Human challenge trials deliberately expose participants to infection, in order to study diseases and test vaccines or treatments. They have been used for influenza, malaria, typhoid, dengue fever, and cholera. Researchers are exploring whether human challenge trials could support the development of vaccines and treatments for COVID-19.
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Superior, Wisconsin, USA
Romania
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USA
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Vestavia Hills, Alabama, USA
We do not have the manufacturing or supply chain capacity to produce the billions of vaccine doses needed across the globe with just one vaccine. Accelerating the development of just one additional safe and effective vaccine by even a couple of days could save thousands of lives.
Measuring the exact impact is difficult. It is currently uncertain how many people COVID-19 will affect worldwide and at what speed its impacts will be felt. Possible outcomes are shaped by interventions like social distancing, the capacity of health systems, potential drug treatments, and many other factors. A vaccine may come after the infection has peaked or once effective pharmaceutical treatments have blunted COVID-19’s impact. But it is clear that COVID-19 will continue to alter daily life until an effective vaccine is fully deployed.
While any estimate is deeply uncertain, to give a sense of the scale of a vaccine’s impact, suppose that daily confirmed COVID-19 deaths remain at July 2020 average of around 5,000 per day. If an additional vaccine could avert just 25% of these deaths, then speeding up vaccine development by:
Vox explains how COVID-19 human challenge trials would accelerate the vaccine development timeline (and interviews some 1Day Sooner volunteers in the process!).
Learn about three primary use cases of COVID-19 human challenge trials.
After a vaccine candidate is created in a lab, it is developed through a combination of pre-clinical evaluation and three phases of clinical trials that test its safety and efficacy. In traditional Phase III trials, participants receive the vaccine candidate or a placebo/active comparator, and efficacy is judged by comparing the prevalence of infection in the vaccine group and the placebo/comparator group, to test the hypothesis that significantly fewer participants in the vaccine group get infected.
In the context of COVID-19, after receiving a vaccine candidate, participants return to their normal daily lives to test the treatment under real world conditions. Since only a small proportion of these participants may encounter the disease, it may take a large number of participants and a many months for these trials to reveal differences between the vaccine and placebo groups.
Phase III trials can be both complex and slow. Many people are careful in this outbreak—by practicing self-isolation, for example—so it may take a very long time and a large number of subjects for a Phase 3 trial to produce statistically significant results.
Given the unprecedented urgency of the COVID-19 pandemic, regulators and researchers are likely to try somewhat unconventional methods to speed up this process, whether or not challenge trials are utilized. For example, Phase 3 trials may be conducted in high-risk populations—people more likely to be exposed to COVID-19, such as healthcare workers—to increase the ability to detect effectiveness in a smaller pool of subjects. In some cases, the Phase 1 and Phase 2 trials may be combined so the process moves more quickly.
If coronavirus human challenge trials (HCTs) are held, willing participants would receive the vaccine candidate and, once the vaccines takes effect, be deliberately exposed to live coronavirus.
Before conducting a challenge trial to test vaccines, scientists must understand the smallest dose of the coronavirus that causes infection. This characterization study starts by exposing a few participants to a very low viral dose. If a majority of those participants are infected, then a dose expansion phase occurs to test the dose in a total of about 20 people. If a majority of the initially dosed group are not infected, then a higher dose is tested among a few participants, and the process is repeated several times as needed.
