Human Challenge Studies Research Articles

Perspectives of research ethics committee members on human challenge studies in the development of vaccines against COVID-19: a mixed methods study.

Vaccines are considered the most effective protection against the coronavirus disease 2019 (COVID-19). Human Challenge Studies can help to shorten the development process of vaccines. The reviewers' opinions from research ethics committees (REC) play an essential gate-keeping role in determining whether a clinical trial can be conducted or not. A convergent mixed-methods study was conducted in a leading general hospital in China. A total of 58 REC members from the institution were invited to participate in an online questionnaire survey. According to the result of the quantitative survey, 15 of these REC members were purposefully selected to participate in qualitative interviews further. Quantitative data were analyzed using descriptive statistical techniques, and thematic analysis was used to analyze the qualitative data. Findings from the quantitative and qualitative analyses were synthesized to deeply illustrate the attitudes, views, and suggestions of REC members on human challenge studies to develop COVID-19 vaccination. The response rate of the online questionnaire was 62% (36/58), and 15 of the respondents were interviewed. All participants deemed that the human challenge study should provide compensation to its participants and that sufficiently informed consent is necessary. The human challenge study was disagreed with by 38.9% of participants. The key points of concern raised were representativeness and fairness of participant selection, benefit, and risk, vulnerable groups, compensation to participants, informed consent, and general view on human challenge studies. Human challenge studies helped accelerate the development of vaccines for disease control to a certain extent, but the bottom line of medical ethics should not have been broken. At any time, the rights and interests of research participants should come first.

Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection

BackgroundShigellosis is a major cause of moderate to severe diarrhoea and dysentery in children under 5 years of age in low and middle-income countries. The Flexyn2a vaccine conjugates the O-polysaccharide of Shigella flexneri 2a to Pseudomonas aeruginosa exotoxin A. We describe a Phase 2b proof-of-concept challenge study that evaluated safety, immunogenicity, and efficacy of the Flexyn2a vaccine to protect against shigellosis. MethodsIn this randomized, double blind, placebo-controlled trial, healthy adults were randomized 1:1 to receive Flexyn2a (10 µg) or placebo intramuscularly, twice, 4 weeks apart, followed by challenge 4 weeks later with 1500 colony forming units (CFUs) of S. flexneri 2a strain 2457T. The primary outcome was vaccine-induced protection. S. flexneri 2a lipopolysaccharide (LPS)-specific immune responses were assessed. FindingsSixty-seven subjects were enrolled, 34 received vaccine and 33 placebo. The vaccine was well tolerated; the majority of adverse events were mild in nature. Thirty vaccinees and 29 placebo recipients received the S. flexneri 2a challenge. Vaccination resulted in a 30.2% reduction in shigellosis compared with placebo (13/30 vs. 18/29; p = 0.11; 95% CI -15 to 62.6). Vaccine efficacy was more robust against severe disease, reaching 51.7% (p = 0.015, 95% CI 5.3 to 77.9) against moderate/severe diarrhoea or dysentery concurrent with fever or severe enteric symptoms and 72.4% (p = 0.07) against more severe diarrhoea (≥10 lose stools or ≥1000 g loose stools/24 h). Vaccinated subjects were less likely to need early antibiotic intervention following challenge (protective efficacy 51.7%, p = 0.01; 95% CI 9 to 76.8). In those who developed shigellosis, vaccinated subjects had a lower disease severity score (p = 0.002) than placebo-recipients. Additionally, LPS-specific serum IgG responses in Flexyn2a recipients were associated with protection against disease (p = 0.0016) and with a decreased shigellosis disease score (p = 0.002). InterpretationThe Flexyn2a bioconjugate vaccine was immunogenic, well tolerated and protected against severe illness after Shigella challenge and is a promising Shigella vaccine construct. We identified a strong association between anti-S. flexneri 2a serum IgG and a reduction in disease outcomes. (Clinicaltrials.gov, NCT02646371.) FundingFunding for this study was through a grant from the Wellcome Trust.

Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine

BackgroundDiarrheal diseases are a leading cause of global morbidity and mortality affecting all ages, but especially children under the age of five in resource-limited settings. Shigella is a leading contributor to diarrheal diseases caused by bacterial pathogens and is considered a significant antimicrobial resistance threat. While improvements in hygiene, and access to clean water help as control measures, vaccination remains one of the most viable options for significantly reducing morbidity and mortality. MethodsFlexyn2a is a bioconjugate vaccine manufactured using novel conjugation methodologies enzymatically linking the O-polysaccharide of S. flexneri 2a to exotoxin A of Pseudomonas aeruginosa. The protective capacity of Flexyn2a was assessed in a controlled human infection model after two intramuscular immunizations. Immune responses pre- and post-immunization and/or infection were investigated and are described here. FindingsFlexyn2a induced lipopolysaccharide (LPS)-specific serum IgG responses post-immunization which were associated with protection against shigellosis. Additionally, several other immune parameters, including memory B cell responses, bactericidal antibodies and serum IgA, were also elevated in vaccinees protected against shigellosis. Immunization with Flexyn2a also induced gut-homing, LPS-specific IgG and IgA secreting B cells, indicating the vaccine induced immune effectors functioning at the site of intestinal infection. InterpretationCollectively, the results of these immunological investigations provide insights into protective immune mechanisms post-immunization with Flexyn2a which can be used to further guide vaccine development and may have applicability to the larger Shigella vaccine field. FundingFunding for this study was provided through a Wellcome Trust grant.

Faith Osier: inspirational immunologist

Faith Osier: inspirational immunologist

Erratum for Patin et al., "The Role of the Gut Microbiome in Resisting Norovirus Infection as Revealed by a Human Challenge Study".

Volume 11, issue 6, e02634-20, 2020, [https://doi.org/10.1128/mBio.02634-20][1]. The third paragraph of the Acknowledgments section should read as follows: “Funding for this study was provided by National Institutes of Allergy and Infectious Diseases grant R01AI137679 and by Colciencias through a

Plumbing the Depths of Ethical Payment for Research Participation

The peer commentaries on our Target Article, “Promoting Ethical Payment in Human Infection Challenge Studies,” (Fernandez Lynch et al. 2021) offer a number of insights that will help advance the co...

Human challenge studies in the time of COVID-19: Pros and cons

Can we speed up coronavirus vaccine development? A human challenge study, in which volunteers would be deliberately infected with coronavirus, could help in theory. In this article, two collaborators from the CTU Geneva explore the potential benefits and the risks associated with SARS-CoV-2 challenge studies.

Prioritizing second-generation SARS-CoV-2 vaccines through low-dosage challenge studies

The design of human challenge studies balances scientific validity, efficiency and study safety. This Perspective explores some advantages and disadvantages of ‘low-dosage’ challenge studies, in the setting of testing second-generation vaccines against COVID-19. Compared with a conventional vaccine challenge, a low-dosage vaccine challenge would be more likely to start, and start earlier. A low-dosage challenge would also be less likely to rule out a vaccine candidate that would have potentially been effective, particularly in certain target uses. A key ethical advantage of a low-dosage challenge over a conventional challenge is that both it and its dose escalation process are safer for each participant. Low-dosage studies would require larger numbers of participants than conventional challenges, but this and other potential disadvantages are less serious than they may initially appear. Overall, low-dosage challenges should be considered for certain roles such as prioritizing between second-generation vaccines against COVID-19.

Promoting Ethical Payment in Human Infection Challenge Studies

To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, we convened a multidisciplinary working group to address ethical questions regarding whether and how much SARS-CoV-2 HICS participants should be paid. Because the goals of paying HICS participants, as well as the relevant ethical concerns, are the same as those arising for other types of clinical research, the same basic framework for ethical payment can apply. This framework divides payment into reimbursement, compensation, and incentives, focusing on fairness and promoting adequate recruitment and retention as counterweights to concerns about undue inducement. Within the basic framework, several factors are especially salient for HICS, and for SARS-CoV-2 HICS in particular, including the nature of participant confinement, anticipated discomfort, risks and uncertainty, participant motivations, and trust. These factors are reflected in a payment worksheet created to help sponsors, researchers, and ethics reviewers systematically develop and assess ethically justifiable payment amounts.

Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections.

Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.

Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study

BackgroundRespiratory syncytial virus (RSV) is a significant cause of severe lower respiratory tract disease in children and older adults, but has no approved vaccine. This study assessed the potential of Ad26.RSV.preF to protect against RSV infection and disease in an RSV human challenge model.MethodsIn this double-blind, placebo-controlled study, healthy adults aged 18–50 years were randomized 1:1 to receive 1 × 1011 vp Ad26.RSV.preF or placebo intramuscularly. Twenty-eight days postimmunization, volunteers were challenged intranasally with RSV-A (Memphis 37b). Assessments included viral load (VL), RSV infections, clinical symptom score (CSS), safety, and immunogenicity.ResultsPostchallenge, VL, RSV infections, and disease severity were lower in Ad26.RSV.preF (n = 27) vs placebo (n = 26) recipients: median VL area under the curve (AUC) quantitative real-time polymerase chain reaction: 0.0 vs 236.0 (P = .012; predefined primary endpoint); median VL-AUC quantitative culture: 0.0 vs 109; RSV infections 11 (40.7%) vs 17 (65.4%); median RSV AUC-CSS 35 vs 167, respectively. From baseline to 28 days postimmunization, geometric mean fold increases in RSV A2 neutralizing antibody titers of 5.8 and 0.9 were observed in Ad26.RSV.preF and placebo, respectively. Ad26.RSV.preF was well tolerated.ConclusionsAd26.RSV.preF demonstrated protection from RSV infection through immunization in a human challenge model, and therefore could potentially protect against natural RSV infection and disease.Clinical Trials RegistrationNCT03334695; CR108398, 2017-003194-33 (EudraCT); VAC18193RSV2002.

Human Challenge Studies with Coronaviruses Old and New.

Coronavirus infections have been known to cause disease in animals since as early as the 1920s. However, only seven coronaviruses capable of causing human disease have been identified thus far. These Human Coronaviruses (HCoVs) include the causes of the common cold, but more recent coronaviruses that have emerged (i.e. SARS-CoV, MERS-CoV and SARS-CoV-2) are associated with much greater morbidity and mortality. HCoVs have been relatively under-studied compared to other common respiratory infections, as historically they have presented with mild symptoms. This has led to a relatively limited understanding of their animal reservoirs, transmission and determinants of immune protection. To address this, human infection challenge studies with HCoVs have been performed that enable a detailed clinical and immunological analysis of the host response at specific time points under controlled conditions with standardised viral inocula. Until recently, all such human challenge studies were conducted with common cold HCoVs, with the study of SARS-CoV and MERS-CoV unacceptable due to their greater pathogenicity. However, with the emergence of SARS-CoV-2 and the COVID-19 pandemic during which severe outcomes in young healthy adults have been rare, human challenge studies with SARS-CoV-2 are now being developed. Two SARS-CoV-2 human challenge studies in the UK studying individuals with and without pre-existing immunity are underway. As well as providing a platform for testing of antivirals and vaccines, such studies will be critical for understanding the factors associated with susceptibility to SARS-CoV-2 infection and thus developing improved strategies to tackle the current as well as future HCoV pandemics. Here, we summarise the major questions about protection and pathogenesis in HCoV infection that human infection challenge studies have attempted to answer historically, as well as the knowledge gaps that aim to be addressed with contemporary models.

33. Intranasal M2SR (M2-deficient Single Replication) Live H3N2 Influenza Investigational Vaccine Induces Serum HAI & Broad Immune Responses in High Proportion of Adults

