[Edit Nov 14 to add Daphne as a co-author given her help with the research; adding section on risk to future pregnancies | Edit Nov 15 updating in-person screening time period — resumes in Dec or Jan, per study sources]
(Or about getting malaria, or hepatitis C (see below), or another exciting disease in an artisanal, curated list of trials in the UK, Canada, and US by 1Day Sooner.)
Hi! My name is Jake. I got dysentery as part of a human challenge trial for a vaccine against Shigella, a group of bacteria that are the primary cause of dysentery globally. I quite literally sh*tposted through it on Twitter and earned fifteen minutes of Internet fame.
I now work for 1Day Sooner, which was founded as an advocacy group in early 2020 for Covid-19 human challenge trials. (Who knew dysentery could lead to a career change?) 1Day is also involved in a range of other things, including pandemic preparedness policy and getting hepatitis C challenge trials off the ground.
What I want to focus on right now is Zika. Specifically, I want to convince people assigned female at birth aged 18-40 in the DC-Baltimore/DMV area reading this post to take a few minutes to consider signing up for screening for the first-ever human challenge trial for Zika virus (ZIKV) at Johns Hopkins University in Baltimore.
Even if you fall outside that category, I figure this might be something interesting to ponder over, and probably less stressful than the cryptocurrency debacle that shall not be named.
1Day Sooner is not compensated in any way by the study/Hopkins for this, nor do I/we represent the study in any official sense. I happen to have become very fascinated by this one in particular because it represents how challenge trials can be used for pandemic prevention with comparatively few resources. This post is meant to inform you of the study with a bit more detail from an EA perspective, but does not supplant information provided by the study staff.
(If you’re a DMV male like me bummed you can’t take part, ask me about current or upcoming malaria vaccine and monoclonal antibody trials taking place at the University of Maryland — I'll be screening next week! If you’re not in the DMV or otherwise just can’t do anything for Zika or malaria, you can still sign up for our volunteer base and newsletter, which will help you keep tabs on future studies. Something we’re very excited about is the emerging push for hepatitis C challenge studies, see the link above.)
Zika is a mainly mosquito-borne disease that has been known since 1947 — The 2015-2016 western hemisphere epidemic showed that Zika could cause grave birth defects (congenital Zika syndrome, CZS) — The disease is very mild in adults at present
The Zika virus (ZIKV) was discovered in the Zika forest of Uganda in 1947, and a few years later, we learned it could cause what was universally assumed to be extremely mild disease in humans. The 2015-16 Zika epidemic that started in South America, and which was particularly severe in Brazil, proved otherwise. This is when it became clear that Zika was linked to horrific birth defects. Zika has since earned its place on the WHO priority pathogen list.
To briefly review the basics of Zika:
- The Zika virus is a flavivirus, in the same family as dengue fever, yellow fever, and Chikungunya, among others. Flaviviruses are RNA viruses, which generally lack genomic proofreading ability and are thus more prone to mutation.
- Zika infection sometimes causes Zika fever, though asymptomatic cases are very common. Zika fever is usually very, very mild, and direct deaths are extremely rare.
- Zika is much more of a concern if you are pregnant — in about 7% of infections during pregnancy, the virus infects a fetus and causes serious, even fatal, birth defects. These defects, which most frequently include microcephaly, are referred to as congenital Zika syndrome (CZS).
- Zika primarily spread through mosquitos, but can also be spread sexually, especially via semen. This trait makes it stand out among other related viruses like dengue fever, wherein sexual transmission appears to be much rarer.
Zika Bad, an Overview
The burden of Zika is serious, but far from a primary existential risk — There are several conceivable scenarios wherein ZIKV mutates and becomes much more dangerous — The nature of Zika makes targeted vaccination highly tractable — There is no vaccine or antiviral, nor advanced candidates
At present, the risk Zika poses to public health is significant, but lower than many other infectious diseases, primarily due to the very low death rate and the relatively low rate of CZS in infected pregnancies. CZS is tragic, to be sure — you can read the heart wrenching stories of the families raising some of the thousands of children with CZS in Brazil here — but the total number of cases due to the epidemic was relatively low, estimated in the low thousands. One review in 2021 estimated an average of anywhere from roughly 10,000 to 80,000 DALYs per year between 2010 and 2019, spiking with the 2015-16 epidemic and its aftermath.
