More than 25,000 people have volunteered so far to be infected with the novel coronavirus through 1DaySooner, an online recruitment organization, as an aid in testing vaccine candidates to prevent Covid-19. These volunteers know that Covid-19 can cause suffering and even death yet they are stepping forward, willing to risk their lives, because some researchers and academics contend that such experiments in humans could accelerate vaccine development.

As a physician and a scientist who has cared for patients and who has been involved in the development of vaccines, I feel the urgency to get a vaccine approved for global use. And I have deep admiration for the courageous volunteers who are willing to put themselves in danger.

In this situation, however, their sacrifice cannot be justified. Volunteers need to be protected from both known and unknown risks. The effort to develop a vaccine should not be jeopardized by this well-intentioned but unnecessary experiment.

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In the context of an ongoing pandemic, the conventional pace of vaccine development frustrates the public, the government, public health experts, vaccine creators, regulators, and others. It is understandable that many are seeking ways to accelerate the demonstration of safety and efficacy of vaccine candidates. The mumps vaccine, considered the fastest vaccine ever developed, took scientists four years to go from collecting viral samples to securing FDA approval in 1967. A decade or longer is more typical. Everyone is hoping that inventing, testing, obtaining approval and producing a Covid-19 vaccine might be on track to set a new record.

The practice of deliberately infecting people with disease, termed “human challenge trials,” has a long history. It is embedded in the origin of the very first vaccine in 1796, when Edward Jenner, an English physician, purposely infected his gardener’s 8-year-old son with cowpox after observing that people previously infected with cowpox, a relatively mild disease, seemed protected from smallpox, one of the deadliest scourges of the time.

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Now, in the midst of the coronavirus pandemic, human challenge studies are being considered again.

In the June 1 issue of the Journal of Infectious Diseases, Nir Eyal, Marc Lipsitch, and Peter G. Smith argue that this approach could accelerate the development and approval of a Covid-19 vaccine by many months. That may sound tempting, but human challenge studies with live virus are unlikely to save time. Moreover, there are ethical and practical reasons for not undertaking human challenge studies with this virus. These authors, like 1DaySooner’s volunteers, are well-intentioned but wrong.

Those in favor of human challenge trials propose enrolling as subjects only healthy young adults, since the Covid-19 mortality rate in this group is low. Just 7% of all Covid-19-related deaths in the U.S. have occurred among those aged 25 to 54 years, compared to 80% in those over age 65. Yet the example of fatal infections in health care workers in the prime of life makes clear that even healthy non-elderly adults may succumb to the novel coronavirus.

Human challenge studies are generally contemplated only when rescue with a lifesaving treatment or intervention is available should a vaccine candidate not protect a volunteer from the disease. But there is no cure or treatment against the SARS-CoV-2 virus that can be deployed with confidence, making viral challenge particularly risky and ethically questionable.

Most people, likely including most of the volunteers, tend to think of vaccines as fully effective: They either work or don’t. This belief generally stems from the success of vaccines for childhood diseases like measles and mumps. But some vaccines, especially those for adults, are much less effective: There are seasons when the flu vaccine is only 70% to 80% effective, or sometimes even less. Imagine, for a moment, that a vaccine candidate undergoing testing turns out to generate immunity in 80% of those who receive it. Then 20% will become infected with Covid-19.

An equally disturbing scenario is what if one of the first volunteers dies, either due to the play of chance, a problem with the vaccine, or the individual’s genetic makeup? This is unlikely to happen but it can, and did, in another setting with consequences that stretched far beyond the single tragic death.

In 1999, Jesse Gelsinger volunteered for one of the first gene therapy trials. The 18-year-old had a rare metabolic genetic disorder, but his condition was managed with medication; he was basically healthy. He volunteered for a safety trial of a virus-based gene-therapy — and died as a result. Missteps in the trial, and the subsequent controversy surrounding his death, set the field of gene therapy back by at least two decades. That hiatus deprived a generation of patients with genetic disorders of treatments.

With vaccines already a target of widespread misinformation campaigns, the death of a single volunteer would likely cause even greater damage. From a public health perspective, it would be especially disastrous if it both slowed the race to develop a coronavirus vaccine and fueled the anti-vaccination movement.

