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Human Challenge Studies in Endemic Settings: Ethical and Regulatory Issues
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Online Open Access: https://link.springer.com/book/10.1007/978-3-030-41480-1
Human infection challenge studies (HCS) involve the intentional infection of research participants with pathogens (or other micro-organisms) with the aim to (i) test (novel) vaccines and therapeutics, (ii) generate knowledge regarding the natural history of infectious diseases and/or host-pathogen interactions, or (iii) develop “models of infection”—i.e., reliable methods (to be used in studies with aims (i) and/or (ii)) of infecting human research participants with particular pathogens. In this comprehensive report we review and provide preliminary analyses of relevant ethical and regulatory issues in endemic settings and/or low- and middle-income countries.
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... On the other hand, opponents argued that challenge studies in this context represented an unfavorable risk-benefit ratio for study participants, particularly in the absence of a rescue therapy (Kahn et al. 2020) and uncertainty in longer term sequelae. Yet, these are not necessarily novel ethical issues or questions; human challenge studies have been conducted for hundreds of years and arguably raise similar ethical questions in non-pandemic contexts (Hope and McMillan 2004;Jamrozik and Selgelid 2021). But there is no doubt that pandemics can intensify the perceived need for challenge studies and consideration of their ethical merits and justification. ...
Research conducted during infectious disease outbreaks or pandemics can be crucial to control or ameliorate their consequences, but scientists are confronted with significant ethical questions about how to conduct research in such contexts. This chapter examines foundational ethical questions and considerations undergirding the research enterprise in pandemic contexts, including whether pandemics necessitate deviations from ethical and scientific standards for research, how research priorities are and ought to be set during pandemics, the ethics of conducting research alongside pandemic response efforts, and how pandemic research ought to be governed and coordinated. Scientists may have only a brief interval to understand the disease and develop medical countermeasures, and social pressures to produce fast results may seem overwhelming. Despite these challenges, this does not justify relaxing fundamental ethical or scientific standards, although there is scope for accelerating procedural requirements. Even during a pandemic, provision of most biomedical research funding by high-resource countries can influence the directions and results of research, leading to interventions that are more applicable in resource-rich than in resource-poor countries. The World Health Organization and other institutions are trying to correct or at least reduce these discrepancies. Biomedical research and health care response to a pandemic need not be rivals for funding support. The 2014 Ebola and 2019 COVID-19 experiences have demonstrated that the two can work synergistically. Both medical care and research responses are integral to our defenses against emerging or re-emerging infectious disease. Finally, the COVID-19 pandemic has made clear the need for changes in global architecture for pandemic response. The scientific and organizational adaptations required must be guided by ethical principles, such as the need to reduce the glaring inequities between high-income and low-income settings across the world as well as within countries. Preparing for the next pandemic will require a blueprint to accelerate the organization, coordination, and conduct of critical research and development.
... In addition, BU disease severity and antibiotic complication rates are particularly problematic in children 27 and the elderly 28 . The ethical considerations for recruiting children into CHIMs is complex 29 , with a widespread presumption against enrolling children in such studies 30 . Therefore, initial studies will include adults aged 18 to 45 years old (inclusive). ...
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This paper describes a provisional clinical protocol for the pilot human challenge model of Mycobacterium ulcerans infection, which causes the skin disease 'Buruli ulcer' (BU). BU is typically painless and begins as a small area of redness or swelling, and is curable with antibiotics. If the diagnosis is delayed, it can result in large ulceration and disability. Side effects from antibiotics are common but rarely severe; nevertheless, preventative strategies, such as vaccination, are urgently needed. The overarching project, known as 'MuCHIM', aims to establish a safe and acceptable controlled human challenge model (CHIM) of this disease in healthy volunteers in Melbourne, Australia. This pilot protocol primarily aims to establish that it is safe and acceptable to participants, and secondarily to confirm successful establishment of infection and the infection rate amongst participants. We also aim to test less invasive diagnostic tests, assess immune responses to infection, to understand changes in the human microbiome during the trial, and explore microbiological characteristics of M. ulcerans infection. If this pilot is successful, we hope to test vaccines and other therapeutics using this model, which could blunt or reduce the rising incidence of this disease in Australia, while further informing vaccine development research.