At present, there is no approved antiviral for Zika, nor any clearly leading candidate in advanced trials. Rapid vaccination of people with childbearing potential/intent in a given area of an outbreak could be relatively straightforward and prevent most suffering caused by the disease, likely more so than an antiviral medication. Testing experimental medical products in pregnant volunteers is much more complicated ethically and legally.
There are several ways Zika could change and become significantly more concerning beyond its existing ability to cause birth defects and wreak havoc on local economies. Xia, Xie, Shan & Shi 2018 offers a useful outline of three hypotheses as to why Zika became more dangerous in the runup to the most recent epidemic, discussing mutations that apparently increase infectivity in mosquitos, increased neurovirulence in mouse fetal models, and increased immune evasion ability. A recent gain-of-function study (cue obligatory booing) demonstrated that a single mutation can lead to greatly increased infectivity and immune evasion in mice.
That Zika virus can be sexually transmitted is also concerning: while not thought to be common compared to mosquito transmission, one can imagine serial human sexual transmission chain of during an outbreak —without any intervening mosquitos — especially since so many infections are asymptomatic. Such a chain could give the virus the opportunity to adapt specifically to humans. A gain-of-function study (again, obligatory booooo) in 2021 demonstrated that adaptation happened very quickly in serial mouse-to-mouse transmission, and the virus became much more deadly.
Zika human challenge trials
Post-epidemic, Zika still circulates globally and is expected to return, at the very least because population immunity will begin to wane — In the US, human challenge trials (HCTs) were rejected, during the epidemic — HCTs are now the only feasible way to test vaccine candidate efficacy; field trials are impossible given the currently low transmission rates — An HCT at Johns Hopkins in Baltimore has since been approved, and is now recruiting
Human challenge trials were proposed in the US during the epidemic in 2016, but an ethics panel convened by the NIH rejected the proposal, causing a bit of a stir. (There’s a New York Times piece on it here — one NIH researcher called it “really insulting” and another leading flavivirus researcher said it “slammed the door on progress”.) Part of the reasoning was that the virus was circulating at high levels at the time, making large-scale field trials feasible.
But within a year, transmission of Zika had collapsed; field trials for vaccine candidates completely failed. Funding and interest for Zika vaccine research dried up as well. Yet it is generally believed that Zika will make a comeback, however, as immunity in particularly hard-hit areas naturally wanes, or as it finds new pockets of flavivirus-naive populations to infect.
So, to review: we have a disease with exceptionally low mortality rates in adults, but that can be devastating during pregnancy, to say nothing of the economic impacts. The disease is generally expected to return en force some day. It is also entirely possible that when it does, it will have evolved in ways that make it even dangerous. But we can’t test vaccines or treatments in the field right now.
In a perfect world, we’d have at least a few promising vaccine candidates lined up from human challenge trials. They could immediately be deployed among a population at the sign of the next outbreak, from which wider efficacy could be confirmed. Regrettably, we do not live in a perfect world.
The rejection of challenge trials in 2017 and the Covid-19 pandemic mean that we are much further behind. But rejoice! The first ever challenge study for Zika is now recruiting at Johns Hopkins University. That’s where you come in, altruistically minded female reader in the Baltimore-DC area. I know you’re thrilled.
The Johns Hopkins Trials, CIR 316
The trial is a dosing trial, a prerequisite for any future vaccine efficacy trials using the two strains to be tested — 16 day inpatient, $5,525 total compensation — At least some, if not many or most in a given cohort will not have a noticeable infection
(Pre-screening survey and contact form are here; the ClinicalTrials.gov summary record is here.) Screening resumes in the next month or so, I'm told, so submit your info and watch out for an email or call.
Before a vaccine-testing challenge trial is conducted, you need to know how much of the pathogen should be given. Use too much, and you could make a cohort abnormally and dangerously sick; too little, and no one might get infected at all. Thus, the prerequisite for vaccine challenge trials is a dosing challenge trial, wherein small cohorts are challenged with increasingly large volumes of the pathogen until the Goldilocks zone is reached.
The Johns Hopkins trial is a dosing trial (also called a characterization trial); no vaccine is being tested. Volunteers will be challenged with one of two strains of the virus, respectively isolated in Brazil (ZIKV-SJRP/2016-184) and Nicaragua (ZIKV-Nicaragua/2016).
It is not a stretch to say that participation in the study represents advancing vaccine development in a very direct way, because this study is a prerequisite for further vaccine challenge trials.