There are other ethical considerations. An important principle in human challenge studies is that subjects must give their informed consent in order to take part. That means they should be provided with all the relevant information about the risk they are considering. But that is impossible for such a new disease.

Covid-19 was initially thought to be mainly a respiratory ailment. We now know that it can damage the kidneys, circulatory system, and the heart. It was initially believed that children could not be sickened by SARS-CoV-2, but it now appears that dozens have developed a severe inflammatory syndrome. And we know nothing about potential long-term complications of Covid-19 because the disease has only been in humans for months. Taken together, this means that no volunteer is able to give true informed consent.

Given these risks, there might still be some justification for a human challenge trial if we knew for certain it would accelerate the development of an effective vaccine. But safer trials can get us to a vaccine in the same amount of time without taking on additional risk for volunteers, especially now that some vaccine candidates already have entered Phase 2 clinical trials and several others are close behind.

In a conventional trial, subjects are injected with either the experimental vaccine or placebo. They are then monitored to see if those who got the vaccine are less likely to contract the disease while going about their daily lives. In a human challenge study, things can theoretically happen more quickly, since volunteers are deliberately infected after getting the trial vaccine or placebo.

But human challenge trials take time, too. For Covid-19, subjects would likely have to receive two doses of vaccine (spaced by weeks), wait for potential immunity to develop, then be infected with the live virus and observed for weeks to months. Since the challenge trial would need to start small and be expanded only with great caution because of the risks involved, it would take months to deliver sufficient data. Safety data, in particular, would be lacking, even though this is one of the biggest issues confronting a new vaccine, because the size of the trial would be too small to garner robust safety data and data about adverse effects of the vaccine would be confounded by the administration of the live virus.

There is no short cut for determining safety.

A large-scale, conventional study could likely be conducted just as quickly. In addition, monitoring and interim analyses of conventional trials raise the possibility of some kind of “conditional” or “emergency use” approval while the trials continue. If that happened, a vaccine might be available for certain high-risk or vulnerable groups in record time, namely 12 to 18 months from laboratory to clinic.

A final issue is that the results of the proposed human challenge studies come exclusively from the experience of younger adults, and cannot be extrapolated to the elderly, who tend to have weaker immune responses and the highest Covid-19 mortality rate. The volunteers might end up having risked their own health without truly helping those who are in greatest need of vaccine protection.

The world is overwhelmed by the pandemic. It is imperative to expedite development and approval pathways without forgoing safety and effectiveness. Ascertaining the risks intrinsic to the disease versus those of a new vaccine in specific populations — health care workers, first responders, the elderly, those with comorbidities, and the like — is essential. But acceleration should not mean forsaking ethical concerns, putting well-intentioned volunteers at needless risk, or setting back global vaccine efforts.

Michael Rosenblatt, M.D., is the chief medical officer of Flagship Pioneering, a venture firm that creates life sciences companies. He is the former chief medical officer of Merck and former dean of Tufts University School of Medicine. He serves as an adviser to Moderna, which is developing a Covid-19 vaccine; he is not a Moderna employee or shareholder. The opinions expressed are his own and do not necessarily reflect those of Flagship Pioneering or Moderna.

  • In reading all these comments in the past 24hrs, I’m now really wondering what the underlying emotions might be for those criticizing HCT? In other words are people thinking, “yikes! we might hurt people!,” or maybe “oh man, if this goes south, anti-vaxxers have more ammo,” or something else?

    Where I’m coming from is just “wow, brave volunteers, more power to ’em!..wish I was as courageous and generous.”

    I’d really like to understand (feel it from their perspective more than trace the logic) why folks might be negative on HCTs? Hope I’m not being too dense. Thanks!

  • If a foreign invader came into our country and started killing 1000people/day and brought our economy to its knees, the military would be called in to fix the problem. People would volunteer to put their lives on the line on the battlefield with the explicit understanding that some of them would never return. If enough volunteers couldn’t be found then we would draft them.

    Like it or not the world today is at war with Covid 19. The way you win such a war is with a vaccine. The faster you get it the more lives are saved. The real moral question is not if we should do challenge studies but why haven’t they started already!

    The argument that you need an available rescue with a lifesaving treatment or intervention is nonsense. In recent years we have asked soldiers to put their lives on the line to disarm IED’s that stood to kill far fewer people than Covid 19. Last I checked if one of those goes off we have no available treatment for that!

