Preparing for a drug-resistant bacteria pandemic---vaccines and challenge trials

 Axel Ockenfels recently alerted me that "The German National Academy of Sciences Leopoldina has established a working group to analyze the economic causes of the problem of global increase in pathogens resistant to antimicrobial agents, and develop better incentives for developing antibiotics and possible solutions. "

I sent him some quick thoughts, as follows:

"one direction that seems potentially worth exploring is vaccines for bacteria pathogens.  Most of our vaccines are antiviral, but there are some vaccines against bacterial infection, even though we mostly deal with bacteria through post-infection antibiotics.  But antibiotic discovery has lots of problems, both economic and technical. And it appears that vaccine technology has advanced a lot, given the speed with which Covid vaccines were developed.  So I wonder if it wouldn’t make sense to start now to develop vaccines against some of the bacteria that we think might be candidates for developing antibody resistance, so that when those variants show up, we’ll be able to protect lots of people from getting infected by vaccinating them. 

 And challenge trials would be very useful for that, since pre-pandemic it’s hard to do conventional trials of a vaccine against a disease that most people don’t get. Challenge trials wouldn’t necessarily be very hazardous if the relevant bacteria aren’t yet highly antibiotic resistant, since the diseases would be curable… (The assumption here is that a vaccine against say, conventional tetanus, would also be protective against antibiotic-resistant tetanus, which might be true since the evolutionary pressure to evade a new vaccine is likely very different from the long evolutionary path that leads to resistance to an existing antibiotic..)"

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Earlier posts, on antibiotics here, and vaccine challenge trials.

Challenge trials for future Covid vaccines are still needed, by Stanley Plotkin and Josh Morrison

 Covid is still with us, new vaccines are needed and will likely continue to be needed into the forseeable future, and the case for human challenge trials to speed selection among promising candidates is stronger than ever.  Two veteran advocates make the case:

Human Challenge Trials Hold Promise for Next-Generation COVID Vaccines— These investigations could accelerate effective development of a pan-coronavirus vaccine as well by Stanley Plotkin, MD, and Josh Morrison, JD November 7, 2022

"Two years ago, the prospect of deliberately infecting fully informed volunteers with COVID-19 to aid in vaccine research and development was controversial. We and many others argued that the risks were justifiable, and the reservations of some bioethicists did not deter nearly 40,000 people from over 160 countries from expressing interest in volunteering for these investigations, called human challenge trials. Yet in the end, while they have been extensively pursued in the U.K.*, there were no such studies in the U.S.

"We have made great strides against COVID-19 illness in the form of vaccination and treatments, but there are still thousands of deaths in the U.S. every week.

...

"The White House hosted a summit on the issue in July, showcasing the myriad ways researchers are going about developing new vaccines. There are hundreds of candidates in early stages around the world, but the resources devoted to COVID-19 vaccine research are a fraction of what they were 2 years ago. Human challenge trials can greatly speed the selection of the most promising in this field of candidates, providing scientific and economic benefits over uniform reliance on large field studies.

...

"The use of human challenge trials offers the greatest promise for testing intranasal vaccines for their ability to reduce infection and transmission. In the case of a live attenuated vaccine, something as simple as regular nasal swabbing can reveal just how much of the live virus is present in the nose over time -- and how much would spread when a patient sneezes, for example.

...

"There are obviously risks to COVID-19 challenge studies, and it was on these grounds that initial proposals for such research faced opposition. However, the risk of death is now lower than it was early on in the pandemic given better immune protection garnered from both vaccination and natural exposure, and various treatments options further reduce the risk.

Of course, long-COVID still looms large, but this risk can also be managed by selecting trial participants at lower risk of serious illness, as more severe COVID-19 illness is correlated with lingering post-COVID symptoms. Ultimately, if COVID-19 becomes endemic, long-COVID may well be a threat to everyone, whether or not they sign up for a challenge trial -- all the more reason we must act quickly to develop vaccines that stop transmission.

"We believe that volunteers are perfectly capable of considering these risks rationally. Those who decide to make a potential sacrifice for the good of humanity should be lauded, not dismissed as naive. (Notably, a study of the nearly 40,000-strong prospective volunteers organized by 1Day Sooner showed that their risk tolerance was the same as a control group, and they were driven primarily by altruistic motivations.)"

"Stanley Plotkin, MD, is professor emeritus in pediatrics at the University of Pennsylvania, a veteran vaccinologist, and a board member of 1Day Sooner, an organization that advocates on behalf of challenge trial volunteers. Josh Morrison, JD, is co-founder and president of 1Day Sooner, and a founder of Waitlist Zero and the Rikers Debate Project."

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Earlier:

Monday, June 20, 2022

Report of a SARS-CoV-2 human challenge trial. In Britain.

* Josh Morrison writes:

there are four COVID challenge studies announced or underway in the UK, though only imperial [the study above] has published results. Besides the imperial one, there’s an Oxford reinfection study, 

https://www.ox.ac.uk/news/2021-04-19-human-challenge-trial-launches-study-immune-response-covid-19 (interestingly the talk one of our staff saw indicated they were having a difficult time getting any infections in previously infected people even when using doses 1,000 times higher than the infectious imperial dose).

 

There has also been an Imperial delta study that’s recruiting now — 

https://www.imperial.ac.uk/infectious-disease/research/human-challenge/covhic002/register-your-interest/

 

And HVIVO has announced an omicron challenge study, though I’m not sure that will happen. 

https://investors.vaxart.com/news-releases/news-release-details/vaxart-announces-agreement-hvivo-develop-worlds-first-human

Josh Morrison profiled in Vox

 Josh Morrison, the founder of WaitlistZero and 1DaySooner, is an unusually energetic and effective effective altruist.   