Some other details:
- Per the study guidelines, volunteers will be “ZIKV and DENV [dengue virus]-naïve female subjects, 18 - 40 years of age” (because seminal transmission is perhaps possible several months after infection). 1Day Sooner reached out to the study staff and confirmed that e.g. trans men would also be eligible; gender identity is not relevant.
- There are 2-3 screening visits, one 16 day inpatient stay (currently slated to begin mid-January 2023) and 11 outpatient follow up visits. Volunteers are released from the inpatient stay only if virus levels in the blood drop below a certain threshold. This, combined with the fact that the study will take place in Baltimore during the winter (no mosquitos), minimizes the risk of transmission to others. I'm told they'll also give you mosquito repellant when you leave. Fun souvenir!
- Volunteers can't travel to a Zika- or dengue-endemic area (most tropical regions) during the study.
- Full eligibility criteria can be found at the ClinicalTrials.gov listing.
- The inpatient stay happens at a dedicated CIR facility within the Johns Hopkins Bayview Medical Center in Baltimore which includes a small fitness room and various other amenities. All meals are provided by staff. No visitors allowed, because it's, y'know, an infectious disease quarantine facility.
Risk/Benefit Calculus for You
Risk of serious illness or death extremely minimal, risk of severe discomfort relatively low — Time commitment is onerous, particularly the 16-day inpatient stay
The only thing you get directly from this is $5,525 in compensation, provided you fully complete the study. You also get to seem like a badass, which is a nice perk.
Zika infection itself will likely not be extremely unpleasant, as detailed below, but the demands of the trial are not trivial. Deliberately contracting a disease necessarily entails risk, however, so it would be dishonest to say “there is a 100% guarantee you will be totally fine the entire time.”
The following is based on 1Day Sooner research and our communications with study staff, though nothing here should be interpreted as official. If you choose to throw your hat in the ring, you’ll be called by study staff, who will ask questions to establish you are eligible, send even more detailed information on the study and schedule, and answer questions you might have. Again, I am not a part of the study, and 1Day Sooner is not a representative of Johns Hopkins or this study in any way.
Zika fever risks
If one develops full Zika fever, a sometimes itchy rash is the most common symptom. These symptoms are generally mild and usually last 2–7 days. A systematic review article in 2021 gave the following as the most common symptoms of symptomatic Zika fever (Halani et al. 2021):
- Exanthema (rash) in 89% of symptomatic cases
- Arthralgia (joint pain), 63%
- Fever, 62%
- Conjunctivitis (“pink eye,” inflammation of the eye), 45%
- Myalgia (muscle pain), 48%
- Headache, 46%
- Diarrhea, 13%
Note that most cases are asymptomatic, however. Evidence quality is not great (because counting the true number of cases when so many are asymptomatic is hard) but the rate of symptomatic infection may be as low as about 20%.
Each randomized, double-blind cohort in this trial will involve 14 people, 4 of whom will receive a placebo challenge agent, so it is possible that you would not actually be exposed to Zika at all. Also, a given cohort may have insufficient volume of ZIKV for infection altogether, given the nature of a dosing study.
All in all, then, a cohort might expect a handful of people to display symptoms, if the cohort is challenged with an adequate dose of the virus.
Death due to Zika fever — miniscule risk. A systematic review in 2021 found a Zika fever case fatality rate of 2.3 per 100,000, and a 2019 systematic review found a rate of 2.0 per 100,000. The majority of deaths occurred in the elderly or those with significant comorbidities. No one over the age of 40 is eligible for the Johns Hopkins study, and those with conditions that would or would likely make them more at risk for complications (e.g. HIV infection, history of neurological conditions) are excluded. A complete list of these conditions are under "Exclusion criteria" in the ClinicalTrials.gov record. Staff will go over these criteria with you and also run some tests to establish you are healthy enough for the trial before enrolling you.
Congenital Zika Syndrome — extremely low risk. The study requires that you agree to two forms of birth control if you are of childbearing potential, e.g., agreement to use a condom plus use of an IUD or hormonal birth control. For exclusively homosexual females, only one form of birth control is required. If you do get pregnant, there is approximately a 7% chance that the fetus is born with CZS. The study will conduct pregnancy tests prior to enrollment.
Guillain-Barré Syndrome — extremely low risk. Zika has been associated with neurological disorders, primarily Guillain-Barré, post-infection. GBS is an autoimmune disorder affecting nerve cells, causing muscle weakness, and in the most severe cases, paralysis or death.