The ability to observe participants closely and gather samples while tracing the progress of infection in real time, knowing exactly when they were infected and with what dose, and being able to follow up over a long period, would offer an unprecedented level of scientific and medical insight into an unfamiliar virus. HCTs can complement Phase III trials in six specific ways:
Backup option:
If none of the first generation candidates work, having a proven challenge model ready in January with significant biocontainment capacity lined up will be immensely valuable (i.e. save multiple months) on later options both by prioritizing which vaccine candidates to do safety testing in and by demonstrating efficacy. A recent report from the Center for Global Development indicated a 50% chance that no vaccine will have been proven safe and effective enough to be approved by a stringent regulator as of April, 2021
Prioritizing Second Generation Vaccines to Test in Large Trials:
If some of the first generation candidates work, the only path to market for the ~160 vaccine candidates not currently in or about to enter Phase III may be to demonstrate greater efficacy than the existing candidates in a challenge study. (Only candidates that generate strong immune responses would be tested with challenge studies). The second generation vaccines are important because: (1) they will be needed to vaccinate low and middle income countries, since (a) there will not be close to 16 billion doses of first generation candidates available in 2021 and (b) the 1st generation’s need for (i) a booster, (ii) injection, and (in some cases) (iii) subzero storage make distribution in the developing world challenging; on the other hand second generation vaccines might be orally delivered, avoid a booster, and have fewer cold-chain requirements; (2) second generation vaccines will likely be more effective and possibly with lower side effects than the first vaccines to make it through Phase III (so proving their value sooner is better).
Testing Second Generation Efficacy if Large Phase 3s Become Impractical:
If either (1) transmission declines post-vaccine in countries where large Phase IIIs are easy to conduct; or (2) it becomes difficult to gather sufficient research subjects in a world with an existing vaccine, challenge studies may be the only way to demonstrate efficacy. The Vaxchora cholera vaccine was approved for use in this way. The National Institutes of Health ACTIV Group wrote in July that challenge trials “might be able to accelerate development of later rounds of vaccine candidates.”
Test Treatments:
Testing treatments has been a very real problem, and challenge trials present a unique opportunity to test treatments in the early days of infection.
Correlates of Protection/Immunity Passports:
Though difficult to quantify, this might be the greatest value to be derived from challenge studies. If you can determine how to tell ahead of time if someone will be immune to COVID-19 (i.e. if a vaccine creates correlates of protection, you don't need to necessarily wait to test efficacy separately before deploying it). This may have particular value for proving effectiveness in high risk populations who are not part of the current vaccine studies. Notably, correlates of protection need to be established to have a well-grounded "immunity passport."
Duration of Immunity:
Challenge studies will also be key to studying how long immunity lasts (both from a vaccine and natural infection) and the extent to which infection by one strain is protective against another (likely quite high but still worth testing).
Altogether, there are scenarios in which the speed of HCTs and the precise data they provide are indispensable to the development of an effective and accessible COVID-19 vaccine, with thousands or even millions of lives spared (depending on the pandemic’s long-term trajectory).
At the same time, there are many legitimate concerns about and objections to HCTs. Click the button below to read about objections to COVID-19 challenge trials, 1Day Sooner’s reply, and links to more resources.
The evidence base for COVID-19 is developing rapidly, and risks have varied by location and access to medical care, so any estimates are unfortunately imprecise.
Several estimates have placed the infection fatality ratio (the proportion of deaths among all infected individuals) for young people at less than 1 in 10,000. In July, an article in Science puts the infection fatality ratio at at 1 in 20,000 for 20-29 year olds. A recent preprint meta-analysis of 111 studies by Levin et al. put the infection fatality ratio for people under the age of 34 even lower, at 1 in 25,000.
Anyone with a preexisting condition would also be excluded from a human challenge trial, which would further reduce the risk significantly. According to the CDC, 92% of COVID-19 hospitalizations involve a preexisting condition. So while the risks are significant, they are within a range we commonly accept in other circumstances. By comparison, the death rate in the U.S. is about 1 in 6,500 for childbirth and 1 in 3,000 for kidney donation.
Even if the risk of death among volunteers is rare, COVID-19 often causes severe illness among patients of all ages. It is not yet known whether the virus causes permanent damage to lungs or other organs. However a study looking at COVID-19 cases in the United States showed that 20.8% of patients aged 20–44 had severe disease which required hospitalization. 4.2% of this age group developed critical disease, which required admission to an intensive care unit (ICU) and included complications like novel coronavirus-infected pneumonia (NCIP), acute respiratory distress syndrome (ARDS), and kidney failure. Other severe complications that have been reported include cardiac injury, septic shock, and multi-organ failure.