Here's a profile in Vox:

Josh Morrison took risks for science, and he thinks you can, too. From kidney donations to human challenge trials for Covid-19 vaccines, Josh Morrison shows the vast good any individual can do. By Muizz Akhtar

"Morrison first became familiar with this kind of direct public health participation when he read about kidney donations in the New Yorker when he was a law student in 2009. In the piece, people explained why they gave their kidneys to strangers in need — though there was slight risk to donors, the reward and benefit for the recipients was more than worth it. Two years later, he donated a kidney himself.

...

“The basic logic of my work in general is to try to use a sort of identity politics to get better political decision-making,” Morrison told me. “So with kidney donation, the theory is if kidney donors are more empowered in the political system as a sort of identity group, then the system will treat donors better and that will mean more people donate.”

HT: Frank McCormick

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I've mentioned Josh Morrison in many of my posts...

Report of a SARS-CoV-2 human challenge trial. In Britain.

 The May issue of Nature Medicine reports what I am pretty sure was the first covid challenge trial. It was a small one, designed to track how the viral load develops after infection, to see how quickly tests detect infection, and to check procedures to pave the way for subsequent challenge trials.  Recall that a challenge trial, also called a human infection trial, is one in which the participants are deliberately exposed to the disease, and then reside in the hospital under close medical observation and care.

Killingley, B., Mann, A.J., Kalinova, M., Boyers, A., Goonawardane, N., Zhou, J., Lindsell, K., Hare, S.S., Brown, J., Frise, R. and Smith, E., 2022. Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults. Nature Medicine, 28(5), May, 1031-1041.

"36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care."

...

"Written informed consent was obtained from all volunteers before screening and study enrollment. Participants were given a donation of up to £4,565 to compensate for the time and inconvenience of taking part in the study (including at least a 17-day quarantine). This was calculated using the National Institute for Health Research (NIHR) formula and the UK national living wage."

Two of the volunteers were found to have previous antibodies, and of the remaining 34, 53% (18 people) were infected with the disease after 5 days.  

Here's a schematic of how the trial proceeded, starting with almost 27,000 people who volunteered online to participate in the trial, from which the final 36 participants were chosen.

In contrast, the Phase 3 clinical trial of the Pfizer vaccine had almost 22,000 people in the vaccine group and in the placebo group, and reported after four months that only 8  participants in the vaccinated group had contracted the disease, compared to 162 in the placebo group.  So the vaccine was 95% effective (only 5% of the 170 infections were in the vaccinated group).

Big (Phase 3) vaccine trials aren't comparable to small preliminary trials, so my point here is just that in the challenge trial the rate of infection of unvaccinated volunteers in 5 days is more than fifty times that rate over four months in the traditional clinical trial, in which participants go about their lives and get infected by chance.  That's one of the reasons that challenge trials offer the possibility of fast and efficient testing.

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When the study was completed, in 2021, the NY Times published a column with the headline

Britain Infected Volunteers With the Coronavirus. Why Won’t the U.S.?,  By Kate Murphy Oct. 14, 2021

It ended with the following paragraph:

"As one participant in Britain’s Covid human challenge trial put it: “You know the phrase ‘one interesting fact about yourself’ that strikes terror into everyone? That’s now solved forever. I did something that made a difference.”

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Of course challenge trials are controversial in lots of ways. See some discussion here of the ethics of paying challenge participants. 

Monday, February 22, 2021

Ethical Payment in Human Infection Challenge Studies in the American Journal of Bioethics

Monday, March 1, 2021

Compensating challenge vaccine trial participants: further discussion in the American Journal of Bioethics

Thursday, October 29, 2020

Paying participants in challenge trials of Covid-19 vaccines, by Ambuehl, Ockenfels, and Roth

"we note that increasing hourly pay by a risk-compensation percentage as proposed in the target article provides compensation proportional to risk only if the risk increases proportionally with the number of hours worked. (Some risky tasks take little time; imagine challenge trials to test bulletproof vests.) "

Sunday, November 1, 2020

What do we know about the effects of payments to participants in challenge trials for vaccines, and other public spirited activities?

Challenge trials in Britain and (not) in the U.S.

 The NY Times has an excellent piece on Covid vaccine challenge trials, and the different traditions (and repugnance) in Britain and the U.S.

Britain Infected Volunteers With Covid. Why Won’t the U.S.? By Kate Murphy

"In an age of masking, compulsive hand sanitizing and plexiglass dividers, it seems inconceivable that for more than 40 years people enthusiastically signed up — and were often put on a waiting list — to have respiratory viruses, including coronaviruses, dripped into their noses.

"They were volunteers at the Common Cold Unit, set up in 1946 by the British government’s Medical Research Council.

...

"the Common Cold Unit established and refined a model for so-called human challenge studies that paved the way for the first Covid-19 human challenge study just completed in Britain, where young, healthy and unvaccinated volunteers were infected while researchers carefully monitored how their bodies responded.

"Then, as now, there were those who decried deliberately infecting or “challenging” healthy volunteers with disease-causing pathogens. It violates the medical principle of “do no harm.” The trade-off is a unique opportunity to discover the causes, transmission and progression of an illness, as well as the ability to more rapidly test the effectiveness of proposed treatments.

...

"“The key benefit of human challenge studies is that they are controlled — everyone gets the same virus, the same amount and they are in the same environment,” said Dr. Christopher Chiu, professor of infectious diseases at Imperial College London and chief investigator in Britain’s Covid challenge study.

...

"In the United States, the regulatory hurdles to conduct challenge studies mean there are precious few, mostly for finding better treatments for malaria, cholera and influenza. Ethicists and regulators are more comfortable approving clinical trials where subjects are given a treatment, say a drug or vaccine, to see if it helps improve a condition volunteers already have, or could prevent them from developing later.