A 2018 review of previous outbreaks suggested that there are about 2 cases for every 10,000 Zika infections; the risk of GBS in general has been found to be lower in females and higher with age (but data was not robust enough to determine if this holds true for Zika-induced GBS). Noticeable GBS symptoms typically developed between 5 and 12 days after Zika infection symptoms arose.
Most people recover from GBS. A systematic review in 2020 found that approximately one-fifth of those with Zika-linked GBS required intensive care, including mechanical ventilation, and that the death rate was up to 4.6% (22 deaths out of 475 cases).
Other neurological conditions — extremely low risk. Zika has also been associated with cases of other neurological disorders besides GBS, primarily transverse myelitis and meningoencephalitis. These conditions affecting the central nervous system can be serious, but occur with even lesser frequency than Guillain-Barré Syndrome. I have been unable to ascertain a solid risk rate or death rate for these, probably due to the infrequency of these cases.
If you want to some day have biological children, don't worry. There is no evidence that women who have completely recovered from the virus have an elevated risk of adverse outcomes if they become pregnant. Zika harms the fetus by infecting nervous system cells and causing cell death during crucial stages of development. Current evidence does not indicate that previous infection alters fertility or poses a risk to future pregnancies.
Zika RNA can be detected in some bodily fluids for several weeks after infection, however. The US CDC thus recommends waiting two months post-infection before trying to become pregnant (see CDC) and the UK NHS recommends waiting three months (NHS). The study will periodically measure Zika levels in participants’ bodies for 90 days following infection. In other words, by the end of the study period, you'll be sure whether there's any Zika left in your blood.
Ultimately, the biggest cost to you may well be time and productivity; even if you do get symptoms, they might not be serious enough to interfere with remote work. It is certainly possible you find the environment productive in at least some way, though. According to a site staff member for hVivo, which ran early Covid-19 challenge trials in the UK, many Covid-19 challenge trial participants (who stayed in individual isolation rooms as opposed to dorm-like facilities) were able to take up those “little projects that in normal life you never get a chance to do” — like trying to learn an instrument, starting a book, or writing essays. Still, 16 days in the same place is a lot to ask, and you will need to take time out of your day to go to pre- and post-challenge appointments as well.
Zika is a bad disease for which we need a vaccine, and challenge trials will be critical in finding good vaccine candidates. While the life-saving is downstream, one can very reasonably say they'll have helped save lives by participating in the Hopkins trial.
Personally, I really love the idea of participation in challenge trials as a humanitarian, charitable act. Challenge trial recruitment is slow and can be quite the bottleneck in testing, and being able to claim even a tiny sliver of credit for a vaccine translates into substantial human life saved over the years. I think that’s pretty cool. Media tends to be fairly fascinated by challenge trials and speaking with participants, so a handful of EAs in a — for lack of a better word — exotic trial like this could create some very positive coverage of challenge trials and perhaps even EA as a movement.
Plus, you get paid. (Do note that while death is far from certain in this trial, taxes still are: income tax still applies to research compensation, unfortunately.)
We have one volunteer who has signed up for screening already, and a staff member, which is great! If you decide to sign up for screening, feel free to tell them 1Day Sooner sent you if asked, and please do send me a note (see my profile for contact details).
As discussed later in this post, a fairly unique (and concerning) feature of Zika is that it can be seminally transmitted for up to several months post-infection, which is unusual for arboviruses. This challenge study's eligibility criteria simply specifies females — the staff clarified when I asked that gender identity is not relevant; trans men are also eligible, because the relevant issue is seminal production.
Hoen et al. 2018, a systematic review: "Among pregnant women with symptomatic, PCR-confirmed ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants."
Blitvich, Magalhaes, Laredo-Tiscareño & Foy 2020.This article is in an MDPI journal, so caveats about quality apply here, but the article still seems useful as a general overview of sexual transmission of arboviruses (that is, viruses spread by arthropods).
There are at least 3,474 cases of microcephaly caused by Zika in Brazil between late 2015 and the end of 2017; CZS numbers are likely greater because not all manifest as microcephaly. Also, this does not take into account miscarriages that would not have occurred otherwise. See Fernandes et al. 2022 for analysis of CZS economic impact in Brazil and related statistics.
Puntasecca, King & LaBeaud 2021. These estimates are, again, annualized over that decade. The WHO/Global Burden of Disease report estimate a much lower burden for Zika in 2019, as the article notes (in the low hundreds of DALYs).