BackgroundA single intranasal (IN) dose of 108 TCID50 M2SR protected a responder subset of adults against infection and disease in a prior human influenza challenge study (EudraCT number: 2017-004971-30). Higher dose levels of M2SR were assessed in this phase 1b study to enhance immune responses and further increase protection levels in adults.MethodsA double-blind, randomized, placebo-controlled dose escalation study (NCT03999554) was conducted at 4 US study sites with two different H3N2 M2SR vaccines that contained HA & NA from either A/Brisbane/10/2007 or A/Singapore/INFIMH-16–0019/2016. Serosusceptible 18–49 year old subjects (n = 206) received 2 IN doses of either saline or 1 of 3 different dose levels of vaccine (108 – 109 TCID50), administered 28 days apart.ResultsStudy vaccination was well-tolerated at all dose levels. A single 109 dose of A/Singapore/2016 M2SR generated significantly increased serum HAI responses compared to the 108 dose of A/Brisbane/10/2007 M2SR that had provided protection against infection & illness in an earlier human influenza challenge study (Fig. 1). HAI titers ≥40 were achieved in 0%, 23% & 58% of subjects after the first dose of placebo, 108 or 109 M2SR, respectively (p< 0.003). Increases also were stimulated in serum microneutralization titers (MNT) to drifted strains of H3N2 (Fig 2) & in serum NAI (Fig 3) and mucosal sIgA (Fig 4) titers. Further increases in serum and mucosal immune response were noted after a 2nd IN vaccination.Proportion of subjects with seroprotective HAI titers after vaccination Proportion of subjects with increased microneutralization titers against drifted H3N2 viruses after vaccination Geometric mean fold rise in serum neuraminidase inhibition antibody titers after vaccination ConclusionAn earlier clinical trial with a 108 dose of M2SR provided protection against infection and illness upon challenge with a highly drifted strain of H3N2. Protection correlated with vaccine induced serum MNT responses. In the current study, a single, 109 dose of M2SR significantly increased serum MNT, HAI & NAI titers as well as mucosal immune responses among greater proportions of study subjects. Since HAI, alone, is a well-accepted surrogate marker for vaccine protection against influenza, these broader enhancements indicate the potential for M2SR to protect against both matched and drifted strains of influenza in a high proportion of adults and strongly support clinical assessment in younger and older age groups as well as development of multivalent M2SR.Geometric mean fold rise in nasal mucosal secretory IgA antibody titers after vaccination DisclosuresJoseph Eiden, MD, PhD, FluGen (Consultant) Ruth Ellis, MD, FluGen (Consultant) Roger Aitchison, ScM, FluGen (Consultant) Renee Herber, BS, FluGen (Employee) Pamuk Bilsel, PhD, FluGen (Employee)

1524. Sex Differences in Influenza: The Challenge Study Experience

BackgroundOur understanding of the impact of biological sex on influenza-associated disease and the mechanisms that underpin it is still incomplete. Further investigation of sex-linked effects on influenza pathogenesis and clinical outcomes may help tailor vaccine strategies. Animal studies have shown female mice experience more symptoms than male mice during influenza infection. Similarly, human females of reproductive age have higher rates of influenza and influenza-related hospitalizations. However, data is sometimes conflicting and may be confounded by other important differences in baseline characteristics. Human challenge studies have demonstrated the importance of NAI titers as a correlate of protection and may also provide an ideal opportunity to study sex differences in a homogenous group of participants controlled for confounders.MethodsData from 168 volunteers who underwent Influenza A/California/04/2009/H1N1 challenge studies affiliated with NIAID’s LID Clinical Studies Unit were compiled to compare differences between sexes. Participants were included in the analysis if they received a challenge dose of virus of 107 TCID50 and were excluded if they had received any vaccines or experimental therapy during the study period.ResultsBaseline differences between male and female participants were observed in NAI titers but not HAI titers or age. Outcomes of interest included presence of viral shedding/duration which were similar among sexes. However, symptom number and duration were higher among female participants (p=0.008 and p=0.045 respectively). Ongoing data analysis also shows females have lower post-challenge NAI titers than males.ConclusionFemale participants in our H1N1 challenge studies had more symptoms and a longer duration of symptoms compared to their male counterparts. Differences in NAI titers may potentially explain the observed relationship between sex and symptoms associated with influenza.Disclosures All Authors: No reported disclosures