Current literature about COVID-19 also indicates both cardiopulmonary and neurological long-term effects. Yet, it is too early to definitively say whether these issues are truly non-recoverable or whether these are the only long-term issues COVID-19 survivors will face. These risks likely vary by demographic, including age, pre-existing health level, age, and race/ethnicity. You can read more about the long-term risks of COVID-19 on our Research page.
Outcomes of COVID-19 disease in patients 20-44 years of age
Adapted from: Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69:343-346.
Disease Outcomes for COVID-19 Patients, United States
Adapted from data within: Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69:343-346.
If human challenge trials for COVID-19 were to occur, the risk of harm would be minimized to the extent possible by selecting people who are relatively young and who have no underlying health conditions.
Such a trial would also likely reduce unnecessary risk by aiming to enroll volunteers who are already likely to be exposed to COVID-19—either during the trial period or sometime afterwards. Unfortunately, many people will fit this description because they live in high-transmission areas, or do jobs involving contact with COVID-19 carriers (such as doctors and nurses).
Finally, study participants would be isolated in highly controlled environments under constant observation. If infection is detected, they would be provided with excellent medical treatment. Hopefully, pharmaceutical treatments will also be available by the time a study is conducted.
COVID-19’s infection fatality rate increases with age, according to data from Mainland China
Adapted from data within: Verity, R., Okell, L. C., Dorigatti, I., Winskill, P., Whittaker, C., Imai, N., Cuomo-Dannenburg, G., Thompson, H., Walker, P. G. T., Fu, H., Dighe, A., Griffin, J. T., Baguelin, M., Bhatia, S., Boonyasiri, A., Cori, A., Cucunubá, Z., FitzJohn, R., Gaythorpe, K., Ferguson, N. M. (2020). Estimates of the severity of coronavirus disease 2019: a model-based analysis. The Lancet Infectious Diseases, 0(0).
Scientists have been using human challenge trials to test the effectiveness of vaccines for hundreds of years. Below you will find a brief timeline of challenge trials that were instrumental in the development of vaccines for deadly infectious diseases.
However, 1Day Sooner is dedicated to learning from the failures of the past as well as its successes. While we feel a responsibility to support challenge trials if they are likely to save lives today, we also have a responsibility to offer that support ethically. 1Day Sooner recognizes that these trials are bound up in a history of medical testing that has often denied patients—particularly ones who are poor, female, or people of color—the right to informed consent. Edward Jenner’s experiment on James Phipps in 1796 is listed here, but the bibliography below and the work we will continue in the future will strive to expand our own understanding of these under-explored histories and make sure they inform our advocacy. If you’re interested in learning more about the history of human challenge trials, a bibliography of their history can be found here.
Moreover, mistreatment of trial participants in clinical research is not merely a thing of the past. Advocacy groups like AVAC and TAG are fighting to create structures to guarantee fully informed consent and ensure that trial participants are reimbursed lost wages and medical expenses. 1Day Sooner hopes to continue this fight in the context of challenge trials. As three 1Day volunteers recently argued in the South Africa Times, “any COVID-19 vaccine trial, especially a human challenge trial, must make informed consent an imperative. Researchers need to be entirely transparent about the risks of a trial to volunteers, and before a trial begins there should be virtually no doubt that volunteers understand those risks.”
The first-ever vaccine, for smallpox, was developed by deliberately exposing people to infection. Physician Edward Jenner created this early version of a vaccine in 1796 by taking samples from a cowpox sore and putting it into the skin of James Phipps—his gardener's eight-year-old son. Jenner then intentionally exposed Phipps to smallpox, but the child did not become infected. Jenner went on to vaccinate around 6,000 other people using the same technique and tested the effectiveness of his method by exposing them to smallpox. Two hundred years later, Jenner’s vaccine allowed us to eradicate smallpox from the global population.
The smallpox vaccine shows both the promise and pitfalls of human challenge research. Eradicating smallpox is one of humanity's greatest achievements, but how the first vaccine was developed—by exposing an eight-year-old boy to the disease—would in no way be considered ethically acceptable today.