... Bystanders, on the other hand, are not used as a means in health research projects. Even so, several bioethicists have explored the limits of acceptable risk for research bystanders (Shah et al., 2018;Jamrozik & Selgelid, 2021). Shah et al. (2018) affirm it is important to protect all research bystanders where they may be unable to protect themselves. ...
Six planetary boundaries have already been exceeded, including climate change, loss of biodiversity, chemical pollution, and land-system change. The health research sector contributes to the environmental crisis we are facing, though to a lesser extent than healthcare or agriculture sectors. It could take steps to reduce its environmental impact but generally has not done so, even as the planetary emergency worsens. So far, the normative case for why the health research sector should rectify that failure has not been made. This paper argues strong philosophical grounds, derived from theories of health and social justice, exist to support the claim that the sector has a duty to avoid or minimise causing or contributing to ecological harms that threaten human health or worsen health inequity. The paper next develops ideas about the duty’s content, explaining why it should entail more than reducing carbon emissions, and considers what limits might be placed on the duty.
... CHIS involve intentionally exposing participants to pathogens in order to study mechanisms of infection and disease and/or the efficacy of experimental vaccines or treatments. CHIS have made important contributions to the treatment and prevention of many infectious diseases (Jamrozik and Selgelid 2021). However, research methods which involve exposing healthy volunteers to a pathogen which can cause infection and disease may seem ethically counter-intuitiveparticularly when natural infections with the pathogen can result in severe disease and death. ...
Global health emergencies such as the COVID-19 pandemic are contexts in which it is critical to draw upon learning from prior research and to conduct novel research to inform real-time decision-making and pandemic responses. While research is vitally important, however, emergencies are radically non-ideal contexts for its conduct, due to exceptional uncertainty, urgency, disruption, health needs, and strain on existing health systems, amongst other challenges. This generates novel ethical challenges and a broader conception of research ethics is necessary to effectively address the complexity of pandemic research contexts. Going beyond traditional approaches to research ethics centring on the design of specific studies, this broader conception requires consideration of fundamental questions relating to the exercise of power and influence throughout research pathways, and a broader attention to both salient ethical issues, and the ethical responsibilities of stakeholders. These include important questions about responsibilities to gather evidence and generate knowledge systematically during emergencies, to implement policy responses in ways that are amenable to evaluation, and even potential moral obligations to participate in research. In situations of heightened uncertainty, additional questions arise about what constitutes sufficient evidence to justify the development and implementation of policy responses, and the responsibilities of scientific and social science researchers involved in policy-making processes. The four cases in this chapter prompt reflection on evolving and at times competing values and responsibilities of policy-makers, regulators, health authorities and researchers during the design and conduct of research, and proposed early implementation of research findings. These cases highlight issues arising when conducting research of national importance in a pandemic, where researchers are required to liaise with authorities responsible for pandemic responses and address complex ethical issues, including protecting the interests of participants and publics when tensions arise between prioritising the completion of research and accelerating the rollout of novel health interventions. This chapter invites reflection on the practical ethical implications of commitments to undertake research during emergencies, including the nature and scope of the relevant responsibilities of a range of stakeholders.
... Controlled Human Infection Model (CHIM) studies can help study disease pathogenesis and immune responses [1] and contribute to the development of approved vaccines, such as the RTS,S vaccine against Malaria [2,3]. CHIMs have become relevant for numerous pathogens, including SARS-CoV-2 [4,5], influenza, respiratory syncytial virus, and others [6], and are crucial components in developing preventive and therapeutic approaches, especially for vaccines. CHIM studies use pathogens (challenge agents) for infecting healthy volunteers in a controlled fashion; therefore, it is paramount that care is taken to minimise the risk to volunteers through careful selection, isolation, development, stability assurance, and production of the challenge agent [7], as well as the availability of rescue treatments [8,9]. ...
