Human infection challenge studies in endemic settings and/or low-income and middle-income countries: key points of ethical consensus and controversy

Abstract

Human infection challenge studies (HCS) involve intentionally infecting research participants with pathogens (or other micro-organisms). There have been recent calls for more HCS to be conducted in low-income and middle-income countries (LMICs), where many relevant diseases are endemic. HCS in general, and HCS in LMICs in particular, raise numerous ethical issues. This paper summarises the findings of a project that explored ethical and regulatory issues related to LMIC HCS via (i) a review of relevant literature and (ii) 45 qualitative interviews with scientists and ethicists. Among other areas of consensus, we found that there was widespread agreement that LMIC HCS can be ethically acceptable, provided that they have a sound scientific rationale, are accepted by local communities and meet usual research ethics requirements. Unresolved issues include those related to (i) acceptable approaches to trade-offs between the scientific aim to produce generalisable results and the protection of participants, (iii) the sharing of benefits with LMIC populations, (iii) the acceptable limits to risks and burdens for participants, (iv) the potential for third-party risk and whether the degree of acceptable third-party risk is different in endemic settings, (v) the conditions under which (if any) it would be appropriate to recruit children for disease-causing HCS, (v) appropriate levels of payment to participants and (vi) appropriate governance of (LMIC) HCS. This paper provides preliminary analyses of these ethical considerations in order to (i) inform scientists and policymakers involved in the planning, conduct and/ or governance of LMIC HCS and (ii) highlight areas warranting future research. Insofar as this article focuses on HCS in (endemic) settings where diseases are present and/or widespread, much of the analysis provided is relevant to HCS (in HICs or LMICs) involving pandemic diseases including COVID19.

Promoting Ethical Payment in Human Infection Challenge Studies

“…Overall, we find no reason to conclude that the basic framework for ethical payment applicable to other types of clinical research cannot also be applied successfully to HICS, which is not to say that the considerations discussed in this section are irrelevant to HICS payment, but only that they do not merit a wholly unique approach. This is in line with available ethics literature regarding HICS, which indicates some familiar concern about financial influence on informed consent, while acknowledging the importance of fair compensation, the need to avoid both exploitation and deception, and analogies to paid employment-and which generally agrees that payment for HICS is not necessarily of unique concern (Miller and Grady 2001;Bambery et al 2016;Shah et al 2017;Anomaly and Savulescu 2019;Grimwade et al 2020;Jamrozik and Selgelid 2020;.…”

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

“…Controlled Human infection (CHI) models present an opportunity to not only disentangle the different parameters at play in endemic settings, but also accelerate the vaccine development pipeline in general. In the implementation of the CHI model, healthy volunteers are intentionally infected with a pathogen with the aim of generating knowledge on natural history of a disease, testing vaccines or therapeutics, and developing reliable and defined models of infection for future studies ( 179 ). These studies are controlled in terms of dose and route, production and selection of the pathogen strain administered.…”

“…These studies are controlled in terms of dose and route, production and selection of the pathogen strain administered. Additionally, a “controlled” condition/environment is key to prevent natural infection during the study period ( 179 ). Therefore, signs and symptoms of disease, and evolution of responses following a defined timing of the exposure can be observed in a well described and managed manner.…”

“…Hence, CHI studies reduce the burdening cost and time requirements, and the high downstream vaccine efficacy failure, associated with classical clinical trials approach. Noteworthy, for safety and ethical concerns, the CHI approach is applicable only for infections/diseases that are self-resolving and or are treatable such as schistosomiasis ( 179 , 180 ).…”

SARS-CoV-2 (COVID-19) Vaccine Development and Production: An Ethical Way Forward

“…Normal Phase III trials often involve thousands of subjects; HCS trials may enroll fewer than 100 while still providing the information necessary to determine if the vaccine is safe and effective. 18 Although physicians participating in HCS trials seemingly breach the basic professional principle to "do no harm," they enter such research to stop or prevent worldwide pandemics. 19 Nonetheless, some argue that HCS trials, with their inherent risk to participants, can only be performed in "treatable or selflimiting diseases where no irreversible pathology is known to occur"-certainly not the case with COVID-19.…”