...

"Dr. Fauci’s office said the institute has no plans to fund Covid-19 human challenge trials in the future. Many bioethicists support that decision. “We don’t ask people to sacrifice themselves for the good of society,” said Jeffrey Kahn, director of the Johns Hopkins Berman Institute of Bioethics. “In the U.S., we are very much about protecting individual rights and individual life and health and liberty, while in more communal societies it’s about the greater good.”

"But Josh Morrison, a co-founder of 1Day Sooner, which advocates on behalf of more than 40,000 would-be human challenge volunteers, argues it should be his and other people’s right to take risks for the greater good. “Most people aren’t going to want to be in a Covid challenge study, and that’s totally fine, but they shouldn’t project their own choices on other people,” he said."

HT: Axel Ockenfels

Participating in a Covid challenge trial: a participant's experience

 The WSJ's Jenny Strasburg has another story on British challenge trials of Covid-19:

Researchers Infect Volunteers With Coronavirus, Hoping to Conquer Covid-19. So-called challenge trials have long been used to study infections, but so far only the U.K. is doing them for Covid-19   By Jenny Strasburg

"On March 8, 23-year-old Jacob Hopkins, a U.K. university student, watched researchers enter his quarantine room’s airlocked entrance at London’s Royal Free Hospital. They wheeled a cart carrying a big red box, like a picnic cooler, labeled “biohazard.”

...

"A few days after the virus was dripped into his nose, he was shivering with a mild case of Covid-19, with the antiviral remdesivir pumped through a thin tube inserted into his arm. He spent 19 days in quarantine and said he felt fully recuperated a month later. He will ultimately be paid about £6,000, equivalent to $8,300, for that time, a year of follow-up tests and phone calls, and a parallel study he agreed to. Trial payments are based on U.K. living wages and go through ethical review."

...

"All volunteers are 18 to 30 years old and screened for known risk factors. They are isolated in quarantine suites with full-time medical care and specialized air systems to contain the virus. Researchers hope to publish peer-reviewed initial findings from the first phase of the challenge trials by this autumn.

...

"Researchers hope trial data will shed light on the durability of immune protection and how Covid-19 affects breathing, heart function, smell and concentration even before symptoms show. They say the model could test new vaccines and treatments head-to-head, eliminating weaker candidates before expensive, large-scale trials. Transmission data could help authorities prioritize who gets booster doses.

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As an observer of repugnant/controversial transactions, I've been following the challenge trial discussion, including in particular about appropriate payments for participants.  There's a part of the medical ethics literature that worries that payments to volunteers might be 'coercive,' particularly to poor volunteers, and that payments should therefore be as small as possible, e.g. minimum wage payments for time spent, and that some things (such as risk) should not be compensated. My colleagues and I have been among those pointing out that there can also be ethical (as well as practical) issues involved in paying too little (or in providing too little post-trial medical care and insurance).

Here are some earlier posts focusing on articles I've coauthored about compensation for participation in challenge trials:

Thursday, October 29, 2020

Paying participants in challenge trials of Covid-19 vaccines, by Ambuehl, Ockenfels, and Roth

"we note that increasing hourly pay by a risk-compensation percentage as proposed in the target article provides compensation proportional to risk only if the risk increases proportionally with the number of hours worked. (Some risky tasks take little time; imagine challenge trials to test bulletproof vests.) "

Sunday, November 1, 2020

What do we know about the effects of payments to participants in challenge trials for vaccines, and other public spirited activities?

Monday, February 22, 2021

Ethical Payment in Human Infection Challenge Studies in the American Journal of Bioethics

Monday, March 1, 2021

Compensating challenge vaccine trial participants: further discussion in the American Journal of Bioethics

Challenge trials for Covid-19 Delta variant

 Before the development of the first Covid vaccines, there was a good deal of discussion about the appropriateness of testing vaccines with human challenge trials, i.e. with tests in which volunteers were deliberately exposed to Covid so that the vaccine effectiveness could be more readily assessed.  Now, with the Delta variant spreading, those issues are once again live.

Only England has authorized challenge trials. Here's a story from the WSJ:

Researchers Ready Lab-Grown Covid-19 Delta Variant for Human Trials. U.K. company is growing the highly contagious variant under tight lab controls for use in challenge studies  By Jenny Strasburg

"While the rest of the world is trying to stamp out the Covid-19 Delta variant, British researchers are making progress growing a carefully controlled batch in a lab that they hope to use to infect volunteers in studies.

"The effort marks a new phase in the U.K.’s human challenge trials, the only Covid-19 studies in the world intentionally exposing participants to the virus with the goal of developing new vaccines and treatments. 

...

"Two Covid challenge trials sponsored by Imperial College London and the University of Oxford started earlier this year in the U.K. They so far have exposed more than 40 healthy, young volunteers under isolated medical supervision to the original Wuhan strain that circulated widely in 2020.

"Since then, the highly transmissible Delta variant has come to dominate infections globally, rendering vaccines less effective and boosting case numbers across the U.K., U.S. and elsewhere. Delta’s fast rise led researchers and U.K. challenge-trial partner hVivo Services Ltd. to focus on trying to grow the variant in the lab.

...

"It took U.K. researchers and government advisers almost a year to plan and gain approval from a U.K. ethics committee and medicines regulators to start the controversial challenge trials for which the Delta strain could eventually be used. The government provided funding; so did the London-based Wellcome Trust, a large healthcare-focused charitable foundation.

...

