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Human Challenge Studies in Endemic Settings: Ethical and Regulatory Issues

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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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... The practice of "intentional infection of human beings with pathogens with the aim of achieving benefits (chiefly, the prevention of more severe disease)" is not new and dates back to the 18th and 19th centuries (Jamrozik & Selgelid, 2021). Physiciansinvestigators conducted poorly controlled experiments involving deliberate infection of humans, which would be explained by their "rudimentary knowledge of microbiology and lack of available treatments at the time, and perhaps also to the callousness of the investigators" (Jamrozik & Selgelid, 2021). ...
... The practice of "intentional infection of human beings with pathogens with the aim of achieving benefits (chiefly, the prevention of more severe disease)" is not new and dates back to the 18th and 19th centuries (Jamrozik & Selgelid, 2021). Physiciansinvestigators conducted poorly controlled experiments involving deliberate infection of humans, which would be explained by their "rudimentary knowledge of microbiology and lack of available treatments at the time, and perhaps also to the callousness of the investigators" (Jamrozik & Selgelid, 2021). Edward Jenner , whose work is regarded as "the first scientific attempt to control an infectious disease by the deliberate use of vaccination" relied on a challenge study to develop the live vaccine against smallpox-a disease with an alarming death toll, worse than leprosy and syphilis in 18th century Europe (Riedel, 2005;Krylova & Earn, 2020). ...
Article
Human challenge trials to deliberately infect volunteers with SARS-CoV-2 should inspire wider debates about research ethics and participants' motivations to take part in such studies.
... Researchers must therefore devise ways in which participants from all walks of life, regardless of education, can access HIC information in a simple and precise way and can ask questions in myriad ways to enhance retention of information and comprehension [11,24,27]. A study conducted by Jamrozick and Selgelid [28], found that among the unresolved issues was the recruitment and payment of research participants. Among the questions raised where for instance, "conditions under which HICs should recruit students and/or highly educated individuals on the one hand, it has been argued that educated individuals are better able to give informed consent; on the other hand, students may feel pressure to participate which could undermine consent and, furthermore, excluding less well-educated individuals may be unfair and/or reduce the generalizability of HICs results to key populations" [28]. ...
... A study conducted by Jamrozick and Selgelid [28], found that among the unresolved issues was the recruitment and payment of research participants. Among the questions raised where for instance, "conditions under which HICs should recruit students and/or highly educated individuals on the one hand, it has been argued that educated individuals are better able to give informed consent; on the other hand, students may feel pressure to participate which could undermine consent and, furthermore, excluding less well-educated individuals may be unfair and/or reduce the generalizability of HICs results to key populations" [28]. We suggest that as discussed earlier that information about HICs is unpacked to be understood even by lay persons and not necessarily include only those educated. ...
Article
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Human Infection Studies (HIC) involve intentional infection of volunteers with a challenge agent or pathogen with the aim of understanding and developing vaccines as well as understanding the disease pathophysiology in a well-controlled environment. Though Africa carries the highest burden of vaccine-preventable diseases, the region is only now being primed to conduct HIC relevant to its population. Given the imminent introduction of HIC in Zambia, we sought to understand potential participants' willingness to volunteer for such studies. We used a qualitative exploratory approach to understand the potential participants' perceptions on willingness to participate in HIC using the example of typhoid. Healthy adults, recruited using random selection and purposive sampling from higher learning institutions in Lusaka, participated in 15 in-depth interviews (IDIs) and 5 Focus Group Discussions (FGDs) respectively. Participants considered typhoid a serious disease with potential for life-long consequences and death. After sharing audio-visual materials introducing the concepts of HIC, some participants expressed open willingness to participate or alternatively the need to consult parents and professors, and expressed fear of death and illness. Though willing to be quarantined for up to six months, participants expressed concerns regarding separation from family and duties, having insufficient information to decide, inadequate access to care, severe disease, life-long injury or side-effects, death, and vaccine failure. These concerns along with possibility of underlying conditions that compromise individual immunity, competing priorities, parental refusal, and distrust of study or vaccine efficacy could lead to refusal to participate. Reasons for willingness to participate included monetary compensation, altruism and being part of a team that comes up with a vaccine. Though afraid of deliberate typhoid infection, potential participants are willing to consider participation if given adequate information, time to consult trusted persons, compensation and assurance of adequate care.
... Human challenge studies involve exposing research participants to infection under controlled conditions and are often used to estimate the efficacy of experimental vaccines before proceeding to larger trials 48 . Phase III vaccine challenge trials typically involve around 100 rigorously screened young healthy adults, whereas standard phase III trials involve tens of thousands of individuals and often a wider age range of participants. ...
... These competing considerations mean that there may be difficult ethical judgements to be made as to whether challenge studies or field trials are the optimal first method of testing vaccines for diseases where VED is a concern. However, because standard trials involve exposing many thousands more individuals to an experimental vaccine than challenge studies, cumulative risks of VED may be far higher in standard trials 48,49 . In particular, where there are many vaccine candidates, prioritising these candidates in challenge studies before proceeding to larger standard trials with only the most promising vaccines may reduce overall aggregate risks (including those related to VED) 49,50 . ...
