Ethical issues surrounding controlled human infection challenge studies in endemic low‐and middle‐income countries

Abstract Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro‐organisms. There have been increased calls for more CHIs to be conducted in low‐ and middle‐income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third‐party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well‐designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly.

CHIs can accelerate the development of new vaccines (and therapeutics) because they can be substantially smaller, shorter, and less expensive than other kinds of studies. 1 Among other advantages, far fewer people need to be given experimental vaccines (that might not turn out to be safe or effective) in CHIs in comparison with vaccine field trials, which require many more participants (e.g., up to tens of thousands per field trial as opposed to the <100 participants in most CHIs). CHIs can also provide unique insights into host-pathogen Although the vast majority of the burden of infectious diseases occurs in low-and middle-income countries (LMICs), CHIs have until recently been conducted almost exclusively in high-income countries (HICs) where many diseases of interest (e.g., malaria, typhoid, schistosomiasis, etc.) rarely occur. Of the more than 40,000 people that have participated in CHIs in the ~70 years since World War II, 6 only around 400 participants took part in LMIC CHIs (in just 13 LMIC studies up to 2018)-i.e., less than 1% of the global total. 7 Potential reasons for the vast majority of CHIs having been conducted in HICs (even for pathogens that are not locally endemic) include: (a) the presence of more/better funded research infrastructure and researchers in HICs; 8 (b) the greater availability of healthcare resources required to care for CHI participants in HICs, thus providing greater assurance of risk minimization; 9 (c) the reluctance to conduct research on apparently "vulnerable" populations in LMICs.
The relative current research capacities of HICs and LMICs, including capacity for CHIs, are arguably the result of longstanding injustices in the global distribution of wealth and thus, inter alia, funding for research. This has in turn contributed to a relative neglect of research regarding pathogens that are mainly endemic in LMICs and the perpetuation of large inequities in the global burden of disease. Furthermore, research on HIC volunteers may not always be generalizable to populations in LMICs (e.g., due to population differences regarding naturally acquired immunity, co-infections, genetics, microbiome, nutrition, etc.), among whom the burden of the relevant disease is often greatest. 10 There have thus been calls for more CHIs in LMICs in order to remedy such neglect, generate results that are more relevant to at-risk populations, and build local research capacity. 11 Despite the potential scientific advantages and other benefits of (LMIC) CHIs, such studies are nonetheless ethically sensitive. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nature Reviews Immunology, 11 (1), 57-64.

| Literature review
The details of our literature review are included in the full Final Report of our research project. 12 Briefly, the review of academic literature and regulatory documents was particularly focused on identifying (a) primary scientific papers detailing LMIC CHIs, (b) relevant historical examples of (other) CHIs, (c) regulatory documents or policy consultations specific to CHIs (whether HIC or LMIC), and (d) bioethical analyses of CHIs and/or ethical issues relevant to CHIs in LMICs.

| Qualitative interviews
We conducted qualitative interviews with 45 participants (Table 1).
Participants were initially recruited based on (a) involvement in the conduct of CHIs in LMICs, (b) scientific or ethical expertise specifically related to CHIs, (c) expertise in research ethics, and/or (d) involvement in the regulation and/or funding of CHIs research. Further informants were recruited by "snowball" sampling based on suggestions from initial participants. As detailed in Table 1, we recruited a diverse group of informants with different kinds of expertise and based in different locations (in most cases, scientist participants based in HICs had been directly involved in LMIC CHIs).
As part of the informed consent processes, interview participants agreed to be quoted anonymously (by pseudonym) and/or to waive the right to anonymity and be quoted by name. Interview recordings were transcribed and all data were stored in a secure manner. Transcripts were de-identified, organized and cleaned before being coded with a combination of pre-set and open coding. The research team agreed upon an initial code list based on the main aims of the study; and coding then progressed openly and iteratively as emergent codes arose and coding categories were further refined as agreed by the research team. Coded data were analyzed to identify overarching themes and sub-themes (that were validated through initial member checking in subsequent interviews and via the mechanisms discussed below) with validated themes being used to inform the structure of the Final Report. 13

| Synthesis and validity checking
The findings of the literature review and thematic analyses of qualitative data were synthesized in the Final Report. This paper presents a subset of themes highly relevant to the ethical acceptability of CHIs in endemic LMIC settings (see Table 2) and includes a selection of interview data. Draft copies of the Final Report were shared with (a) a subset of participants who provided feedback to the research team (enabling an assessment of internal validity) and (b) participants at two international meetings of researchers and policymakers with relevant expertise (enabling an assessment of external validity and transferability). 14 Comments were incorporated and/or addressed as appropriate (in most cases with de-identified acknowledgement in light of participants' wishes).

| E THI C AL ISSUE S REL ATED TO ENDEMI C LOW-AND MIDDLE-IN COME COUNTRY CONTROLLED HUMAN INFEC TI ON S TUD IE S
Controlled human infection studies raise a number of ethical issues, many of which are familiar within research ethics discourse more generally (and/or discussed elsewhere in this Special Issue), though they may have specific implications in the context of (LMIC) CHIs (see Table 2). Assuming CHIs are, at least in-principle, ethically acceptable an initial question relates to the degree of ethical justification for conducting a particular (type of) study in a particular (type of) setting. Below, we consider why there may be an especially strong case for conducting (appropriately designed) CHIs in endemic settings, presenting several reasons raised by interviewed experts. We show that certain ethical issues related to their design and conduct nonetheless warrant particularly careful attention in later sections of this paper that focus on (a) potential direct benefits for participants, (b) risks to participants, In the next section we address each of the following topics and their specific implications in the context of endemic LMIC CHIs: (a) the potential for direct participant benefit, (b) the potential risks for participants, including the evaluation of such risks in light of background risk, (c) the potential risks to third parties, (d) appropriate informed consent practices, (e) appropriate payment of participants, and (f) appropriate community engagement and its relevance to local community acceptance of CHIs.