"The challenge trials faced pushback from some U.K. academics and foreign researchers, as well as from some government officials, who considered them unsafe or otherwise unethical, people involved in the process say. Delays have caused friction among partners. hVivo, part of London-listed pharma-services company Open Orphan ORPH 3.08% PLC, had hoped to use the Covid-19 challenge-trial model by now to test antivirals and other products for drug companies, executives have told industry peers. A U.K. government spokesman said the pace of the challenge studies has reflected appropriate caution, and the trials have been safe.

"Challenge trials have been used for decades to study viruses and other pathogens by deliberately exposing volunteers and studying the body’s response. While scientists in the U.S. and Europe also pushed to do Covid-19 challenge studies, only the U.K. has moved forward."

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Other posts about challenge trials.

Challenge trial for Covid-19 reinfection, in Britain.

A second round of (controvesial) challenge trials is being conducted in England, this one designed to assess how susceptible are people to reinfection with Covid-19, after recovering from it once.

The WSJ has the story 

Covid-19 ‘Challenge Trial’ Will Purposely Reinfect Adults. Dozens of quarantined volunteers in U.K. to receive coronavirus in study focused on reinfection  By Jenny Strasburg

"University of Oxford scientists plan to reinfect dozens of adult volunteers with the coronavirus in the second U.K. clinical trial to study deliberate Covid-19 infection in quarantine—this time among people who have already recovered from the virus.

"Such “human challenge” trials are controversial because they involve intentionally infecting healthy humans, and the U.K. is the only country so far conducting them with Covid-19, researchers said.

...

"The first Covid-19 challenge study, led by Imperial College London infectious-disease researchers, started in March with a handful of volunteers isolated inside London’s Royal Free Hospital, part of the state-funded National Health Service. That study received a pledge of more than $45 million from the U.K. government.

...

"the U.S. and other countries have steered clear of purposely infecting healthy people with the coronavirus. Critics argue the risks aren’t justified, given the broad presence of naturally circulating virus and the success of vaccines already available.

...

"Challenge-trial proponents argue there is no substitute for the precision of controlled studies. They have been used for decades to study diseases including typhoid, malaria and tuberculosis and to develop vaccines. With Covid-19, Prof. McShane told journalists in a briefing last week, “We don’t know whether someone has not been infected because they haven’t been exposed or [because] they have protective immunity.” Controlling exposure will help with those questions, she said.

...

"Volunteers will be tracked for a year. They will be paid around £5,000, equivalent to $6,917, for their time in quarantine and for follow-ups, Prof. McShane said."

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Related posts here:  https://marketdesigner.blogspot.com/search/label/challenge 

Ethical Payment in Human Infection Challenge Studies in the American Journal of Bioethics

 There are likely more vaccine trials ahead of us, of new vaccines and modifications of old ones to defend against new variants of covid. Here's a just-published paper, written when vaccine trials were still in the future. It's still relevant, because challenge trials (in which volunteers are exposed to a particular virus) can be much more focused than ordinary vaccine trials (particularly as the prevalence of disease begins to decline...see yesterday's post).

Promoting Ethical Payment in Human Infection Challenge Studies

Holly Fernandez Lynch, Thomas C. Darton, Jae Levy, Frank McCormick, Ubaka Ogbogu, Ruth O. Payne, Alvin E. Roth, Akilah Jefferson Shah, Thomas Smiley and Emily A. Largent            

Published online: 04 Feb 2021, The American Journal of Bioethics,  https://doi.org/10.1080/15265161.2020.1854368

Abstract: To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, we convened a multidisciplinary working group to address ethical questions regarding whether and how much SARS-CoV-2 HICS participants should be paid. Because the goals of paying HICS participants, as well as the relevant ethical concerns, are the same as those arising for other types of clinical research, the same basic framework for ethical payment can apply. This framework divides payment into reimbursement, compensation, and incentives, focusing on fairness and promoting adequate recruitment and retention as counterweights to concerns about undue inducement. Within the basic framework, several factors are especially salient for HICS, and for SARS-CoV-2 HICS in particular, including the nature of participant confinement, anticipated discomfort, risks and uncertainty, participant motivations, and trust. These factors are reflected in a payment worksheet created to help sponsors, researchers, and ethics reviewers systematically develop and assess ethically justifiable payment amounts.

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Here's a link to the original (long) working paper:

Wednesday, August 19, 2020

The ethics (and some economics) of paying participants in Human Infection Challenge Studies, for a coronavirus vaccine

Human infection challenge trials for Covid vaccine to move forward in UK

 The BBC has this story:

Covid-19: World's first human trials given green light in UK

"Healthy, young volunteers will be infected with coronavirus to test vaccines and treatments in the world's first Covid-19 "human challenge" study, which will take place in the UK.

"The study, which has received ethics approval, will start in the next few weeks and recruit 90 people aged 18-30.

"They will be exposed to the virus in a safe and controlled environment while medics monitor their health.

...

"The Human Challenge study is being delivered by a partnership between the UK government's Vaccines Taskforce, Imperial College London, the Royal Free London NHS Foundation Trust and the company hVIVO, which has pioneered viral human challenge models.Clive Dix, interim chair of the Vaccines Taskforce, said: "We have secured a number of safe and effective vaccines for the UK, but it is essential that we continue to develop new vaccines and treatments for Covid-19.

"We expect these studies to offer unique insights into how the virus works and help us understand which promising vaccines offer the best chance of preventing the infection."

...

"Initially, the study will use the virus that has been circulating in the UK since the pandemic began in March, which is of low risk to healthy adults, to deliberately infect volunteers.

"In time, a small numbers of volunteers are likely to be given an approved vaccine and then exposed to the new variants, helping scientists to find out the most effective jabs - but this phase of the study has not yet been given the go-ahead."