    • 100% agree, Adam. 100%.

      And everyone would agree if we knew that, say, 100 million people were going to die in the world in six months if we didn’t have a vaccine. And even if the chance of death in an HCT were 5% for participants in that scenario, there would be no lack of volunteers because of the magnitude and urgency.

      Something about COVID has too many people thinking there isn’t enough urgency, there isn’t enough magnitude, to allow volunteers to assume a 1 in 1000 risk of permanent harm (or 1 in 100 in a second round involving older guys like me). Somehow, 125,000 deaths/month and the collapse of economies worldwide is not enough urgency or magnitude. I don’t begin to understand how people could think that.

    • Yes, the author did not try to give any projected numbers, but the death toll alone is so huge, it justifies taking a lot of risks. And the death toll does not include all the economic damage – and the complications which mean long term serious damage to health for many people who survive.
      I think it is impossible to make any argument based on all the projected numbers, so they go to generalities which sound reasonable.
      I think there is a big fear of the anti-vaxxer movement gaining ground if there are really bad side effects and people in an HCT die, but it could go the other way – HCT and rapid vaccine development leads to the CoV2 vaccine being viewed as saving the world, and all vaccines get a boost from that.

    • Patrick,

      Ever seen the Normandy beach landing footage, or at least seen the recreation of it in the movie saving Private Ryan? The losses in that first wave of the invasion were devastating but those great heroes set in motion the downfall of Nazism and we all today owe a great level gratitude for their sacrifice.

      I have to wonder if the medical world took a “storm the beaches” approach where tomorrow large groups of people were given different vaccines in different experimental doses and then directly exposed to the virus could we have a winner in a matter of a month or two? How many hundreds of thousand if not millions of lives would be saved globally vs those lost to such an effort?

      If the risk benefit requirements used by our medical profession to sanction vaccine testing was applied to war I am pretty sure we would all be speaking German before that beach was safe to land troops on!

  • Being myself one of the volunteers who signed up via 1DaySooner to participate in a challenge trial, I can tell you with certainty that I didn’t sign up because I “misunderstood” anything about vaccine efficacy or disease risk.
    I’m an RN, so I fully understand that a vaccine might not be fully effective. But the reality is that this illness will not go away, and there is a risk every single day, particularly for those of us who cannot “shelter at home” even if we wanted to (as a nurse, I neither can, nor do I want to).

    I signed up because I believe strongly that the “normal life” that is being so maligned right now is actually the only thing that gives life meaning. That if we are doomed to keep each other “safe” only by long-term isolating from each other and from activities we enjoy…well, to me…that is not a life I want to live.

    Thus I’d much rather take a deliberate, calculated risk to be able to return quality of life to more people, even if it means I die doing it. Just having a heartbeat isn’t good enough for me, I confess—and “hiding from danger” while trying to pass that off as real life shouldn’t be something society is forced to accept. Basically, I think the reason many of us signed up for 1DaySooner is that many, MANY of us fear other things far more than we fear death. Living in long-term dread and sustained loss of quality of life in the name of false “safety” are MUCH higher on my personal list. If you must hide in your home, refrain from activities you enjoy, and stay separated from people you love in order to stay “safe”….then what precisely are you even living for at that point??

    So I shall remain on the 1DaySooner list, because I fully understand the risks, and they are MORE THAN worth it to me.

  • None of the arguments seem to consider that some people may WANT to be part of Human Challenge Testing because they want protection from the virus, because they are in a moderate to high risk group?

    If animal testing shows some extremely high effectivity of a vaccine candidate, such that there is a very high chance one would get immunity from it – then signing up for challenge testing may be the best way to protect oneself.
    Depending on your circumstances- like if you are a wealthy person in New Zealand who can go into isolation for a couple years, in the country with “Zero” Cov2, or a poor person in some extremely crowded and dirty place in a very poor country – with high CoV2 – a challenge trial would look very appealing.

    • There is another cohort likely to “want” to be in the challenge trial- young healthy volunteers who see the outcomes as A) I end up immune due to vaccine and B) I end up immune by getting a manageable illness- See Chicken Pox parties circa 1960. This is not to ignore the risks of the vaccine or the risk of a more severe infection although the odds of either are likely low for this group assuming the vaccine passed Phase 1

  • I appreciate your points and agree with several of the issues – The unknown long-term risks of infection the risk of a PR disaster…

    But I strongly dispute the logic of suggesting “Safer trials can get us to a vaccine in the same amount of time without taking on additional risk for volunteers.”