Article
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Vaccination is a cornerstone of global public health. Although licensed vaccines are generally extremely safe, both experimental and licensed vaccines are sometimes associated with rare serious adverse events. Vaccine-enhanced disease (VED) is a type of adverse event in which disease severity is increased when a person who has received the vaccine is later infected with the relevant pathogen. VED can occur during research with experimental vaccines and/or after vaccine licensure, sometimes months or years after a person receives a vaccine. Both research ethics and public health policy should therefore address the potential for disease enhancement. Significant VED has occurred in humans with vaccines for four pathogens: measles virus, respiratory syncytial virus, Staphylococcus aureus, and dengue virus; it has also occurred in veterinary research and in animal studies of human coronavirus vaccines. Some of the immunological mechanisms involved are now well-described, but VED overall remains difficult to predict with certainty, including during public health implementation of novel vaccines. This paper summarises the four known cases in humans and explores key ethical implications. Although rare, VED has important ethical implications because it can cause serious harm, including death, and such harms can undermine vaccine confidence more generally – leading to larger public health problems. The possibility of VED remains an important challenge for current and future vaccine development and deployment. We conclude this paper by summarising approaches to the reduction of risks and uncertainties related to VED, and the promotion of public trust in vaccines.
... Since HIS can help to address global burdens of vaccinepreventable diseases, their conduct in countries that carry the highest burden of these conditions is potentially important [3,7,8]. Although many HIS have been conducted in the high-income countries in the past decades, more recently they have been increasing number of HIS also being conducted in low-and middle-income country (LMIC) settings [9][10][11]. This recent increase in the number of HIS in LMICs may be associated with advances in research infrastructure, technical expertise and clinical facilities; more accommodating ethics and regulatory environment; and changing cultural norms [12]. ...
Article
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Background: Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy. Methods: Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives. Findings: Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers' families, study staff and the research institution's reputation more widely. Conclusion: Developing ethically and scientifically strong HIS relies on grounded accounts of volunteers, study staff and the wider community, understood in the socioeconomic, political and cultural context where studies are implemented. Recognition of the diverse, and sometimes perverse, nature of potential benefits and burdens in a given context, and who this might implicate, is critical to this process. Prior and ongoing stakeholder engagement is core to developing these insights.
... However, there are several works dedicated to linguistic and cultural study of moral and ethical concepts (Abulad, 2018;Jamrozik, 2020;Lehnmann, 2018, etc.) and particular writings covering issues of foreign language teaching based on linguistic and cultural concepts (Koilybaeva, 2018;Mashanova, 2019;Shirinxon, 2020;Svenkerud, 2020, etc.). Moreover, there are special studies on concepts based on materials of Russian and other languages (including concept "druzhba" (friendship)): A. Vezhbitska (Vezhbitska, 2001), G.V. Prikhodko (Prikhodko, 2011), M.A. Khizova (Khizova, 2005), A.D. Shmelev (Shmelev, 2002), G. Harras (Harras, 2020), S. Günthner (Günthner, 2019), R. Schmitt (Schmitt, 2018), N.R. Ruzibaeva (Ruzhibaeva, 2021), Ling Wei (Ling Wei, 2020), M. Schramm (Schramm, 2019), etc. ...
Conference Paper
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Due to increasingly larger role of remote technologies the current educational reality is closely related to reduction of time devoted to live interactions between the participants of the educational process. Certain detachment of students from real intercourse may result in growing pressure in communication field, with the representatives of other countries, in particular. At the same time, socialization of modern young people is happening in the environment of prospering society's ideas of consumption, when moral self-identification becomes an issue, an issue of state safety as well since it affects decisions made by a person. In this connection works dedicated to moral development of personality in the modern society from the perspective of cross-cultural communication, i.e. dedicated to development with due consideration of national specifics of main moral concepts in target-language countries, seem to be relevant for the foreign language teachers. Purpose of the conducted study is development of exercises for students studying foreign languages based on linguistic and cultural analysis of concepts of moral field, "druzhba" (friendship) and "Freundschaft", supporting formation of a productive language personality. This goal has been achieved by methods of componential analysis of dictionary definitions, contextual use, by comparative study of above mentioned moral concepts in folk literature. The conducted investigation resulted in development of a list of efficient, cross-culturally relevant types of exercises for thorough examination of specifics of moral concepts "druzhba" (friendship) and "Freundschaft". Materials and results of the study can be applied in development of training courses and special courses on cultural linguistics, cross-cultural communication, in practical foreign language teaching; they can be used in further studies of concept field "friendship" in various world cultures.