HT: Tom Darton

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And here's a story from the NY Times, which touches on the issue of compensation for participants (and the associated debate about whether that is repugnant):

U.K. Approves Study That Will Deliberately Infect Volunteers With Coronavirus. Researchers hope to learn things about how the immune system responds to the coronavirus that would be impossible outside a lab.  By Benjamin Mueller

"After being exposed to the virus, the participants will be isolated for two weeks in the hospital. For that and the year’s worth of follow-up appointments that are planned, they will be paid 4,500 pounds, or about $6,200. The researchers said that would compensate people for time away from jobs or families without creating too large an economic incentive for people to participate."

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Related posts on challenge trials:   https://marketdesigner.blogspot.com/search/label/challenge

What do we know about the effects of payments to participants in challenge trials for vaccines, and other public spirited activities?

There is starting to be an empirical literature associated with payments for socially productive activities, such as participating in challenge trials of vaccines, donating plasma, etc.

Here's a blog post in the Medical Ethics blog of the Journal of Medical Ethics:

Is it acceptable to pay nothing or little to challenge trial participants?  By Sandro Ambuehl, Axel Ockenfels and Alvin E Roth.   October 30, 2020

Here's a paragraph (with some links).:

"we hope that the debates about payments in medical research, and on other transactions subject to restrictions on payments such as blood plasma donations, will converge as empirical results accumulate. To date, there is empirical evidence on the underlying motivations for volunteering, on the impact of high payment on human risk taking, on decision quality and well-being, on the signal value of small payments, on strategies to evade regulation, and on the general public’s assessment of appropriate activities and  payments. Moreover, there are studies that document biases affecting normative judgment in general, and biases affecting paternalistic restrictions and moral intuitions in particular.

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This blog post was written in connection with our paper in the JME:

Payment in challenge studies from an economics perspective 

by Sandro Ambuehl, Axel Ockenfels, and Alvin E. Roth

published online early, Oct 28, 2020. http://dx.doi.org/10.1136/medethics-2020-

Challenge trials for Covid-19 vaccine are being planned (and a recent NBER cost/benefit analysis)

 Here's the NY Times:

To Test Virus Vaccines, U.K. Study Will Intentionally Infect Volunteers--The hotly contested strategy of deliberate exposure, known as a human challenge trial, could speed up the process of identifying effective coronavirus vaccines.  By Benjamin Mueller

"Scientists at Imperial College London plan to deliberately infect volunteers with the coronavirus early next year, launching the world’s first effort to study how vaccinated people respond to being intentionally exposed to the virus and opening up a new, uncertain path to identifying an effective vaccine.

"The hotly contested strategy, known as a human challenge trial, could potentially shave crucial time in the race to winnow a number of vaccine candidates. Rather than conducting the sort of trials now underway around the world, in which scientists wait for vaccinated people to encounter the virus in their homes and communities, researchers would purposely infect them in a hospital isolation unit.

"Scientists have used this method for decades to test vaccines for typhoid, cholera and other diseases, even asking volunteers in the case of malaria to expose their arms to boxes full of mosquitoes to be bitten and infected. But whereas the infected could be cured of those diseases, Covid-19 has few widely used treatments and no known cure, putting the scientists in charge of Britain’s study in largely uncharted ethical territory.

...

"The volunteers in London will be paid roughly Britain’s minimum wage, which is about £9, or $11, per hour, for their time in taking part in the trial and their two to three weeks in mandatory quarantine. The researchers said they were wary of offering additional incentives that could cloud the judgment of volunteers."

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And here's a recent NBER paper on the efficiency of challenge trials:

A Cost/Benefit Analysis of Clinical Trial Designs for COVID-19 Vaccine Candidates

Donald A. Berry, Scott Berry, Peter Hale, Leah Isakov, Andrew W. Lo, Kien Wei Siah & Chi Heem Wong

ID w27882, DOI 10.3386/w27882, October 2020

Abstract: We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional randomized clinical trials and adaptive and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 504 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits—averting an additional 1.1M infections and 8,000 deaths in the U.S. compared to the next best clinical trial design—if its set-up time is short or the pandemic spreads slowly. In most of the other cases, an adaptive trial provides greater net benefits.

Paying participants in challenge trials of Covid-19 vaccines, by Ambuehl, Ockenfels, and Roth

 Here's a new short paper in Journal of Medical Ethics: (it's ungated, you can read it all at the link): 

Payment in challenge studies from an economics perspective 

by Sandro Ambuehl, Axel Ockenfels, and Alvin E. Roth

published online early, Oct 28, 2020. http://dx.doi.org/10.1136/medethics-2020-

"Participants in medical studies perform a service. Outside the domain of research participation, there is nearly universal agreement that workers providing a service should be compensated fairly, and that work involving more discomfort and risk should be compensated more generously. Accordingly, labour regulations impose floors (minimum wage laws), not caps on compensation. Caps, even if intended to protect against undue inducement, also raise concerns about illegal price-fixing that disadvantages workers. Such limits on payment for egg donors have successfully been challenged in court.

...

"Payment caps can lead to attempts to circumvent the regulation. For example, many countries that prevent payment for the donation of blood plasma instead import it from the USA where payment is legal—the volume of the US export market for plasma products approaches $20 billion per year.ii Similarly, restrictions on CHIM trial payments may lead to an increase in trials in countries with less stringent regulation.

...

"we note that increasing hourly pay by a risk-compensation percentage as proposed in the target article provides compensation proportional to risk only if the risk increases proportionally with the number of hours worked. (Some risky tasks take little time; imagine challenge trials to test bulletproof vests.) To ensure that equal consequences are compensated with equal amounts across a wide variety of studies, we instead recommend a three-part contract consisting of: (1) salary for time involvement that is adjusted to account for the amount of discomfort experienced during participation, (2) insurance against ex post adverse outcomes and (3) ex ante compensation for risks that cannot be compensated ex post (such as death). Such a scheme also increases transparency about what is requested from participants and thus contributes to high-quality participation decisions."