    Conventional trials are not ‘safer’ than challenge trials. They must not be to be valid. In order to prove the efficacy of a vaccine, a significant number of patients must be exposed to the virus. The only question is: is the exposure: controlled and intentional, or random? The risk to those who are exposed is ultimately the same whether they are intentionally infected or exposed via community spread. For the unvaccinated control in the conventional the risk may in fact be higher as they get none of the possible benefit from the vaccine candidate. Further, in a challenge trial the volunteers can be monitored more closely and given earlier interventions if an active infection is detected, which may lower their risk further.

    I don’t agree with the premise that the researchers are morally “off the hook” if the exposure is random; but morally responsible if the exposure is intentional and controlled. The whole point of the test is to have enough of the subjects exposed to the virus to test the efficacy. Arguing “They would have been infected anyway” in the conventional group, is unknowable and philosophically dubious.

    To me this is similar to a trolley problem. Is it more ethical to have one brave volunteer crash test a new seatbelt knowing he might be injured or killed. But with a safety team and medical help at the ready. Or do we install the new untested seatbelts on city buses (but on only half the seats) and wait for an accident that might kill or injure dozens of unsuspecting passengers? To my mind, we should let the volunteer(s) test and try to prevent “the buses” from crashing as much as possible in the meantime.

    • Your Comment is great. I wish the doctor had told us why the conventional testing can take place by the same point in time, that seems impossible.

    • Having heard some of the discussions, I think I can answer. Many of the bioethicists willing to consider HCT are only willing to do so with many measures in place to make it as safe as possible for the participants and as accurate to assess the results as possible. That starts with carefully manufacturing pure forms of the virus (with no other contagions) and then going through careful dosing trials (currently being done *one* person at a time serially) to see what is an appropriate amount of infectious agent to apply. Only when that is figured out would you then be able to give it to a cohort and feel that the results that you are getting can be interpreted accurately. And those dosing trials take months. So, right now, even 1DaySooner is only expecting that challenge trials have the potential to replace Phase III trials and save just a few months.

      I happen to think that is 99% rubbish. We should put all the cohorts on a cruise ship (including a volunteer crew of young healthy individuals who will be guaranteed to be in vaccine groups), get them vaccinated, wait until there are immune responses, then bring on some (young and otherwise healthy) infected individuals. Let everyone party like it’s 1999. If a vaccine is a rock star (protecting more than 80% from infection), we would be able to identify it by those means. If it is only marginally more effective than the placebo, we would need to do more rigorous testing (which could be going on simultaneously).

    • I don’t think Dr. Rosenblatt is concerned with getting Moderna “morally off the hook.” I think he’s concerned with getting them legally off the hook.

      Every one of the subjects in the placebo arm of the trial could get covid-19 and half of them could die, but Moderna would have zero legal responsibility and no public-relations repercussions. Likewise 100k people could die waiting for this vaccine and Moderna would be completely legally and ethically “off the hook.” But if one single challenge volunteer died, Moderna could potentially be sued and it would certainly be a PR disaster for them. (Not to mention that nobody would buy their vaccine.) So I think Dr. Rosenblatt is a lot more concerned with money than ethics.

  • Well put. In engineering we have a maxim: test like you fly. If you want to test a system or component, for a mission critical application, you need to get it into conditions that look like the conditions it will be used in. For example, if you build a new type of electric car, while it is great to take it for test drives on a track, you had better also subject it to street driving with non-professional drivers.

    Human challenge trials are a test-track driving with professional drivers. The viral dose they get needs to be carefully controlled and will never cover the wide variation in loads experienced in the wild. The population of volunteers, as noted, does not represent the population who will be vaccinated. Etc.

    A randomized, double blind controlled clinical trial, as described is ‘test like you fly’ engineering. Once the safety of the vaccine is assessed, it can then be administered to such a wide population as to encompass all the folks who will need it, young, old, healthy, sickly. Then, all those volunteers, will be subject to real world flight conditions. They will be everyone from nurses in hospital wards being attacked by billions of virus particles, bus drivers being sneezed on my passengers, to recluse fine artists who see no one but the delivery man. Real world test conditions, on a large scale.