Human challenge trials have progressed a great deal since their early origins and have played a key role in studying disease and developing vaccines and treatment for influenza, malaria, and cholera. They have also improved our understanding of typhoid and dengue fever.
The first well-described influenza challenge study was published in 1937 and involved the inhalation of a human influenza virus. Because only a small number of volunteers (20%) developed mild disease, this model was used across studies for many decades. These challenge studies allowed us to understand more about the human immune response to influenza and test preventative and therapeutic measures.
In the 1980s and 1990s the University of Virginia School of Medicine conducted challenge studies with influenza A and B which helped speed the development of oseltamivir (Tamiflu)— an antiviral medication that features on the World Health Organization’s List of Essential Medicines.
After the 2009 H1N1 pandemic, researchers at the National Institute of Health (NIH) began using human challenge models to investigate and develop countermeasures against influenza A. They began with a dose-finding study in 46 participants, which led to the development of a challenge virus. This virus was subsequently used to challenge participants who had received a broad-spectrum influenza vaccine candidate, FLU-v. The results of this challenge trial demonstrated the FLU-v vaccine was safe, and induced a long-lasting immune response.
In 1976 the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, began conducting challenge studies with cholera, which allowed scientists to realize that their leading vaccine candidate was not going to work. These studies also gave us a better understanding of effective immune responses and identified a new vaccine candidate. This candidate, known as Vaxchora, is the first vaccine approved by the US Food and Drug Administration (FDA) for prevention against cholera infection. The approval process relied heavily on the results of the cholera challenge studies conducted at NIAID.
Malaria challenge studies have played a key role in speeding up the development of malaria candidate vaccines for many years now and are routinely used in the United Kingdom, United States and the Netherlands to accelerate the process of vaccine testing. In these studies, healthy adult volunteers have either been exposed to the bites of infectious mosquitos or injected with the blood-stage of the malaria parasite, in a highly controlled environment. They are then monitored regularly for signs of infection and treated with antimalarial drugs if they develop a malaria infection. The malaria vaccine currently being deployed in three countries in Africa was developed using malaria challenge studies.
In 2011, the Centre for Clinical Vaccinology and Tropical Medicine in Oxford, United Kingdom, ran a human challenge trial which exposed forty-one adults to the pathogen that causes typhoid fever. After receiving the candidate vaccine, participants drank a solution containing increasing levels of bacteria and were closely monitored for two weeks. The vaccine tested in this trial is now recommended by the World Health Organisation’s Strategic Advisory Group of Experts for use on anyone over 6 months old who lives in a region where typhoid is common.
In June 2013, researchers at Johns Hopkins used a weakened version of dengue to challenge volunteers who had received a vaccine designed by NIAID. All of the volunteers on the NIAID vaccine remained healthy but all of the participants who received placebo developed symptoms of dengue fever. Based on these results, an institute in Brazil was able to begin a large-scale Phase 3 clinical trial that is scheduled to finish in August 2021. This model could also be used to check the effectiveness of other candidate vaccines early on in the process, which limits the risk of running larger but ultimately unsuccessful trials.
In 2016, researchers suggested using a human challenge study where healthy volunteers would be intentionally exposed to the Zika virus, which was a new and growing public health concern at the time. The plan was to use the study as an opportunity to understand the early stages of Zika infection and test whether vaccines would offer protection. The trial was supposed to run in the United States, using healthy volunteers who would not otherwise be exposed to Zika. However, two potential funders of the trial—the NIAID and the Walter Reed Army Institute of Research—had ethical concerns. An independent ethics committee of relevant experts offered an early ethical framework for the Zika trial and decided that Zika challenge studies could be ethically justified, but that it was too early to conduct one at the time. Their two main concerns were that (i) researchers did not have a good enough understanding of how the virus was transmitted, which meant it would be difficult to protect non-volunteers, and (ii) existing studies were looking at Zika so it was not clear whether a Zika challenge study was needed to speed up vaccine development.