...

"The current discussion about payment in challenge trials is important because the potential benefits of well-designed challenge trials that could accelerate the development of safe and effective vaccines are enormous. Overall, economic research has shown, first, that ethical concerns over high payments may rely on intuitive predictions about behavioural effects that find little or no empirical support, and that the dangers of underpayment are at least as real as those of overpayment. Second, a part of the ethics literature attaches significantly more weight to concerns of undue inducement than the general population. Accordingly, it appears to us that there is sufficient public support for preparing for challenge trials, with paid participants, without a need for excessive ethical concern that payments might inadvertently become too generous to trial participants."

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Our article is an invited commentary on

• Payment in challenge studies: ethics, attitudes and a new payment for risk model

  Olivia Grimwade Julian Savulescu Alberto Giubilini Justin Oakley Joshua Osowicki Andrew J Pollard Anne-Marie Nussberger  J Med Ethics, 2020

Related comments appear in

1. Compensating for research risk: permissible but not obligatory
   Holly Fernandez Lynch et al., J Med Ethics
2. Payment of COVID-19 challenge trials: underpayment is a bigger worry than overpayment
   Jennifer Blumenthal-Barby et al., J Med Ethics, 2020
3. How much money would it take for you to be infected with COVID-19 for research?
   
   By Olivia Grimwade and Julian Savulescu., JME blog, 2020

Broad public support for challenge trials for Covid-19 vaccines

 A broad based survey suggests that challenge trials are not generally regarded as repugnant.

Broad Cross-National Public Support for AcceleratedCOVID-19 Vaccine Trial Designs

by David Broockman, Joshua Kallay, Alexander Guerrero, Mark Budolfson, Nir Eyal, Nicholas P. Jewell , Monica Magalhaes,  Jasjeet S. Sekhony

Abstract: A vaccine for COVID-19 is urgently needed. Several vaccine trial designs may significantly accelerate vaccine testing and approval, but also increase risks to human subjects. Concerns about whether the public would see such designs as ethically acceptable represent an important roadblock to their implementation, and the World Health Organization has called for consulting the public regarding them. Here we present results from a pre-registered cross-national survey (n = 5,920) of individuals in Australia, Canada, Hong Kong, New Zealand, South Africa, Singapore, the United Kingdom, and the United States. The survey asked respondents whether they would prefer scientists to conduct traditional trials or one of two accelerated designs: a challenge trial or a trial integrating a Phase II safety and immunogenicity trial into a larger Phase III efficacy trial. We find broad majorities prefer for scientists to conduct challenge trials (75%, 95% CI: 73-76%) and integrated trials (63%, 95% CI: 61-65%) over standard trials. Even as respondents acknowledged the risks, they perceived both accelerated trials as similarly ethical to standard trial designs, and large majorities characterized them as "probably" or "definitely ethical" (72%, 95% CI: 70-73% for challenge trials; 77%, 95% CI 75-78% for integrated trials). This high support is consistent across every geography and demographic subgroup we examined, including people of diverging political orientations and vulnerable populations such as the elderly, essential workers, and racial and ethnic minorities. These findings bolster the case for these accelerated designs and can help assuage concerns that they would undermine public trust in vaccines.

Human infection challenge trial(s) for covid-19 vaccine likely to start in UK in January

 The Financial Times has the story:

UK to test vaccines on volunteers deliberately infected with Covid-19--‘Human challenge trials’ intended to accelerate vaccine development programmes   by  Clive Cookson.

"London is to host the world’s first Covid-19 human challenge trials — in which healthy volunteers are deliberately infected with coronavirus to assess the effectiveness of experimental vaccines.

"The UK government-funded studies are expected to begin in January ...

"The researchers, who did not want to comment publicly ahead of the launch, said the trials would play a vital role in narrowing the large field of promising Covid-19 vaccines likely to move into clinical testing early next year.

"Volunteers will be inoculated with a vaccine and a month or so later receive a “challenge” dose of Sars-Cov-2, the virus that causes Covid-19, under controlled conditions."

"About 2,000 potential volunteers have signed up for challenge studies in the UK through the US-based advocacy group 1Day Sooner, which campaigns for Covid-19 infection trials and has enlisted 37,000 people worldwide. Traditional clinical trials need tens of thousands of participants and researchers would struggle to attract enough for multiple vaccine studies."

The ethics (and some economics) of paying participants in Human Infection Challenge Studies, for a coronavirus vaccine

 

Here's a paper (that is perhaps not too long when you divide by the number of authors) seeking to provide some background for payment decisions in connection with  human infection studies (i.e. challenge trials) of covid-19 vaccines.

Lynch, Holly Fernandez and Darton, Thomas and Largent, Emily and Levy, Jae and McCormick, Frank and Ogbogu, Ubaka and Payne, Ruth and Roth, Alvin E. and Jefferson Shah, Akilah and Smiley, Thomas, Ethical Payment to Participants in Human Infection Challenge Studies, with a Focus on SARS-CoV-2: Report and Recommendations (August 14, 2020).  

