Deliberate Dysentery: Q&A about Human Challenge Trials

post by Niko_McCarty (niko-2) · 2024-01-21T19:05:35.754Z · LW · GW · 1 comments

This is a link post for https://www.asimov.press/p/human-challenge-trials

Contents

  Introduction
  Interview
    Participation
    Successes
    Safety and Risks
    Economics
    Conclusions
  Footnotes
None
1 comment

Introduction

The intentional infection of human beings with pathogens under study has been going on for centuries. In 1796, an English physician named Edward Jenner inoculated an 8-year-old boy against smallpox with cowpox lesions he retrieved from the hands of a dairymaid. Today, refined versions of these human challenge studies have become standard practice in testing vaccines for vector-borne diseases (e.g., yellow fever, malaria, and dengue), evaluating new drugs or treatments, and studying pathogenesis, the process by which a disease develops. 

In the centuries since Jenner’s experiments, scientists have developed a microbiological understanding of infectious diseases, along with methods to safely and reliably induce them. Human challenge trials were an indispensable part of the development of the malaria vaccine, R21/Matrix-M, endorsed by the World Health Organization last October. That particular vaccine is expected to save millions of lives. 

But for all of their benefits, human challenge trials have their drawbacks. Beyond how they highlight that the vast majority of vaccine candidates fail, challenge trials are difficult to recruit for, participants are often underpaid, and their overall impact is hard to quantify.

The following is an interview with Jake Eberts, communications director at 1Day Sooner, a non-profit that advocates for people’s right to voluntarily participate in human challenge studies. Jake himself has participated in both Zika and Shigella challenge trials. 

This interview has been edited for length and clarity.

Interview

Asimov Press: Challenge trials date back hundreds of years, but have become much more common in the past several decades. A 2022 survey identified 284 human challenge trials that have been conducted since 1980. The number of challenge trials almost doubled from the 2000s to the 2010s. Why are challenge trials becoming more popular?

Jake Eberts: I would credit their rising popularity to two things: ethical reforms and perhaps a snowball effect as they became established for certain diseases like malaria. The ethics reforms in the United States came after a syphilis study in African-American men in Tuskegee between 1932 and 1972 caused widespread backlash. Scientists studied black men infected with syphilis for several decades while withholding known treatments. That then led to the Belmont Report, in 1979, which laid out ethical guidelines for working with human subjects. It introduced concepts like informed consent and risk/benefit analysis for clinical studies. Before then, there were horrible human rights abuses going on, including within human challenge studies.¹

I would also credit the uptick to the development of really solid challenge models that helped demonstrate human challenges can indeed be done safely. A lot of work was done to figure this out for malaria in the 1970s and 1980s in the U.S. and Europe. When those studies showed that challenge trials could be ethical, safe, effective, and useful, they became more enticing and doable for other diseases.²

 

AP: A news story in Nature about your organization, 1Day Sooner, discussed some recent challenge trials involving the hepatitis C virus. It sounded like those trials were initially considered to be too dangerous, but that circumstances changed. How are disease targets selected for challenge trials?

JE: When doing a challenge study, you want to balance scientific utility with risks to participants. We wouldn't do a challenge trial for Ebola, because the disease is extremely severe, and there are currently no licensed treatments or vaccines. You cando a challenge trial with deadly diseases, but you need a “rescue therapy.” Challenge studies are generally restricted to diseases that are treatable or self-limiting and don't pose significant risks of long-term complications.

With hepatitis C, what changed within the last 10 years was the development of direct-acting antivirals, or DAAs, which are packaged into pills that you can take once a day for a few months. Hepatitis C used to be really difficult to treat, and those treatments had high failure rates, but DAAs revolutionized the field. Hepatitis C was unthinkable for challenge trials beforehand, because the condition would have been, for at least some participants, chronic and incurable. Now, we have upwards of 98 or 99 percent cure rates in some cases. If the first round treatment fails, you can just try a different type of DAA, because there are several well-tolerated options.

So when we talk about selection, we ask: Is there a bottleneck in vaccine development or treatment development? Is that something that a challenge study or challenge model could fix? And if so, could you do that ethically without causing undue harm to participants? 

AP: It’s possible that a future pandemic will be caused by another coronavirus, and so there are a lot of ongoing efforts to make all-in-one vaccines that protect against the SARS-like betacoronavirus. Do human challenge trials fit into efforts to prevent future pandemics, or do they mostly respond to the needs of the moment? 