Within the Innovative Health Initiative (IHI) Inno4Vac CHIMICHURRI project, a regulatory workshop was organised on the development and manufacture of challenge agent strains for Controlled Human Infection Model (CHIM) studies. Developers are often uncertain about which GMP requirements or regulatory guidelines apply but should be guided by the 2022 technical white paper “Considerations on the Principles of Development and Manufacturing Qualities of Challenge Agents for Use in Human Infection Models” (published by hVIVO, Wellcome Trust, HIC-Vac consortium members). Where those recommendations cannot be met, regulators advise following the “Principles of GMP” until definitive guidelines are available. Sourcing wild-type virus isolates is a significant challenge for developers. Still, it is preferred over reverse genetics challenge strains for several reasons, including implications and regulations around genetically modified organisms (GMOs). Official informed consent guidelines for collecting isolates are needed, and the characterisation of these isolates still presents risks and uncertainty. Workshop topics included ethics, liability, standardised clinical endpoints, selection criteria, sharing of challenge agents, and addressing population heterogeneity concerning vaccine response and clinical course. The organisers are confident that the workshop discussions will contribute to advancing ethical, safe, and high-quality CHIM studies of influenza, RSV and C. difficile, including adequate regulatory frameworks.
... HCTs are nonetheless ethically sensitive and raise important questions for healthy volunteers, including (i) the acceptance of intentional infection; (ii) the kinds and levels of benefits; (iii) the acceptable limit of burdens (risks); (iv) the need for protection of third-parties from infection (by participants); (v) fair participant selection/exclusion, (vi) appropriate financial payment of participants; (vii) the potential need for special ethical principles and/or review procedures (e.g., special committees); etc. [89]. In 2020, WHO also published the Key Guidance for the Ethical Acceptability of Human Challenge Studies for New Coronaviruses. ...
Influenza vaccines faced significant challenges in achieving sufficient protective efficacy and production efficiency in the past. In recent decades, novel influenza vaccines, characterized by efficient and scalable production, advanced platforms, and new adjuvant technologies, have overcome some of these weaknesses and have been widely licensed. Furthermore, researchers are actively pursuing the development of next-generation and universal influenza vaccines to provide comprehensive protection against potential pandemic subtypes or strains. However, new challenges have emerged as these novel vaccines undergo evaluation and authorization. In this review, we primarily outline the critical challenges and advancements in research and development (R&D) and highlight the improvements in regulatory responses for influenza vaccines.
Critical knowledge gaps have impeded progress towards reducing the global burden of disease due to Mycobacterium ulcerans , the cause of the neglected tropical disease Buruli ulcer (BU). Development of a controlled human infection model of BU has been proposed as an experimental platform to explore host-pathogen interactions and evaluate tools for prevention, diagnosis, and treatment. We have previously introduced the use case for a new human model and identified M. ulcerans JKD8049 as a suitable challenge strain. Here, we present a provisional protocol for an initial study, for transparent peer review during the earliest stages of protocol development. Following simultaneous scientific peer review and community/stakeholder consultation of this provisional protocol, we aim to present a refined protocol for institutional review board (IRB) evaluation.
This scoping review maps research ethics and integrity challenges and best practices encountered by research actors in the DACH countries (Germany, Austria, and Switzerland), including researchers, funders, publishers, research ethics committees, and policymakers, during the COVID-19 pandemic. The COVID-19 pandemic brought research and, in turn, research ethics and integrity, into public focus. This review identified challenges related to changing research environments, diversity in research, publication and dissemination trends, scientific literacy and trust in science, recruitment, research redundancy and study termination, placebo and human challenge studies, data management, and informed consent. These challenges are linked to two crucial factors: first, actors in the DACH research ecosystem lacked a sound knowledge base to assess the risks and benefits of research during the COVID-19 pandemic. Second, researchers in the DACH region faced pressure from policymakers, funders, and the public to generate relevant, timely, and consistent findings to mitigate the impacts of the COVID-19 pandemic. In addition, this review highlights best practices to mitigate the effects of future crises on research ethics and integrity, including enhanced cooperation among actors, continuous ethics assessments, and support for public scientific literacy.