As the authors explain, each of these had been demonstrated to have occurred in at least some Asian strains of Zika (the lineage that caused the 2015-2016 epidemic). Strains of the more geographically isolated African lineages, concerningly, "were shown to have higher fitness and virulence in mosquitoes and mice than the Asian strains" in other studies. It is unclear why the African strains have not yet caused outbreaks of global concern yet.
One trial referenced frequently in the media at the time was for VRC-ZKADNA090-00-VP, a DNA vaccine. The trial involved more than 2000 people but garnered only three confirmed infections; no conclusions about efficacy could be drawn. See the "Number of Participants With Virologically Confirmed Cases of ZIKV (Part B Only)" table under the results tab here.
It is possible that in the future, other strains will be chosen as well, but that does not necessarily mean that these two strains will be useless. It is also possible that another Zika epidemic occurs before a promising vaccine candidate is developed. This would probably make field trials feasible again. Even so, if there is a well established Zika challenge model, field trials may well be preferred for initial efficacy testing, given that they are quicker and easier to run.
Haby, Pinart, Elias, Reveiz 2018, a meta-analysis if 23 studies covering over 11,000 subjects. The authors concluded that "82% of the population infected with Zika virus were asymptomatic" but stressed that the data issues mean we can't take these results at face value: "Better-quality research is needed, using standardized methods, to determine the true prevalence of asymptomatic Zika virus and whether it varies between populations or over time."
Per the US CDC on a page last updated in 2022: "Current evidence suggests that Zika infection prior to pregnancy would not pose a risk of birth defects to a future pregnancy."
No one working at 1Day Sooner is required or pushed to get some exotic disease as a condition of their employment, because that would be completely insane. But we're an enthusiastic lot, so many of us have or have tried to volunteer.
I like the idea of human challenge trials, but I think it's a very bad use of EA human capital.
I also think the risk of "long Zika" or ME/CFS is underestimated in your post. I don't know the incidence rate of it. I personally know one person with ME/CFS who got it from Dengue (I know a lot of people with ME/CFS though).
Some risk factors which would make me more strongly disencourage this, based on Long Covid and ME/CFS literature:
I would also not recommend a challenge trial for a disease without a cure/effective antivirals. I don't know about Zika antivirals. HCV has very effective antivirals with 90-95% efficacy though.
Hi! These are all valid concerns, and I'll note that many of them are covered in the study eligibility criteria (see NCT05123222). People are excluded if there is any "[e]vidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease", among many other factors.
The approx. 2.0 per 10,000 Guillain-Barré incidence estimate is based on the published scientific literature. The 2018 review (Romero, Delorey, Sjevar & Johansson 2018) covers outbreaks or sub-outbreaks in 11 places. Like I stated above, I was unable to find comprehensive estimates for other neurological conditions, which occur with lower frequency. If you have more recent estimates, I'd be happy to update.
Whether or not someone participates is, of course, up to them. I was able to get work done during my inpatient Shigellosis stay and enjoyed the experience, to the extent you can "enjoy" getting awful diarrhea. I don't think this is very much a waste of human capital for everyone — plenty of people may have downtime they're willing to donate to a cause. For Zika, the productivity loss is probably relatively minor (if you can work remotely) for reasons outlined in the post. I do not agree that it would be a "very bad use" of EA human capital, which I think is a pretty high bar.
Participation in any medical study involving exposure to a pathogen necessarily entails risk and no one should ever feel pressured to participate in any study, especially if they're worried about potential health consequences. I'll note that several trials are run even though there are no rescue treatments, e.g. Covid-19, in which 1Day Sooner has had several volunteers, and norovirus. It is often precisely because treatments are lackluster that these sort of trials are important. There have been no deaths in a human challenge trial to our knowledge since at least 1980 (Adams-Phipps et al. 2022, based on research 1Day Sooner commissioned) (this, of course, is not predictive of what happens in a Zika challenge trial, but does underscore that these trials are generally designed with participant safety as the foremost priority).
Incidentally I am the 1Day staff member who signed up for screening and can confirm that I'm unreasonably enthusiastic about this idea! Would be happy to explain my thought process to anyone else in the trial demographic who might be interested and would like to talk things through.
I'm interested in the malaria trials at UMD and other applicable ones for a 28 y/o male in the DMV.
One of my classmates recently completed the challenge trial for Zika at Hopkins and is happy to answer any questions if you have any :)
Reach out to me if you want her contact!