JE: They should absolutely fit into efforts like that. This is what my organization, 1Day Sooner, thinks is incredibly important. There exist what are known as “priority pathogens” and high-pandemic-potential pathogens. These are families of viruses and bacteria that we know are dangerous. The Coalition for Epidemic Preparedness Innovations, CEPI, maintains a priority diseases list. People are well aware that coronaviruses have a strong tendency to cause scary outbreaks; there are MERS, SARS-COV-1, SARS-CoV-2, and so on. Experts predicted that a pandemic would be caused by a transmissible coronavirus before it actually happened. 

Challenge studies have a role here. If scientists wanted to devise a broad-spectrum influenza vaccine or a broad-spectrum coronavirus vaccine, it would be useful right now to be doing human challenge studies in distantly related strains of those diseases. Ideally, you could take a potential vaccine and see if it can work against the common cold coronavirus, SARS-CoV-2, Delta variant, Omicron variant, or Wuhan variant. If it can, that’s a good indicator that the vaccine can prevent disease from many coronavirus strains. So yes, challenge trials that focus on priority pathogens absolutely contribute to biosecurity and pandemic preparedness. 

AP: It seems like you would ideally do both—focus on testing treatments or vaccines that currently exist and then also look forward to novel pathogens to intercept them before they get bad. Is there a way to think about prioritization, or do we just have to triage pathogens after they appear?

JE: In a perfect world, you'd be focusing on both. In terms of triage, human challenge studies aren't enormously expensive, but they can be demanding. When setting up a new challenge trial, you have to characterize the strain of the virus, bacteria or parasite and that's technically complicated. This is in addition to the regulatory and bureaucratic hurdles that have to be jumped through when you're deliberately infecting someone with a pathogen.

For example, the United States F.D.A. treats a new challenge agent—the standardized infectious sample—like it’s a new drug. A challenge agent has to be approved under an IND, an Investigational New Drug application, which assesses it for purity, potency, and manufacturing methods. The challenge agent also has to be produced under very stringent protocols. The European Medicines Agency (EMA) is similar in this regard, although interestingly, that’s not the case in the United Kingdom, where regulators are not so directly involved in assessing a challenge study beforehand.

Ultimately, I don't think that they are mutually exclusive. I think there is plenty of space to do challenge studies for diseases that have a high burden right now and then also as part of biosecurity and pancoronavirus programs in the future.

Participation

AP: Before this interview, you mentioned that the first challenge trial you participated in was to study Shigella. What is Shigella and how pernicious is it?

JE: Shigella is a family of bacteria that can lead to dysentery. They cause gastroenteric infections and, in severe cases, can kill people. It is a tricky little bacteria to treat because there are many different serotypes, or distinct variants of the bacteria. Four species of Shigella are of primary concern when it comes to human infection. Of those, Shigella flexneri is a species that disproportionately affects the developing world and alone has 19 serotypes. That makes it difficult to develop a vaccine.

Shigella is treatable with antibiotics, but there's been an emergence of antimicrobial-resistant strains. In most cases, the burden of Shigella infection falls disproportionately on the very young and old. There are high death rates among those groups compared to the general population. And people who recover after a severe infection, particularly children, often have lasting developmental effects.

In my experience, Shigella just sucks the energy out of you for however long you're sick, and I was pretty fortunate. I had world-class medical treatment and immediate access to the specific antibiotic that they knew would work, but I've had friends who had Shigella from traveling, and they got knocked out for like a week or more because it can be just an awful disease. It kills upwards of (and the estimates vary) close to a quarter of a million people per year, mostly in the developing world.³

AP: That sounds awful. What was the purpose of the particular study you participated in? 

JE: The study I was in was a straightforward challenge trial to test a vaccine. The vaccine was called SF2A-TT15 and it was developed by Institut Pasteur in France. We got two vaccinations with this experimental vaccine that had already undergone phase 1 safety testing. And then, a month or two later, we went to the inpatient unit of a hospital in Baltimore and drank a shot glass of the Shigella bacteria.

Volunteers were divided into the placebo-control and active vaccine groups. My cohort had a little more than a dozen people. There are multiple randomized cohorts, with blind assignment of the vaccine or placebo. There were recruitment difficulties that delayed the study for a while. On day one, at least one person who had signed up tested positive for COVID and had to drop out. You can't have someone in there who's sick with anything else because that messes up the study. 