This review examines the advancements and methodologies of artificial feeding systems for the study of vector-borne diseases, offering a critical assessment of their development, advantages, and limitations relative to traditional live host models. It underscores the ethical considerations and practical benefits of such systems, including minimizing the use of live animals and enhancing experimental consistency. Various artificial feeding techniques are detailed, including membrane feeding, capillary feeding, and the utilization of engineered biocompatible materials, with their respective applications, efficacy, and the challenges encountered with their use also being outlined. This review also forecasts the integration of cutting-edge technologies like biomimicry, microfluidics, nanotechnology, and artificial intelligence to refine and expand the capabilities of artificial feeding systems. These innovations aim to more accurately simulate natural feeding conditions, thereby improving the reliability of studies on the transmission dynamics of vector-borne diseases. This comprehensive review serves as a foundational reference for researchers in the field, proposing a forward-looking perspective on the potential of artificial feeding systems to revolutionize vector-borne disease research.
Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo . Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity.
Registration: ClinicalTrials.gov identifier NCT02739763 .
Vaccines can be extremely cost-effective public health measures. Unfortunately the research and development (R&D) of novel vaccines is suffering from rising costs and declining success rates. Because many vaccines target low- and middle income markets (LMIC), output needs to be maintained at a constrained budget. In addition, scientific neglect and political uncertainty around reimbursement decisions make it an unattractive arena for private investors. The vaccine development pipeline for LMIC thus is in need for a different, sustainable, and cost-effective development model. In conventional vaccine development, objectives for every clinical development phase have been predefined. However, given the scarcity of resources, the most efficient clinical development path should identify vaccine candidates with the highest potential impact as soon as possible. We argue for a custom-made question-based development path based on the scientific questions, success probabilities and investments required. One question can be addressed by several studies and one study can provide partial answers to multiple questions. An example of a question-based approach is the implementation of a controlled human malaria infection model (CHMI). Malaria vaccine R&D faces major scientific challenges and has limited resources. Therefore, early preliminary efficacy data needs to be obtained in order to reallocate resources as efficiently as possible and reduce clinical development costs. To meet this demand, novel malaria vaccines are tested for efficacy in so-called CHMI trials in which small groups of healthy volunteers are vaccinated and subsequently infected with malaria. Early evaluation studies of critical questions, such as CHMI, are highly rewarding, since they prevent expenditures on projects that are unlikely to succeed. Each set of estimated probabilities and costs (combined with market value) will have its own optimal priority sequence of questions to address. Algorithms can be designed to determine the optimal order in which questions should be addressed. Experimental infections of healthy volunteers is an example of how a question-based approach to vaccine development can be implemented and has the potential to change the arena of clinical vaccine development.
Human infection challenge studies (HCS) involve intentionally infecting research participants with pathogens, often with the ultimate aim of developing new interventions against infectious diseases. Despite ethical concerns about research involving vulnerable populations, there are both scientific and ethical reasons to consider conducting more HCS in low-and middle-income countries where neglected diseases are often endemic. HCS researchers can reduce the risks to participants (and the risks of transmission from participants to others) by controlling multiple factors (eg those related to the laboratory environment, participant selection, the pathogen, and the timing of treatment); but HCS nonetheless raise important ethical issues, some of which may be particularly pertinent to HCS in endemic settings. This article provides background on HCS in general, as well as recent HCS in low-and middle-income countries, and an overview of the ethical issues associated with HCS in endemic settings.
The Oxford Textbook of Clinical Research Ethics is the first systematic and comprehensive reference on clinical research ethics. Under the editorship of experts from the National Institutes of Health of the United States, the book offers a wide-ranging and systematic examination of all aspects of research with human beings. Considering historical triumphs of research as well as tragedies, the textbook provides a framework for analysing the ethical aspects of research studies with human beings. Through both conceptual analysis and systematic reviews of empirical data, the textbook examines issues ranging from scientific validity, fair subject selection, risk benefit ratio, independent review, and informed consent as well as focused consideration of international research ethics, conflicts of interests and other aspects of responsible conduct of research. The editors of The Oxford Textbook of Clinical Research Ethics offer a work that critically assesses and advances scholarship in the field of human subjects research with human beings.