코로나19 판데믹과 인간 챌린지 연구의 윤리

2019년 12월 중국 우한에서 처음 보고된 이후 코로나19는 전세계로 퍼져나갔다. 코로나19가 세계적인 판데믹으로 접어들면서 대유행을 종식시킬 수 있는 효과적인 치료제와 백신의 빠른 개발에 대한 국제적 요구가 높아지고 있다. 연구 대상자들을 의도적으로 병원체에 노출시켜 질병에 백신 효능을 테스트 하는 인간 챌린지 연구가 코로나19에 대응하기 위한 도구로 주목되기 시작하였다. 인간 챌린지 연구가 백신 개발을 크게 단축시킬 것이라는 기대도 사회적 지지층을 형성하게 하였다. 하지만 사람들을 의도적으로 치명적인 병원체 노출시키는 연구 방법은 여러 윤리적 논란을 낳게 된다. 뎅기열, 콜레라, 지카바이러스 등 인간 챌린지 연구의 역사적 사례로 분석하여 볼 때 코로나19 인간 챌린지 연구는 수행의 윤리적 근거로서 충분한 사회적 가치를 가져야 한다. 코로나19 인간 챌린지 연구가 백신 개발 기간 단축에 유의미한 기여를 할 수 있을 지가 분명하지 않다면, 사회적 가치에 대비해 얼마만큼의 위험을 용인 할 수 있는지에 대한 판단 보류 되어야 한다. 위험성의 관리가 정당화되기 위해서는 치료제의 확보, 약독화된 균주의 생산 및 적용, 혹은 그에 준하는 병원체에 대한 안전 조치는 대상자 안전 확보를 위한 최소한의 윤리적 기준이 되어야 한다. 코로나19 인간 챌린지 연구의 윤리적 고려에 대한 논의는 현재 백신 개발 단축이 가져다 줄 수 있는 불확실한 사회적 가치 보다 장기적인 판데믹 대응 역량의 일환으로 논의될 필요가 있다. 신종 감염병에 의한 전세계적 유행은 코로나19에 그치지 않고 지속적으로 반복될 것으로 예측되고 있으며, 이에 대응할 수 있는 신속한 과학적, 윤리적 대응이 무엇일지에 대해 고려해봐야 한다.

The Role of the Gut Microbiome in Resisting Norovirus Infection as Revealed by a Human Challenge Study.

Norovirus infections take a heavy toll on worldwide public health. While progress has been made toward understanding host responses to infection, the role of the gut microbiome in determining infection outcome is unknown. Moreover, data are lacking on the nature and duration of the microbiome response to norovirus infection, which has important implications for diagnostics and host recovery. Here, we characterized the gut microbiomes of subjects enrolled in a norovirus challenge study. We analyzed microbiome features of asymptomatic and symptomatic individuals at the genome (population) and gene levels and assessed their response over time in symptomatic individuals. We show that the preinfection microbiomes of subjects with asymptomatic infections were enriched in Bacteroidetes and depleted in Clostridia relative to the microbiomes of symptomatic subjects. These compositional differences were accompanied by differences in genes involved in the metabolism of glycans and sphingolipids that may aid in host resilience to infection. We further show that microbiomes shifted in composition following infection and that recovery times were variable among human hosts. In particular, Firmicutes increased immediately following the challenge, while Bacteroidetes and Proteobacteria decreased over the same time. Genes enriched in the microbiomes of symptomatic subjects, including the adenylyltransferase glgC, were linked to glycan metabolism and cell-cell signaling, suggesting as-yet unknown roles for these processes in determining infection outcome. These results provide important context for understanding the gut microbiome role in host susceptibility to symptomatic norovirus infection and long-term health outcomes.IMPORTANCE The role of the human gut microbiome in determining whether an individual infected with norovirus will be symptomatic is poorly understood. This study provides important data on microbes that distinguish asymptomatic from symptomatic microbiomes and links these features to infection responses in a human challenge study. The results have implications for understanding resistance to and treatment of norovirus infections.

Adaptive Multi-Channel Event Segmentation and Feature Extraction for Monitoring Health Outcomes.