I'm not sure what happened with that trial. It’s been more than a year-and-a-half since I’ve heard anything, so it’s possible they nixed the study or are writing a paper that I don’t know about.

AP: How often does that happen? I mean where something happens and the data ends up being not that useful?

JE: Well, that's kind of the whole point. If a challenge trial runs three or four cohorts and nobody's protected from the disease, then the data safety monitoring board is probably going to be like, “Look, this is probably an uphill battle and there's no point in continuing.” And that’s a good thing. Most vaccines fail. The number of vaccines that make it out of phase 2 is really small. It's extremely difficult to make a vaccine.

The challenge method is a less costly way to figure out that something is going to fail before you give a medicine or vaccine to hundreds and hundreds of people and track them across time. There's a really good example of this from the 1990s.

A challenge trial for Shigella was conducted as a precursor for a traditional clinical trial with soldiers in the Israeli military. The challenge trial showed that the vaccine failed, but the study designers continued with the larger study anyway. What happened was that, out of 1,300 military members, none of them got Shigella naturally. So they spent an immense amount of time and money giving this experimental vaccine to 1,300 people and nothing happened. They didn't learn anything from that. So yes—failure is pretty common.

Successes

AP: That Nature news story I mentioned had a quote from Josh Morrison, the co-founder of 1Day Sooner. He said, “You know what keeps me up at night? I don't yet feel like we've had a significant win.” What did he mean by that?

JE: What Josh means is that we were lucky that the COVID challenge trials were not necessary to develop the vaccines.⁴ We got vaccines, and the field studies were done in record time, which was fantastic. Operation Warp Speed put close to $20 billion into not even a dozen vaccine candidates.

It wasn’t a given that the mRNA vaccines were going to work as spectacularly well as they did. They were based on an unproven technology and could have turned out to be duds. We could have had a world where the vaccines had crappy efficacy, like 30 or 40 percent, right? We're incredibly lucky that that did not happen.

But if it did, we would have been left with hundreds of vaccine candidates just sitting around and rapidly depleting resources and we would have needed to triage them. Having a challenge model up and running that allows you to test the efficacy of these vaccines would have been valuable. 

That's what Josh was getting at. I think there was still worthwhile information that came out of COVID challenge models, and there's plenty of future value, especially if we work on a broad-spectrum coronavirus family vaccine of some sort. 

AP: Human challenge trials supported the F.D.A. licensure of a cholera vaccine in 2016, established correlates of protection for influenza that same year, and helped accelerate approval of paratyphoid vaccines in 2019. Are there other kinds of concrete cases where there’ve been clear successes? 

JE: Walter Reed's yellow fever experiments from 1900 offer a great early example. These were challenge studies done to show that mosquitoes transmit yellow fever, which was groundbreaking for the time and helped radically alter the way we treat that disease. 

Walter Reed and his team found that when you expose healthy volunteers to the mosquitoes that have fed on the blood of someone in the community affected with yellow fever, they get yellow fever. That was a pretty slam dunk “this is the cause of infection,” which was up for dispute at that time. A few people died in those early challenge trials, though, including a nurse named Clara Maass, who was challenged multiple times. Again, we wouldn’t run a challenge trial today for a disease that could reasonably kill someone, but this is an example where a challenge trial helped discover something important. 

It’s difficult to quantify clear successes from human challenge trials. When a vaccine fails, that can have downstream effects on how other researchers in the field approach their own vaccine development, and how funding gets moved around. But it's hard to find the counterfactual. If a Shigella vaccine fails, researchers save a lot of money by not testing it in the field and having it fail there. Or the knowledge that a vaccine is difficult to test in the field would never have allowed it to be developed in the first place. 

Hepatitis C is a good example. The making of a hepatitis C vaccine has stagnated because the only way to test it is among people who inject drugs. That’s the only population that is naturally exposed to hepatitis C and has a high incidence of the disease. So you have to do a field study. People are hesitant to do this because it's not a particularly flashy disease to research, nor is this population the focus of major pharmaceutical companies. So if you're a researcher, you can pour your heart and soul into a hepatitis C vaccine, and it probably won't ever get tested. The economics and circumstances have to line up and success is never guaranteed.

But sometimes a challenge trial leads to rapid success. The malaria R21 vaccine was tested in challenge trials and will probably save hundreds of thousands, if not millions, of lives in the long run.

Safety and Risks

AP: Do trial participants have a reasonable expectation of safety? What are some of the concerns when it comes to risk-benefit trade-off? 