    Test like you fly.

    • You are making a number of assumptions that don’t need to be made.

      A challenge trial could involve people across demographics. A first one would probably only involve young, healthy subjects, but a second one testing a “rock star” from the first could involve older subjects with some comorbidities (like me), and a third one could expand even further. There will never be a lack of volunteers.

      A challenge trial does not need to involve every person getting a precise dose of the infectious agent. You could put 1000 participants on a cruise ship testing four vaccines (200 for each with a placebo group) and then have 20 infected people come aboard and mix, just like the Diamond Princess. Or you could simply have multiple dose levels of the infectious agent.

      The “real world test conditions” of a Phase 3 trial take an enormous number of participants and a lot of time (typically a year or more), especially if there is little community transmission. And you literally do not know if people who arrive at the end of it uninfected *ever* encountered the virus. You are hoping that the percentage of people in the control group who encountered the virus at various viral load levels matches the test groups well enough that your statistical inferences are valid.

    • Rob MacDonald:
      I do not think your “test like you fly” maxim applies to this situation.
      First off, you are comparing the chaotic real world of human error and unforeseen circumstances with the very very complex, but typically highly, highly ordered world of the immune system. I think they are not comparable in this way.
      In either type of testing, you give the volunteer a trial vaccine – so that is the same – and then you test for antibodies – that is the same- then in one case you watch and wait, in another you dose with virus.
      The fact the volunteer being watched for infection gets the virus in a different way, not via injection, but in his mouth or eyes or nose of lungs – is not thought to make a difference, BUT, if this was a concern, he could be sprayed directly in the face with it. A lot more dangerous for the researchers than injection, but doable with fairly high safety.
      Trying to start an infection through a natural route and watching the progress of it might give researchers more information about immune response, but nearly all the vaccinations we are given are given by injection. There seems to be no question it is a good way to confer immunity to all routes of infection in dozens of diseases, it already is used successfully.
      But again, test by spraying virus in the places it goes when people get natually infected, and you eliminate that concern.

  • The essential difference between the history and the present is an individual expressing his/her/zhe right to choose whether to be involved or not. It is the responsibility of the tester to be as upfront and honest as possible as to the potential risks. It is up to the testee to understand and accept those risks.

    • And that will undoubtedly include statements like, “There may risks that are not yet identified and could be very nasty.” And volunteers already know that and are accepting the risk.

  • Gosh, interesting perspective. Darn I’m probably dense but I don’t understand. I like that Dr. Rosenblatt is getting out another take on all this (which is just plain complicated, and that’s just the way it is), but shouldn’t the title have been something like “Challenge Trials – More Viewpoints for the Courageous Volunteers?”

    Just my unasked for 2 cents…thanks.

  • Young vaccine challenge volunteers would have an incentive to fully vitamin up to prepare for the virus challenge. This could represent a different safety profile compared to the general public.

    • Vitamins would have very little impact on whether you get infected in the presence of a significant amount of virus. Perhaps they help in dealing with the symptoms and fighting off the infection, but not the initial infection itself.

  • I have to agree with the people who said the author did not really make his case very well. I can not think of much to add, except:

    Allowing human challenge testing does not mean all precautions must be thrown out.

    One can easily imagine, to test the vaccine candidate for safety, a large number of test animals are given the vaccine right before humans are, and those same animals are inoculated with the virus before the humans. And the humans are tested for their production of neutralizing antibodies before being inoculated with virus.

    And, since you are going to infect all the human test subjects, is there a neeed for double-blind studies, where human volunteers are given a placebo vaccine, then infected with real virus? It would seem to me that is not necessary where everyone is getting a dose of virus presumed to infect.

    These may be the wrong protocols – the point is, safety protocols can still be used with challenge testing, they are not all automatically thrown out the window.

    • In general, in vitro and animal studies will have been completed before challenge trials. Right now, there isn’t even an active consideration about doing challenge trials prior to Phase 3, which is why there is only talk of shaving off months, rather than more than a year. Personally, I think as soon as a virus is ready for Phase 1 human trials, HCT should be considered, but the mindset has not shifted there yet.

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