To develop a multi-channel device event segmentation and feature extraction algorithm that is robust to changes in data distribution. We introduce an adaptive transfer learning algorithm to classify and segment events from non-stationary multi-channel temporal data. Using a multivariate hidden Markov model (HMM) and Fisher's linear discriminant analysis (FLDA) the algorithm adaptively adjusts to shifts in distribution over time. The proposed algorithm is unsupervised and learns to label events without requiring a priori information about true event states. The procedure is illustrated on experimental data collected from a cohort in a human viral challenge (HVC) study, where certain subjects have disrupted wake and sleep patterns after exposure to an H1N1 influenza pathogen. Simulations establish that the proposed adaptive algorithm significantly outperforms other event classification methods. When applied to early time points in the HVC data, the algorithm extracts sleep/wake features that are predictive of both infection and infection onset time. The proposed transfer learning event segmentation method is robust to temporal shifts in data distribution and can be used to produce highly discriminative event-labeled features for health monitoring. Our integrated multisensor signal processing and transfer learning method is applicable to many ambulatory monitoring applications.

Back to WHAT? The role of research ethics in pandemic times

The Covid-19 pandemic creates an unprecedented threatening situation worldwide with an urgent need for critical reflection and new knowledge production, but also a need for imminent action despite prevailing knowledge gaps and multilevel uncertainty. With regard to the role of research ethics in these pandemic times some argue in favor of exceptionalism, others, including the authors of this paper, emphasize the urgent need to remain committed to core ethical principles and fundamental human rights obligations all reflected in research regulations and guidelines carefully crafted over time. In this paper we disentangle some of the arguments put forward in the ongoing debate about Covid-19 human challenge studies (CHIs) and the concomitant role of health-related research ethics in pandemic times. We suggest it might be helpful to think through a lens differentiating between risk, strict uncertainty and ignorance. We provide some examples of lessons learned by harm done in the name of research in the past and discuss the relevance of this legacy in the current situation.

For now, it’s unethical to use human challenge studies for SARS-CoV-2 vaccine development

The prospect of a widely available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine is an increasingly high priority for an effective response to the coronavirus disease 2019 (COVID-19) pandemic and an area of intense interest and attention for professionals, politicians, and the public alike. The understandable desire for such a vaccine has led to significant discussion and even some planning for the possibility of human challenge studies (HCS) as a tool for accelerating the process for identifying, testing, and developing an effective vaccine (1⇓–3). Proponents of human challenge studies suggest that they will accelerate the time to approved vaccines. But the facts don’t support those claims. Image credit: Shutterstock/REDPIXEL.PL. Typically, undertaking HCS in vaccine development requires that the disease for which a challenge would be introduced either has an available rescue therapy to treat those who become infected or the disease is known to be self-limiting. There is no rescue therapy for SARS-CoV-2 infection, and proponents of HCS have claimed that the infection is likely to be self-limiting and mild in young, healthy volunteers based on current understanding of the infection. If accurate, the basic requirements for undertaking an HCS could be met if conducted with that population. Proponents further argue that such HCS are ethically acceptable in the current pandemic. Most critically, they contend that these studies are likely to speed the development of effective vaccines. But based on our assessment of these arguments, we disagree. We believe it is unethical to move forward with such trials at the current time. Whereas proponents of these studies suggest that such studies will accelerate the time to approved vaccines, the facts fail to support these claims. HCS to address SARS-CoV-2 face unacceptable ethics challenges, and, further, undertaking them would do a disservice to the public by … [↵][1]1To whom correspondence may be addressed. Email: jeffkahn{at}jhu.edu. [1]: #xref-corresp-1-1

Key criteria for the ethical acceptability of COVID-19 human challenge studies: Report of a WHO Working Group

This report of the WHO Working Group for Guidance on Human Challenge Studies in COVID-19 outlines ethical standards for COVID-19 challenge studies. It includes eight Key Criteria related to scientific justification, risk-benefit assessment, consultation and engagement, co-ordination of research, site selection, participant selection, expert review, and informed consent. The document aims to provide comprehensive guidance to scientists, research ethics committees, funders, policymakers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining criteria that would need to be satisfied in order for such studies to be ethically acceptable.