JE: Past results don't predict future returns, but studies that go forward must have strong safety profiles. In some cases, I’d argue that a malaria challenge trial is safer than a typical oncology phase 1 drug trial, where you're taking people who don't have cancer and testing the safety of a drug that has maybe been tested in mice but has never been used in humans. 

There have been deaths in phase 1 medical and drug research among healthy participants. But there have been no deaths in human challenge studies in at least four decades. That's not coincidental. When we're doing a human challenge study, it is with a well-characterized virus or pathogen. Still, you should never trivialize the risks from being infected with a disease.

An adverse event is “any untoward medical occurrence" associated with the challenge. Severe adverse events are defined differently across studies, but are typically not life-threatening and don't require hospitalization. F.D.A. criteria includes adverse events that result in death, hospitalization, disability, or permanent damage.

Even at the edge of the Overton window, when it comes to what is an acceptable challenge trial, such as for COVID, we were talking about challenge trials among people who are under the age of 30, and didn’t have asthma or other risk factors. You're stacking the deck to make sure that a challenge trial is safe for people, which can actually cause other problems. You're not using people who look like the day-to-day person who's infected and who would be protected by a vaccine. Instead, you're using an idealized, healthy person who is not going to necessarily have the same sort of immunological responses to a disease or a vaccine that people in target populations would. So that's a drawback. 

But overall, the track record for the past 40 years, since the revolution in bioethics and the imposition of modern ethical controls on human subject research, suggests that the risk profile for challenge trials is often much lower than other acts of medical altruism, such as kidney donation.⁵

AP: Who decides your risk level? How much of it is you saying “Here's what I think my risk is” as opposed to other bodies or regulatory agencies establishing your risk for you?

JE: It’s almost exclusively other bodies. The F.D.A. and institutional review boards at the respective research institutions have a say in this. 

Perception of risk also matters here, though. There's a recent paper out of Johns Hopkins that surveyed people who had done a phase 1 or 2 vaccine trial, or a challenge trial. And the survey results showed that participants' perception of risk went down after completing the trial.⁶

Ultimately, there's a lot of paternalism involved in setting acceptable risk parameters. I worry that paternalism makes things more difficult in general; it makes recruitment harder and limits the participation of people who would otherwise want to join.

AP: How do these external bodies think about the risk posed to people who are not directly participating?

JE: I have a pretty expansive view of volunteer autonomy, but that does not extend to those who don’t consent. Third-party protection is important, but you can't just imprison and detain people. So social trust has to be involved here. And it's in the interest of volunteers to cooperate, right? It's not in my interest to leave the dysentery ward with an active infection because that would suck for me.

There is an infamous example from the United Kingdom, though. Malaria human challenge trials are often done outpatient. Volunteers are infected with malaria, but then it takes five to seven days for the disease to become infectious. Starting on day six or seven, participants go to the clinic every morning for blood tests. If a test comes back positive, they call you in and have you start the treatment immediately.

But in 2010, this guy participating in a challenge trial in Oxford committed sexual assault and then ran from the law and was a fugitive, while participating in this study. He fled to the Netherlands, and the Oxford scientists were frantically calling him up because he could die without medical treatment. They even notified the police because he wasn't responding to their messages, like, “Sir, you have an active malaria infection, you need to show up.”

Personally, if I were trying to break the law, I would not do it during a human challenge trial because people worry about your location. But in terms of the protection of third parties, your interests align with the researchers as a participant. You want to receive treatment, and you don’t get paid if you leave early. I'm not aware of recent cases where someone just waltzed out with an active infection and caused an outbreak. 

AP: Does the virulence of the disease target inform the protocols? If it takes thousands of bacteria to get infected with Cholera whereas, for Shigella, it only takes a small number, are the challenge trial designers more lenient in their protocol design and oversight with one or the other?

JE: With shigella, as few as 10 live bacteria can cause an infection. The infectious dose for cholera is in the millions.⁷ However, I don't think that has a huge effect on these protocols. How infectious a disease is depends on a lot of factors. For the majority of challenge studies, you do have a system where it's pretty easy to say that once they leave the quarantine or isolation facility, as long as they follow study procedures, they're not going to be infectious to others.

The Zika studies are a notable exception. With Zika, we were kept inpatient for as long as we had it in our blood because mosquito-borne transmission is a concern. That's the primary way that Zika is spread. Rarely, it can be sexually transmitted. And so, there was a lot of debate about that back in 2017 and 2018, when they were considering these trials in the first place. We have to ensure compliance but can’t guarantee that a participant is always going to use barrier contraception.

