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.
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.
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.
Maybe someone can tell me if my theory is correct:
Another poster imputed bad motives to the author, protecting Moderna financially, from liability, but I do not think he necessarily has any bad motives.
Pretty much everyone in medicine is too conservative for this situation.
But, not pointing to the author or anyone else in particular – but to me, it seems like a prohibition on challenge testing – because there has to be liability legislation to protect the companies doing it, and effectively, the powers that be have prohibited it by making it impossible to get legal cover for it – it seems to me the prohibition GREATLY benefits “Big Pharma” – ie, the companies with the resources to do the Phase 1, 2, 3 the old fashioned way.
Some grad student in a lab might be able to cook up a vaccine, scalable, which would be much better than nothing for the next year at least – and, with enough volunteers, prove efficacy with a few dozen people by challenge testing -from what I read, this is totally plausible – but she can not afford any of the extremely expensive steps to get a vaccine approved under the current system.
So, only companies with big resources can get their product out – which means it is very much in the self interest of companies with vaccines in the pipeline not to let someone cut in front of them with challenge testing.
Is this incorrect? I really do not know anything about the pharmaceutical industry, so I do not pretend to know, but does anyone who does know the industry have comments?
I do feel certain of one thing – this has been talked about as a war – if this was really a war, like WW2, our response so far would have already lost it. There has been nothing like and all-in effort, damn red tape and previous conventions, to “win”.
That makes sense to me Steve White. I’m with you in terms of really wanting to understand this article, mainly why it was written?
Maybe I’m too naive, but any kind of big conspiracy thing never seems to be what it is. It’d be great if Dr Rosenblatt could talk a little more about all this (though wading into a blog might not be comfortable for him). If I had to guess, it might be more like wanting to state his thoughts as kind of an authority, even though he may not really even be so hard set on what he wrote? In other words, a tad of the publish or perish thing since he has kind of a pundit role (sorry Dr if I’m getting this wrong)?
What is not considered is that many will resort to self infection anyway as a way to return to normal. This is where science and the real word collide. Maybe they can work on a vaccine for suicide because if there isn’t progress to mitigate the virus the dark days of winter with further shutdowns will result in a catastrophic uptick in deaths of despair. They are being ignored by the media now because it doesn’t fit an agenda but have already ticked up significantly.
The TL;DR of this article:
Tens of thousands of volunteers have agreed to potentially self-sacrifice themselves to save the world from the worst of a catastrophic pandemic. But did they really agree to that? Do they really know how bad COVID-19 is? Does anyone know how bad it is? I mean we know COVID-19 is deadly but could it be even worse? What if COVID-19 brings you back to life in your grave years later and then kills you a second time? In the end we have to care for the hundreds of volunteers who will risk their lives ahead of the millions who will surely die if we don’t expedite a vaccine.
I tend to not want to get too harsh on someone writing a serious article… but that’s darn funny! And not to far off.
Hardy har! That’s really funny, but boy there’s no way that that’s what Dr Rosenblatt was really feeling when he wrote this!
I really would like to know though…really would like to try and put myself in his shoes about this!
I don’t think it’s too hard to empathize. Medical professionals get sued six ways from Sunday when they make mistakes, be they real or perceived. Sometimes, those settlements are in the billions of dollars (e.g., silicone implants). Sometimes, the most well-meaning of public health efforts go awry (the Swine Flu vaccine in the Ford years is often referenced). The world is full of quacks that promise miracle cures with no/very little basis in science (e.g., Covid-Organics). There are truly horrific examples of medicines released and used broadly that were later discovered to have serious side effects (e.g., Thalidomide). And there have been even more horrific examples of enormously unethical experimentation on humans (e.g., Tuskegee syphilis study and, of course, Nazis).
No one in the medical profession wants to add to that list, and there is a concern that some unlikely outcomes of HCT could. Tremendous safety protocols have been put in place over the years around all sort of medical trials, and it is understandable not to want to relax those out of fear.
I happen to think the potentially vast benefits far outweigh the almost certainly small risks. We are nearly certain that this virus is going to keep killing 100K/month even with our mitigations in place, and it would certainly be killing way more if we went back to “normal”, so we have the additional loss of life quality of shut down economies, which is devastating to many people, especially outside the rich countries. Thus far, all that we’ve learned about treating it has improved our chances to save someone from death by probably about 30% or so, so we still have dark months ahead of us.
On the other hand, the profile of volunteer for a first round of HCT tests probably has a 1 in ~3000 chance of dying from COVID, and an additional chance of a bad reaction to a vaccine. We can probably guess with some confidence that 99% of volunteers would skate through fine, 0.9% would require some mild hospitalization, and 0.1% might have some long-term negative effects, possibly including a few deaths. With proper framing to the public, I do not expect those outcomes would be harmful to the public’s perception of medical science and public health. And if they lead to finding a successful vaccine in record time, it could well stifle the objections of most anti-vaxxers for a time.
Thank you Patrick Dean Rusk! Hmm, the way you frame it (I’m summarizing it by calling it a certain kind of conservatism that’s part of the culture of the medical profession?) really helps! Really appreciate you laying that out.
Funny. I was about to respond with a TLDR of my own. IE “you can’t know every probable or possible outcome, so you can’t have informed consent” is really a pretty juvenile and risk adverse opinion. I wouldn’t want this guy in charge of my care. Life itself is a risk, and the longer your alive the riskier it gets. Eventually your number comes up.
Part of being an adult is the ability to weigh risk and information. Either people are adult enough to sign consent forms, own property, drink, drive cars, and go to prison or their not. If the person is legally an adult and can sign legal forms and the study provider is honest and open about what risks they know about and don’t know about (and “you might die” is a pretty honest and open statement) then its up to them to make that choice based on the information they have. If you always wait for the information to be 100% you’ll never move forward and never be first, just like if you jump in without any or enough information you’ll eventually get burned.
Its part of the title “adult”. Our modern world seems to forget that and try and nanny all of us.
Yeah Ben, I had that same twinge of “wait what about my own ablility to choose!” But in reading what Patrick Dean Rusk wrote, I think I can sort of see why Dr Rosenblatt wrote this they way he did? Of course he means well, as we all do…but maybe he’s just coming from a culture (i.e. the lawsuit heavy medical field but where there’s also a doctor-should-be-father-knows-best thing still lingering) that is not immediately easy for a non-doctor to understand? I dunno.