later in the US.

We estimate that the current hepatitis C challenge model development plan would see the first vaccine tested in about five years, if all goes smoothly. There are a number of places where accepting additional risk — even relatively limited risk — could accelerate the timeline by up to nearly 900 days.^[10] Well-informed participants who advocate their right to take risks could potentially accelerate the study along these lines through advocacy.

For example, a single study design change could shave four months off of the time needed to establish the hepatitis C challenge model;^[11] a number of other potential design modifications exist, and having earnest prospective volunteers actively involved in study design could help ensure design decisions appropriately weigh risks to volunteers against global health benefits.

Relatedly, earnest prospective volunteers will be able to advocate for changes that make the model more robust. Robustness includes not only speed, but also scientific quality, transparency and data-sharing, adoptability by other research sites, and ability to support regulatory approval. An organized corps of former volunteers, for example, could persuasively lobby for equitable distribution of vaccines globally, for automatic sharing of study data, or for the provision of funding for related vaccine research. 

In addition, hepatitis C generally lacks public attention and urgency due to its chronic nature, and in wealthy countries, its concentration among vulnerable and stigmatized populations, namely, people who inject drugs.^[12] A public advocacy campaign around the challenge studies could have downstream effects of raising the profile of this serious disease more generally. 

How Bad Would Deliberate Infection with Hepatitis C be?

Our FAQ document discusses this in detail, but the short answer is there are real risks of being in the study, though they are likely lower than living organ donation or COVID-19 challenge studies would have been early in the pandemic. Risk of death is extremely low. Below are some highlights from the FAQ.

Hepatitis C is treatable with a well-tolerated daily pill taken for 2-3 months. Cure rates range from 95–99%. Relevant factors include general health/comorbidities, the type of drug, the genotype of the virus, and adherence to treatment. 98% is a commonly cited figure.^[13]

• Groups of healthy, extensively screened volunteers will very likely fall on the high end of the range.
• People who fail the first round of treatment can be treated again with different, related drugs with a similarly high success rate. A 2023 review found 22 cases of fully reported second-round treatment after first round failure in medical literature. All 22 were cured.^[14] (There are other known cases of failures after second-round treatment, however.^[15])
• Viral samples with identifiable genetic signs of resistance to treatment will not be used to infect volunteers.

Most people infected with hepatitis C (around 80%) are asymptomatic in the months following infection. Possible symptoms include fatigue, fever, jaundice, and nausea/vomiting, among others. Symptoms may last several weeks, but are generally intermittent and relatively mild, though they still could impact work and day-to-day life.

Evidence suggests short-term infection among otherwise healthy individuals does not cause significant long-term negative impacts (namely, cancer) in the liver.^[16] Researchers will monitor liver health with regular check-ins, and at certain thresholds treatment would be initiated early.

Am I Personally Obligated to Be in a Hepatitis C Challenge Study? 

No. It requires a chronic infection of a serious disease and significant numbers of appointments in potentially inconvenient locations. We do not believe anyone is obligated to be in any medical study. That said, we do think that it could produce very significant  value for the world that is far greater than the cost to the participant and is thus the type of supererogatory action we believe falls into the category of effective altruism. 

Arguments against Our Approach

1Day Sooner may have been wrong about COVID-19 challenge. COVID challenge studies have not yet been meaningfully helpful in reducing disease burden. This may imply 1Day Sooner’s judgment is poor.

Hep C disease burden decreases would likely materialize multiple decades from now and are thus highly speculative. A vaccine developed in the next five years would see substantial effect 25-45 years from now, due to both the long timeline of hepatitis C mortality and the time it takes to deploy a new vaccine. Insofar as artificial intelligence or other phenomena — nuclear war, climate apocalypse, zombie plague, etc. — drastically change the world, they make the benefits unpredictable or potentially irrelevant. 

Hep C vaccine development may be unsuccessful or unnecessary. The hepatitis C virus is extremely prone to mutation, and within the same person, chronic infection can result in numerous “quasi-species” of the virus. This makes the task of vaccine development harder, and means efficacy may not be high. Also, there are countries — Egypt in particular — that have been able to substantially reduce the burden of hepatitis C through coordinated public health campaigns combining screening and DAA treatment. 

Challenge studies could harm the reputation of effective altruism. Deliberately infecting people with dangerous diseases sounds outlandish, and most people would not want to volunteer. Promoting an effective altruist affiliation with challenge studies may seem off putting or otherwise damage the reputation of effective altruism, especially if a death or other serious adverse event occurs in the study. 

Strong longtermism could be correct. If future lives are roughly morally equivalent to present day lives, reductions in catastrophic risk are tractable, and the probability of near-term human extinction is sufficiently low not to make mitigatory efforts futile, altruistic acts aimed at averting extinction or otherwise dramatically improving the long-term future may vastly outweigh efforts aimed at present-day disease burden.