Abstract: To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, this report offers an expert analysis of ethical approaches to paying research participants in these studies, as well as HICS more broadly. The report first provides an overarching ethical framework for research payment that divides payment into reimbursement, compensation, and incentive, focusing on fairness and promoting adequate recruitment and retention as counterweights to ethical concerns about undue inducement. It then describes variables relevant to applying this framework to any type of study, including the prospect of direct medical benefit, early participant withdrawal, study setting and location, pandemic circumstances, study budget, and participant perspectives. We conclude that there is no need for a unique payment framework specific to HICS or SARS-CoV-2 HICS, but that there may be features of particular relevance to ethical payment for these studies. Participants have varied motivations for enrolling in HICS, including financial considerations, altruism, and other interests, but undue inducement does not seem to be a significant problem based on available evidence. Payment in these studies should reflect the nature of participant confinement, anticipated discomfort from induced infection, risks and uncertainty, participant motivations, and the need to recruit from certain populations, as relevant. Where HICS involve significant risks and highly contingent social value, special review confirming the ethical permissibility of these studies can help promote confidence in the ethical permissibility of offers of payment to participate in them. We do not propose specific payment amounts for potential SARS-CoV-2 HICS, as these will be highly variable based on the relevant factors described in the report. Instead, we note that it is reasonable to start from payments offered in other similar studies, while adopting a systematic approach based on the ethical framework herein, as reflected in a pragmatic payment worksheet describing goals, coverage, factors to consider, and potential benchmarks.

Josh Morrison and health policy activism: kidneys and covid

Here's a profile of Josh Morrison, one of the most interesting health care policy activists I've encountered.  I first met him when he was the general counsel of the kidney exchange organization The Alliance for Paired Kidney Donation, and since then he's created new organizations (with evocative names) and new policies.

One Man’s Quest to Infect People With Covid-19 for Science

Inside the movement to launch a human challenge trial for Covid-19

by Andrew Zaleski

"Morrison donated a kidney in 2011, months into his job as a corporate attorney. A few years later he abandoned the law for a more mission-driven career helping people find kidney donors, eventually starting the nonprofit Waitlist Zero in 2014.

"In his telling, his parents “really hated” the idea of being a live organ donor. What he’s planning next terrifies them: Morrison wants to give himself Covid-19 for the sake of science.

...

"The 35-year-old from Brooklyn is the leader of 1Day Sooner, a grassroots organization he co-founded in the spring with a radical idea: Speed up vaccine testing by giving the coronavirus to willing recruits. Including Morrison and his co-founder, 22-year-old Stanford human biology graduate Sophie Rose, more than 30,000 people from 140 countries are signed up — a pool of applicants offering to enlist in what’s known as a human challenge trial.

...

"Human challenge trials involve deliberately infecting small groups of vaccinated volunteers. In a time of social distancing, mask-wearing, and the public’s general leeriness of contracting Covid-19, some researchers, doctors, and ethicists say challenge trials are worthwhile. Unlike traditional Phase 3 clinical trials, which sign up thousands of participants, inject some with a vaccine and others with a placebo, and then wait for people to encounter the virus in everyday life, there’s no waiting on people to catch a virus in a challenge trial. This means it can be completed in weeks instead of months or years, potentially yielding data on vaccine efficacy much more quickly.

"On July 15, human challenge trials for the coronavirus received their biggest endorsement. Adrian Hill, director of the Jenner Institute at the University of Oxford in the U.K., announced that Oxford scientists — already hard at work on a promising coronavirus vaccine — want to launch a challenge trial."

Open letter supporting human challenge trials for COVID-19 vaccines

Here's the website of the advocacy organization 1 Day Sooner (where you can read about human challenge trials, and volunteer for one). It was founded by Josh Morrison (who also founded the kidney transplant donor advocacy organization Waitlist Zero) and Sophie Rose.

Here's the open letter they recently sent to Dr. Francis Collins, at the National Institutes of Health
 Challenge Trials for COVID-19

Here's the press release:
1Day Sooner Open Letter Press Release
"15 NOBEL LAUREATES, OVER 100 PROMINENT FIGURES, AND OVER 2,000 1DAY SOONER VOLUNTEERS SIGN OPEN LETTER TO DR. FRANCIS COLLINS IN SUPPORT OF COVID-19 HUMAN CHALLENGE TRIALS

"Adrian Hill, Director of the Jenner Institute at the University of Oxford, writes that “Oxford’s Jenner Institute and 1Day Sooner are collaborating on work towards the production of a COVID-19 human challenge virus,” and “collaborative human challenge studies should be feasible and informative in the coming months.”

I'm one of the signers of the open letter, and the quote that goes along with my picture in the press release is
“A safe and effective vaccine will be incredibly valuable, and the sooner the better.  Challenge trials make sense. We should prepare carefully, and proceed bravely and gratefully.”
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Earlier posts:

Friday, May 29, 2020

Human Challenge Trials for COVID-19 vaccines

Friday, May 8, 2020

Human Challenge Trials (aka Controlled Human Infection studies) for corona virus vaccines

Human Challenge Trials for COVID-19 vaccines

Yesterday I blogged about trying to speed up vaccine development and distribution by taking some of the risk out of it for pharma companies via an advanced market commitment, and today let's consider again one of the proposals being discussed  for speeding up the testing process.

Here's a white paper proposing some steps to further consider and prepare for human challenge trials (aka controlled human infection studies)  to speed up the testing of potential Covid-19 vaccines.It is put out by the organization 1 Day Sooner, which seeks to promote such trials, and has started assembling a list of volunteers in case challenge trials should become practical, to help vaccines become available sooner.