So there's a downstream risk of infection of others. Even though the baseline risk of sexual transmission is pretty low, the study doesn’t surveil us or ask all of our sexual partners if we’re using condoms, so the risk is not zero.

Economics

AP:  How much are participants paid, and who sets the rate?

JE: I've never seen a challenge that pays more than $10,000 US dollars, including studies outside the US. It may have happened, but that would be rare. Most often we're talking mid-ish thousands, maybe as low as $2,000 or $3,000 for flu studies.

The highest I've seen in the United States is about $9,100 for a Shigella re-challengewhere they do the Shigella challenge twice.⁸ It includes two, 10-day inpatient stays that are spaced out, because they're trying to figure out what cross-protection there is with two different serotypes of the same bacteria.

But still, I think volunteers aren’t paid enough. Recruitment for challenge studies is really difficult, because you’re asking people to go into quarantine for a week or more. A Zika trial requires a 9-day quarantine.  But the big difficulty with recruitment is ipso facto a sign that payments are not high enough. At the end of the day, you're not trying to recruit people that have some obscure form of cancer or some rare disease, and therefore, really want to get the experimental treatment. You’re trying to recruit healthy people. 

Compensation rates are usually set by the investigators or study sponsors. Compensation tends to be arbitrary, even for the same disease and across time within the same institution. There's been a lot of hand-wringing and consternation about what constitutes fair payment. This raises a problem in the field of research ethics known as “undue inducement.” This is the idea that you can make an offer that is so enticing that it compromises someone’s ability to rationally assess risk, reward, and so on. That makes some sense. People do stupid crap for money all the time, and you wouldn't want someone to be doing that for something as risky and serious as a medical experiment, but it also suppresses wages.

AP: The Nature news piece put a number on the Zika trial that you just participated in. You were paid $4,875, is that correct?

JE: I was paid a little bit more because we had a “fun little bonus” involving mosquitos. They were trying to figure out if the dominant species of mosquito in Maryland poses a significant transmission risk.

They wanted to figure out if a mosquito that feeds on someone with high viral titer in their blood could transmit infection in Maryland or the Northeast United States. So they took this little cup that had 15 mosquitoes and mesh on the bottom, and we held it up to our arm for 15 minutes and let them bite us, which was super freaky and interesting.⁹

These were lab-raised mosquitoes, not just ones that were plucked out from the air, that could have some gross disease. Next, they take those mosquitoes and let them digest the blood. After that, entomologists involved in the study used something which they described to me as “basically a glorified Margarita shaker“ to turn them into a little pulp and which they then analyzed to see how infectious they were. 

I asked the investigator, if one mosquito out of 500 is infectious, is that an acceptably low level of risk to others?¹⁰ She told me that's a question for the biosecurity and biosafety folks. 

Long story short, I got paid 300 extra dollars…

AP: Are you typically paid more for standard clinical trials or challenge trials? 

JE: It’s arbitrary. In general, I think that challenge studies pay more, because you have to stay inpatient for a while, and so you need to compensate people for days that they are sacrificing their autonomy and freedom to stay in a glorified hospital wing.

Challenge studies in the United States are often done by universities or the National Institute of Health, and those organizations don’t respond to the same profit motives as a contract research organization or pharmaceutical company. I also had to pay taxes on my dysentery money, which is funny. 

AP: I feel like I would be indignant if I were forced to pay taxes on dysentery money. Is it cheaper to develop a drug or a vaccine through standard trials or challenge trials? 

JE: It depends on the disease. It's expensive to develop the model for a challenge trial because there is a lot of research required to determine the infectious dose of a specific pathogen and come up with an acceptable dose to infect volunteers. That's what my Zika study was for. And if I'm a pharmaceutical company, I don't get any profit out of designing a model to test a vaccine or medicine. I can't patent it and license the fact that it is safe and feasible to do a challenge study with disease sample X to my competitors.

You can find the news coverage that exists for the Zika model already. Several developers are really interested in being able to use this model because they've been sitting on a vaccine candidate basically since the end of the epidemic in the Western Hemisphere and have no way to test it. If you have that sitting on the shelves, you are probably thinking we need to find something to use it for. So the cost is often pretty opaque, and there are a lot of budgets that just don't get published. 

Overall, I hesitate to call challenge trials “a cost-saving mechanism” because that sounds like it's cutting corners, but it is financially de-risking clinical trials, which can cost millions of dollars.