The Oxford Textbook of Clinical Research Ethics is the first systematic and comprehensive reference on clinical research ethics. Under the editorship of experts from the National Institutes of Health of the United States, the book offers a wide-ranging and systematic examination of all aspects of research with human beings. Considering historical triumphs of research as well as tragedies, the textbook provides a framework for analysing the ethical aspects of research studies with human beings. Through both conceptual analysis and systematic reviews of empirical data, the textbook examines issues ranging from scientific validity, fair subject selection, risk benefit ratio, independent review, and informed consent as well as focused consideration of international research ethics, conflicts of interests and other aspects of responsible conduct of research. The editors of The Oxford Textbook of Clinical Research Ethics offer a work that critically assesses and advances scholarship in the field of human subjects research with human beings.
The Oxford Textbook of Clinical Research Ethics is the first systematic and comprehensive reference on clinical research ethics. Under the editorship of experts from the National Institutes of Health of the United States, the book offers a wide-ranging and systematic examination of all aspects of research with human beings. Considering historical triumphs of research as well as tragedies, the textbook provides a framework for analysing the ethical aspects of research studies with human beings. Through both conceptual analysis and systematic reviews of empirical data, the textbook examines issues ranging from scientific validity, fair subject selection, risk benefit ratio, independent review, and informed consent as well as focused consideration of international research ethics, conflicts of interests and other aspects of responsible conduct of research. The editors of The Oxford Textbook of Clinical Research Ethics offer a work that critically assesses and advances scholarship in the field of human subjects research with human beings.
Regulators rely on clinical trials for drug approval and labeling decisions. Health systems and clinicians rely on the evidence from trials to determine treatment, and patients rely on it to decide which courses of care to undertake. Many of these stakeholders presume that the careful review of individual studies is enough to address the ethical and scientific questions that arise in clinical trials. In what follows, however, we demonstrate that explicit consideration of trial portfolios—series of trials that are interrelated by a common set of objectives—is crucial. the ethical acceptability and evidentiary probity of individual trials can change depending on the characteristics of the portfolios in which they are embedded. Second, how trial portfolios are composed, how well they are coordinated, and how efficiently they use information determines the balance of risks and benefits they present as well as their different prospects for generating socially valuable information; these three factors also raise distinct questions of justice.
Controlled human malaria infection (CHMI) is a powerful tool to evaluate the efficacy of malaria vaccines and pharmacologics. Investigators at the University of Maryland, Baltimore, Center for Vaccine Development (UMB-CVD) pioneered the technique in the 1970s and continue to advance the frontiers of CHMI research. We reviewed the records of 338 malaria-naive volunteers who underwent CHMI at UMB-CVD with Plasmodium falciparum from 1971 until 2017. These 338 volunteers underwent 387 CHMI events, including 60 via intradermal injection or direct venous inoculation (DVI) of purified, cryopreserved sporozoites. No volunteer suffered an unplanned hospitalization or required intravenous therapy related to CHMI. Median prepatency period was longer in challenges using NF54 (9 days) than in those using 7G8 (8 days), P = 0.0006 by the log-rank test. With dose optimization of DVI, the prepatent period did not differ between DVI and mosquito bite challenge (log-rank test, P = 0.66). Polymerase chain reaction (PCR) detected P. falciparum infection 3 days earlier than thick smears (P < 0.001), and diagnosis by ultrasensitive PCR was associated with less severe symptoms than smear-based diagnosis (39% versus 0%, P = 0.0003). Historical studies with NF54 showed a shorter median prepatency period of 10.3 days than more recent studies (median 11.0 days, P = 0.02) despite significantly lower salivary gland scores in earlier studies, P = 0.0001. The 47-year experience of CHMI at UMB-CVD has led to advancements in sporozoite delivery, diagnostics, and use of heterologous challenge. Additional studies on new challenge strains and genomic data to reflect regional heterogeneity will help advance the use of CHMI as supporting data for vaccine licensure.
Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants’ understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.