... In research ethics, asymptomatic infection might also raise a range of ethical issues, for example, regarding appropriate policies regarding the management of (1) infections that are incidentally diagnosed as a result of research participation (similar to incidental findings in human genetics research) (Magiorkinis et al. 2019) or (2) The potential for such findings might have implications regarding the expected benefits and risks of relevant research (including both risks to participants and risks to third parties, who could potentially be infected by participants identified as carriers), as well as for consent and follow-up of participants. More generally, infectious disease research often involves potential risks to third parties (who might be infected by research participants) whether or not participants who carry an infection develop symptoms, and researchers might have particularly strong duties to mitigate such risks in certain types of research-such as human challenge studies, which involve intentional infection of research participants (Shah et al. 2018;Eyal et al. 2018;Jamrozik and Selgelid 2020a). It is noteworthy that asymptomatic infection is sometimes an explicit consideration in the design of vaccine trials, which sometimes (including during epidemics, discussed below) require detection of asymptomatic infection in order to determine vaccine efficacy (Kahn et al. 2019). ...
Article
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Interactions between microbes and human hosts can lead to a wide variety of possible outcomes including benefits to the host, asymptomatic infection, disease (which can be more or less severe), and/or death. Whether or not they themselves eventually develop disease, asymptomatic carriers can often transmit disease-causing pathogens to others. This phenomenon has a range of ethical implications for clinical medicine, public health, and infectious disease research. The implications of asymptomatic infection are especially significant in situations where, and/or to the extent that, the microbe in question is transmissible, potentially harmful, and/or untreatable. This article reviews the history and concept of asymptomatic infection, and relevant ethical issues associated with this phenomenon. It illustrates the role and ethical significance of asymptomatic infection in outbreaks, epidemics, and pandemics–including recent crises involving drug resistance, Zika, and Covid19. Serving as the Introduction to this Special Issue of Monash Bioethics Review , it also provides brief summaries of the other articles comprising this collection.
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The traditional regulatory pathway for the evaluation of new vaccine candidates generally proceeds from preclinical through three successive phases of human trials, and the demonstration of efficacy is usually done through randomized-controlled clinical trials. However, human challenge trials or controlled human infection models have been used in vaccine clinical development to generate supportive data for establishment of correlates of protection, supportive data for licensure, as well as licensure in the case of Vaxchora® by the US FDA. Despite this, there are no codified regulations from national regulatory authorities (NRAs) that specifically address HCTs, nor guidance related to standardization of approaches to HCTs among regulators. NRAs may agree that HCTs are innovative, promising tools to accelerate vaccine development; however, a strong benefit/risk assessment is needed to ensure the safety of study participants. Lastly, it is important to consider the regulatory framework in which the human challenge trial may be conducted.
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The pandemic caused by the new SARS-CoV-2 virus is driving the need to test and approve new vaccines quickly. The report enucleates the ethical criteria that must be respected in this context. It describes the scientific and methodological aspects underlying the experimentation of vaccines, the regulatory aspects, the procedures adopted to reduce the time needed to grant authorizations. It highlights the need to not deviate from the rigor of the methodology and the ethical requirements that must always be guaranteed, even in emergency conditions.
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Human challenge trials (HCTs) are a potential method to accelerate development of vaccines and therapeutics. However, HCTs for COVID‐19 pose ethical and practical challenges, in part due to the unclear and developing risks. In this article , we introduce an interactive model for exploring some risks of a severe acute respiratory syndrome coronavirus‐2 (SARS‐COV‐2) dosing study, a prerequisite for any COVID‐19 challenge trials. The risk estimates we use are based on a Bayesian evidence synthesis model which can incorporate new data on infection fatality risks (IFRs) to patients, and infer rates of hospitalization. The model estimates individual risk, which we then extrapolate to overall mortality and hospitalization risk in a dosing study. We provide a web tool to explore risk under different study designs. Based on the Bayesian model, IFR for someone between 20 and 30 years of age is 15.1 in 100,000, with a 95% uncertainty interval from 11.8 to 19.2, while risk of hospitalization is 130 per 100,000 (100–160). However, risk will be reduced in an HCT via screening for comorbidities, selecting lower‐risk population, and providing treatment. Accounting for this with stronger assumptions, we project the fatality risk to be as low as 2.5 per 100,000 (1.6–3.9) and the hospitalization risk to be 22.0 per 100,000 (14.0–33.7). We therefore find a 50‐person dosing trial has a 99.74% (99.8–99.9%) chance of no fatalities, and a 98.9% (98.3–99.3%) probability of no cases requiring hospitalization.
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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 .
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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.
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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.
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We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with five doses at 0, 4, 8, 12, and 20 weeks of 2.7 × 105 PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and 52% (time to event) or 29% (proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge. Twenty- to thirty-year-old men were randomized to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial. Vaccine efficacy was assessed 3 and 24 weeks later. Adverse events were similar in vaccinees and controls. Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria-naïve Americans, but significantly higher than in Malians. All 18 controls developed Pf parasitemia after CHMI. Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by time to event, P = 0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by time to event analysis). Plasmodium falciparum SPZ Vaccine was safe, well tolerated, and induced durable VE in four subjects. Controlled human malaria infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in United States or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.
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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.
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