Further Reading

• Liang, Feld, Cox & Rice (2018), “Controlled Human Infection Model — Fast Track to HCV Vaccine?” New England Journal of Medicine. This article made the case early on for hepatitis C human challenge studies.
• 1Day’s Hep C Challenge Volunteer FAQ — includes breakdowns of questions that people might have when they consider signing up. Discusses things like treatment rates, risk, and purpose of the studies in greater detail.
• Clinical Infectious Diseases Vol. 77, Supplement 3 (August 2023) — series of articles discussing hepatitis C challenge model ethics, science, feasibility, etc. 
• Overview of the hepatitis C vaccine landscape, a review by Paul Zimmer-Harwood commissioned by 1Day Sooner
• EA Should Spend Its “Funding Overhang” on Curing Infectious Diseases, a previous forum post by Josh
• Andrea Cox (September 2022), “A challenge trial can streamline testing of hepatitis C vaccines,” STAT News. This article is by a scientist who ran a site of the only field efficacy trial ever completed for a hepatitis C vaccine. 
• Our previous funding request to Open Philanthropy for 2022-2023, which includes info about hepatitis C work and may be useful information generally.

1. ^{^}

   Estimate for the year 2019 from the Global Burden of Disease 2020 

2. ^{^}

   Forecast in Foreman et al. 2018. We do not know how confident to be about these and provide them to orient towards an order of magnitude.

3. ^{^}

   Calculated by $416 million in spending (sum of all 2022 donations here) at $100/DALY (GiveWell’s impact spreadsheet is here). Note that GW does not report their estimated impact in DALYs and cautions that their numbers are extremely rough. Based on their AMF analysis, we’re making a rough estimate that they save an under-5 life per $5,000 (see footnote 6 here) and saving such a life is the rough equivalent of 50 DALYs. Note also that judgments about discount rates (i.e., the value of averting a hep C death in 20-40 years vs. a malaria death today) can heavily influence the comparison between GiveWell numbers and deploying an effective hep C vaccine.  

^{^}

 Specifically, QALYs. An interactive version of the model described in the paper is available here. This is based on an 11% chance of success for each candidate with 20% uptake in the affected population of a 70% effective vaccine. Note that we expect more than 300 people to ultimately be required for hep C challenge studies and also expect to test more than three candidates.

^{^}

 Feld et al. 2023: "Alternatively, the CHIM approach could also be used to document vaccine efficacy for regulatory purposes. Because all those who participate in a CHIM study are exposed to HCV, it is conceivable that more acute infections could occur and be evaluated in a phase 2/3 CHIM study with dozens of volunteers than in a large RCT with hundreds of participants."

^{^}

The first approved malaria vaccine took 23 years. See this excellent Works in Progress piece.

^{^}

E.g. the antigens developed by NIAID’s Vaccine Research Center for COVID and RSV.

^{^}

This provides a sketch of our vision for faster vaccine development. 

^{^}

We don't think EAs will need to be the exclusive supporters, of course. Plenty of people have expressed interest to 1Day Sooner across the political and philosophical spectrum. Compared with EAs, on average, they may not have quite as cohesive an ideological framework amenable to arguments about accelerating CHIM/vaccine development and sustained advocacy around particulars of study design and implementation. 

^{^}

 We’re not at liberty to get into explicit detail, but these are based on our analysis of not-yet-public protocol document drafts and other knowledge gained from our discussions with researchers. There are other factors that could delay the study, with varying degrees of mitigatibility. Examples include regulatory approval delays, issues with laboratory capacity, negative press coverage, or difficulty sourcing donors for challenge inocula. 

^{^}

 For example, a study may choose to challenge people in a sequence rather than all at once in early stages to ensure that infection with a given sample (inoculum) of the hep C virus can be cured reliably. If someone is hep C virus-free 12 weeks after treatment ends, this is generally considered an acceptable proxy for a cure (true cure is at 24 weeks). Instead of waiting for 12 weeks after treatment to challenge a subsequent cohort, a study could wait four weeks. 98% of people who are virus-free at 4 weeks are virus-free at 12 weeks (Yoshida et al. 2015). 

^{^}

The Lancet Gastroenterology and Hepatology editorial board 2021: “[T]he chronic nature of HCV, often in marginalised communities, and in combination with the stigma associated with the disease, has left it neglected.” Brunner & Brugman 2021: “Hepatitis C infection is responsible for high morbidity and mortality rates globally as well as for significant indirect costs. … [Yet] Hepatitis C infection was and still is not on the radar of most politicians and health authorities.”

^{^}

Estimates vary based on the health of the user, the genotype of the virus, the type of DAA, etc. In general, cure rates are very high among healthy people.

^{^}

Martinello, Naggie, Rockstroh & Matthews 2023. Obviously, 22 is a small number. People certainly fail second-round treatments; a third (and fourth!) round of treatment is also possible, see the following footnote.

^{^}

For example, this 2020 report of a person with HIV and hepatitis C who failed three rounds of treatment and was successfully treated on a fourth round.

^{^}

Hsu et al. 2023.

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