Evaluating use cases for human challenge trials in accelerating COVID-19 vaccine development
Linh Chi Nguyen , Christopher W Bakerlee, T. Greg McKelvey, Sophie M Rose, Alexander J Norman, Nicholas Joseph, David Manheim,, Michael R McLaren, Steven Jiang, Conor F Barnes, Megan Kinniment, Derek Foster, Thomas C Darton, Josh Morrison; for the 1Day Sooner Research Team

Abstract: Recently, human challenge trials (HCTs) have been proposed as a means to accelerate the development of an effective SARS-CoV-2 vaccine. In this paper, we discuss the potential role forsuch studies in the current COVID-19 pandemic. First, we present three scenarios in which HCTs could be useful: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We go on to outline the practical limitations of HCTs in these scenarios. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be vastly beneficial and, thus, the option of using HCTs to accelerate COVID-19 vaccine development should be preserved. To this end, we recommend an immediate, coordinated effort by all stakeholders to (1) establish ethical and practical guidelines for the use of HCTs for COVID-19; (2) take the first steps toward an HCT, including preparing challenge virus under GMP and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs amid the evolving pandemic.

Here's the main experimental design element:

"In HCTs, a relatively small number of healthy volunteer participants are administered a vaccine candidate or a placebo. However, unlike in conventional trials, consenting HCT participants are then administered an infectious dose of pathogen, and the outcomes of this infection is tracked. By challenging participants with pathogens under close observation in a clinical setting, HCTs can provide a unique opportunity to assess efficacy of a vaccine candidate."

And here are their concluding recommendations:

"To preserve the option to implement HCTs in scenarios such as this, we recommend an immediate, coordinated effort by all stakeholders to address the considerations outlined in this manuscript and make the necessary preparations. These include:
 1. Convening experts to discuss the ethical and practical considerations associated with HCTs for COVID-19, concluding in a set of  recommendations and guidelines for their use in the present pandemic and their role in the licensure process (which, notably, could provide guidance that is broadly useful in the event of future pandemics, too),
2. Taking the first practical steps toward an HCT, including preparing challenge virus under GMP and making preliminary arrangements with volunteers, vaccine developers, regulators, academic institutions, and clinical researchers to run HCTs in situations where they are expected to be highly useful,
3. Keeping informed of the evolving situation, periodically conducting a systematic reevaluation, and adjusting course based on the progress of the pandemic and the outcomes of the first drug and vaccine trials.

"HCTs have the potential to considerably shorten the COVID-19 pandemic, saving many lives and enabling economies and societies to return to normality. But we must act now to ensure this opportunity is not missed."
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It's an admirably careful and balanced paper for one with a policy recommendation, and it sets the stage for a useful and timely debate.

As an experimenter,  I have one reservation about the proposed controls. In the passage I quoted above, they said " healthy volunteer participants are administered a vaccine candidate or a placebo," i.e. the control is a placebo.  That strikes me as potentially controversial given that the next step of the experiment is to infect the participants with Covid-19.  I might prefer a study in which the control for one vaccine was a different potential vaccine, so that no subjects were (relatively) sure to contract the disease.

But this doesn't detract from the usefulness of the preparations they recommend: conducting further discussions, and taking initial practical steps.
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Here is my earlier post on this subject:

Friday, May 8, 2020 

Human Challenge Trials (aka Controlled Human Infection studies) for corona virus vaccines

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Here's a similar in spirit paper, considering when and why human challenge trials might be appropriate, put out by the World Health Organization

Key criteria for the ethical acceptability of COVID-19 human challenge studies
WHO Working Group for Guidance on Human Challenge Studies in COVID-19
Authors:  WHO

"Overview: This document aims to provide guidance to scientists, research ethics committees, funders, policy-makers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining key criteria that would need to be satisfied in order for such studies to be ethically acceptable."
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Here's a news story from CNN, complete with some anecdotes about the sometimes sketchy history of human challenge trials:

Thousands of people want to be exposed to Covid-19 for science
By Robert Kuznia

"Human challenge studies date all the way back to the first vaccine, for the highly lethal smallpox disease. The vaccine was developed in the late 18th century by physician Edward Jenner, who aimed to put a piece of folklore to the test: that milkmaids seemed to contract a milder form of the disease, called cowpox.
"In an experiment that today would warrant steep criminal charges, Jenner took pus from the scab of a milkmaid and inserted it into an incision on the arm of an 8-year-old boy. The child, James Phipps, developed a headache, chills and other mild symptoms, but when directly exposed to smallpox -- again through incisions on the arm -- he proved impervious."
**********

Here's an op-ed from the Washington Post, by the philosophers Richard Yetter Chappell and Peter Singer:

Pandemic ethics: The case for experiments on human volunteers

They conclude:
"We are ethicists, not medical or biological scientists. When it comes to factual beliefs about the pandemic, we defer to expert scientific opinion, as everyone should. But what we ought to do with the facts we have, and how we should go about seeking facts we still lack, are ethical questions. Ethicists have a crucial role to play in this debate.

"There is too much that we don’t know about covid-19. The longer we take to find it out, the more lives will be lost. (That’s why the website asking for vaccine volunteers is called “1 Day Sooner.”) If healthy volunteers, fully informed about the risks, are willing to help fight the pandemic by aiding promising research, there are strong moral reasons to gratefully accept their help. To refuse it would implicitly subject others to still graver risks."
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And here's a  post  from the Volokh Conspiracy (pointed out to me by Frank McCormick) focusing on the question of paying volunteers for human challenge trials:

The Moral Case for Testing Coronavirus Vaccines through "Challenge Trials" on Paid Healthy Volunteers
Doing so can potentially save many thousands of lives. And moral objections to this practice are weak. The issues here are very similar to the longstanding debate over whether we legalize organ markets.  by ILYA SOMIN .

He concludes:
"Like others who risk their lives to benefit others, challenge trial volunteers deserve our gratitude, and proper compensation for their efforts. And there is no good moral justification for forbidding them to take those risks. To the contrary, we should move ahead with challenge trials as soon as feasible. Every day of delay could literally be a matter of life and death—a great many lives and deaths."