Conclusions

AP: There are obviously ethical questions about transparency and payment. Is there anything else regarding the safety, ethicality, and effectiveness of human challenge trials that you want to speak to?

JE: In the United States, there isn’t a universal healthcare system. There are no laws requiring that clinical trials reimburse or compensate participants for injuries that result from a study. Even if I'm an insurer, and I don't know much about human challenge studies, I'm gonna look at this and think: “This is insane. We're gonna charge these study investigators a ridiculous premium because they're deliberately giving someone malaria.” The risk profile for a challenge trial is not zero, but it's pretty safe. Still, participants ought to be compensated for even the slight degree of risk that remains despite the best protocols. 

There’s also an issue of distributive justice. This is not only true for challenge trials, by the way. But evidence suggests that phase 1 medical research, where new drugs are first tested in humans, disproportionately falls on black and Hispanic people. 

Remember that survey I mentioned, from Johns Hopkins? It included responses from 152 people who had completed a clinical or challenge trial at that university. Of the respondents, 78 percent were Black and 42 percent had an income below $18,500 per year. If you assume that those respondents are representative of the wider population of people who have done these trials in Baltimore, then that suggests Hopkins is disproportionately recruiting people from historically marginalized groups for their trials. I don’t think that that is intentional at all, to be clear. Unfortunately, important, baseline medical research that does not benefit participants often falls on traditionally marginalized groups. That problem is closely linked to payment.

When you try to calibrate payment to be not unduly inducive, you create a price ceiling that selects for lower-income people. In the same way that we would never say it's progressive or protective to cap the salaries of construction workers because they're mostly working class and because they die on the job, it's ridiculous to argue that it is somehow in the interest of participants and vulnerable participants to have this “ethical” ceiling on their payment.

That's what is under-discussed: the serial underpayment of volunteers in medical studies can lead to unfair research burdens on some demographics, plus a lack of compensation for research-related injury, which I would argue is even more salient in drug trials where you can get pretty serious side effects.

AP: Who would you encourage to participate in human challenge trials? What is your pitch for them?

JE: I regularly harass my friends, “Hey, do you want to get malaria?” At this point, they all just laugh me off. The ones who are interested have already signed up for mailing lists, the rest of them are like, “Jake, you're insane.” I would say if you are interested in making a difference in the world and are, like me, bad at math, and have no hope of ever becoming a doctor or a vaccine developer who could directly save someone's life—just go for it—especially if you have an email job like mine, where you can work remotely. Just understand what you're getting into.

Often, the worst part is just the burden on your schedule and the productivity hit. Especially for diseases that aren't dysentery, those factors can be much worse than the actual sickness itself, in my opinion. 

My pitch would be—human challenge studies can have a really disproportionate effect on scientific advancement. And if you're lucky, you could be like my colleague, who was in the R21 malaria trial and they can say, “I directly was a small part of this vaccine that might go on and save millions and millions of lives.” That’s just extraordinarily cool.

Footnotes

1. Mentally disabled children institutionalized in a Staten Island school, called Willowbrook, were deliberately infected with viral hepatitis between the 1950s and 1970s.
2. Between 1971 and 2017, scientists at the University of Maryland infected at least 338 volunteers with malaria, none of whom “suffered an unplanned hospitalization” as a result of the study.
3. The World Health Organization (WHO) puts these numbers at 212k deaths a yearwhile the Center for Disease Control (CDC) places them at 600k annually.
4. 1Day Sooner was founded originally to advocate on behalf of people who wanted to be in COVID challenge trials.
5. Kidney donation is still generally considered to be low-risk: In one study of over 80,000 living kidney donors, death from surgery was 3.1 per 10,000 donors.
6. Before the study, 46 percent of participants thought it was “not at all risky.” After the study, that number increased to 73 percent.
7. The infectious dose of V. cholerae depends on the strain and person, but a dose between 100 million and 100 billion cells is required to produce consistent colonization in healthy, North American volunteers.
8. Oxford just posted one for up to £9,955 (~$12,625.83) but it was for three malaria challenges in one study.
9. This was done three times. The mosquito was held against the arm for 15 minutes each time.
10. The goal is to see how infectious this species of mosquito common in Maryland is after it feeds on us. If the answer is "not infectious at all," then the Zika challenge studies could maybe be done at least partially outpatient, as is the case with malaria challenge studies, since the risk to third party infection via mosquito would be minimal.

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