Abstract: Recently, human challenge trials (HCTs) have been proposed as a means to accelerate the development of an effective SARS-CoV-2 vaccine. In this paper, we discuss the potential role for such studies in the current COVID-19 pandemic. First, we present three scenarios in which HCTs could be useful: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We go on to outline the practical limitations of HCTs in these scenarios. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be vastly beneficial and, thus, the option of using HCTs to accelerate COVID-19 vaccine development should be preserved. To this end, we recommend an immediate, coordinated effort by all stakeholders to (1) establish ethical and practical guidelines for the use of HCTs for COVID-19; (2) take the first steps toward an HCT, including preparing challenge virus under GMP and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs amid the evolving pandemic.
See full press gallery here.
Drs. William F. and Virginia Connolly Mitty Professor of Bioethics, Department of Population Studies, NYU Langone Health
Professor of Psychology and Neuroscience, Georgetown University
Ira W. DeCamp Professor of Bioethics in the University Center for Human Values, Princeton University
Frontier Markets Investment Advisor
Henry Rutgers Professor of Bioethics and Director of the Center for Population-Level Bioethics (CPLB), Rutgers University
Kathrine Robinson Everett Professor of Law, Duke University School of Law
Professor Emeritus of Pediatrics at the University of Pennsylvania and at the Wistar Institute.
Mary B. Saltonstall Professor of Population Ethics and Professor of Ethics and Population Health, Harvard University
Professor of Law & Philosophy at Duke University; Founding Director of Duke Science & Society, Chair of the Duke MA in Bioethics & Science Policy
The Lawson Family Charitable Fund
Associate Professor of Medicine and Acting Director, Hope Clinic, Emory Vaccine Center
Clinical Research Regulatory Counsel, Bass Berry & Sims PLC, Former General Counsel of St. Jude Children’s Research Hospital and Sidra Medicine
Professor of Epidemiology, Harvard University
Resident Scholar at the American Enterprise Institute
Co-Founder, Executive Director
Executive Director at Waitlist Zero
josh@1daysooner.org
Director of Clinical Research
Former Technical Officer at the WHO's Antimicrobial Resistance and Rapid Research and Innovations Cell for Covid-19
UK Petition Organizer
Cancer Biomedicine Undergraduate Student at UCL
alastair.fraserurquhart@1daysooner.org
Co-Founder
MHS in Infectious Disease Epidemiology Candidate at Johns Hopkins Bloomberg School of Public Health
Director of Research
Former Mass Care Branch Director, COVID-19 response Emergency Operations Center in Larimer County, Colorado; PhD in Molecular Biology; MS is in Cellular and Molecular Biology; former US Public Health Service Officer
research@1daysooner.org
Volunteer Organizer, Design Team
Digital Arts BA Candidate at the University of Witwatersrand
Director of Operations and Organizing
organizing@1daysooner.org
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Pharmacist and Clinical Research Professional
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communications@1daysooner.org
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Research Team
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MSc Candidate in Social Data Science at University of Oxford
Vaccine Equity Lead
Molecular Biochemist and Mandela Washington Fellow (ASU)
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PhD Candidate in Applied Philosophy focusing on healthcare policy at Bowling Green State University
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BA in Moral Philosophy at Princeton
isaac.martinez@ 1daysooner.org
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Teacher, Architect, Designer; BA in Architecture and Urbanism from Fundação Armando Alvares Penteado
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Public Historian and Independent Scholar
Volunteer Ambassadors are unpaid volunteers who help workshop 1Day Sooner’s media talking points and speak with the press about their decision to take part in a potential COVID-19 challenge trial. Volunteer Ambassadors share their personal perspectives as potential challenge trial volunteers and are are expected to maintain a high standard of scientific accuracy and historical awareness. They are entirely free to disagree with any of 1Day Sooner’s institutional views, including the above talking points
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Read about the principles and vision that inform our advocacy.
Meet our staff and volunteers.
Our four departments: Advocacy, Communications, Organizing Research.
Answers to frequently asked questions about 1Day Sooner and COVID-19 challenge trials.
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