| Potential individual benefits for participants
CHI participants in non-endemic settings would usually have little or no chance of benefiting directly from controlled infection with pathogens (which they would not encounter in daily life). However, if a person is at high risk of infection with the relevant pathogen in daily life (e.g., in endemic settings), being infected in the course of CHIs will often (a) entail less risk than being infected "in the wild" (e.g., because of more immediate diagnosis and comprehensive medical care) and in some cases (b) confer a benefit in terms of immunity (whether partial or complete/"sterile") similar to that of vaccination of not participating and … deliberate exposure." Such  In summary, if risks are minimized through appropriate study design (e.g., the development/use of appropriate study infrastructure and the exclusion of individuals with relevant comorbidities) CHIs in endemic settings will involve at most the same risk and, in many cases, less increased risk to participants (e.g., for those with prior immunity and/or innate resistance) as compared with those in non-endemic settings.

| Third-party risks
Depending on how a study is designed (and on local epidemiological factors) CHIs may be associated with some level of risk of transmission of the challenge infection from participants to third parties.
Regarding such risks in infectious disease research more generally, some have argued that investigators have significant ethical duties to third parties, extending even to the need to seek consent from (identifiable) potentially at-risk third parties before commencing a study. 32 One way to obviate the need for such additional consent procedures is to reduce third-party risks to near zero by (a) rigorous infection control and biosafety procedures at CHIs research centers, and, in some cases (b) strict isolation of participants (e.g., by keeping them in an "inpatient" setting for the period during which they are potentially contagious), although this in turn may entail significant burdens for participants. Given this potential controversy, and given the potential for thirdparty risks to undermine public trust in research, the potential for such risks would constitute an additional reason for robust community engagement (to assess community views on the importance of such risks and/or to seek "community consent" for the research to proceed) and for carefully designed research procedures that reduce third-party risks.

| Consent
Recent CHIs in both HICs and LMICs have generally been conducted with relatively comprehensive and stringent consent processes, involving multiple information sessions for participants, and tests of understanding to ensure that prospective participants comprehend important aspects of the study before consenting to enrolment. 35 Given that such processes involve complex information, it is sometimes thought that it would be more ethical to recruit those with higher levels of education as research participants because this may improve informed consent (e.g., if educated participants more easily understand information about the study). Some CHIs (including in LMICs) have thus aimed to recruit tertiary-educated individuals and/ or university students (especially medical students) in particular. 36 Despite these apparent advantages, there are also several ethical disadvantages of such a recruitment strategy: (a) excluding less educated individuals might be unjustified if they are able to understand a study well enough to provide adequate informed consent, (b) university students (or those who have received university education) may not be representative of the eventual target population for an intervention (e.g., because they are more likely to be affluent and/or to live in cities and less likely to live in highly endemic parts of LMICs and/or because in some countries women are much less likely than men to receive university education), (c) excluding less well educated individuals from CHIs research may thus be unfair, especially where poor and/or less well educated and/or female individuals are at higher risk of the disease in question (yet excluded from research regarding a given pathogen), (d) students may feel pressure to participate (e.g., from academics within the faculty with an interest in the study) making consent less voluntary, and (e) educated individuals (e.g., healthcare workers) may sometimes actually be less compliant with study protocols than other potential participants. 37 In practice, LMIC investigators have sometimes been successful in recruiting enough tertiary-educated individuals for CHIs, 38 whereas others have found it difficult to recruit as many students as planned (and thus recruited others with lower average education levels). 39 Social scientists embedded with some recent challenge studies have suggested that many less educated individuals appeared to be able to provide adequate informed consent, especially with well-designed community engagement and multiple opportunities for careful explanation of the study. 40 As one researcher noted: There were all kinds of education levels. so you need to … research whether it's going to work in that population as well.
There may be one additional way in which recruiting those who live in or near highly endemic areas, even if they are less educated, is ethi- In summary, (a) presumptions in favor of recruiting only tertiary-educated individuals may not always, on balance, be ethically justified; and (b) those in endemic settings who are familiar with the disease in question may be well placed to understand the risks inherent in CHIs and may also be more motivated to participate in research aiming to reduce the (local) burden of relevant diseases.

| Payment
Many LMIC populations in endemic areas have relatively high levels of economic disadvantage as compared with those in (non-endemic) HICs. Thus, issues related to payment and/or undue inducement may be (or be perceived to be) particular concerns in LMICs (although such concerns are not unique to CHIs). With regard to payment, participation in CHIs often involves significant time commitments and other burdens for participants (including, in some cases, long inpatient stays) and, in HICs, attracts relatively high levels of payment. There was widespread agreement in our qualitative data that it is considered appropriate to provide payment to participants, including those in LMICs, in order to offset these burdens. As one HIC scientist suggested: Often the procedures for challenge studies are really quite onerous compared to other studies so if you just add all that up together, just logically, the amount that they should be paid is more than for other studies.
How much that should be should probably be linked to local purchasing parity. That makes sense to me. social science components, which may help to clarify the importance of such effects as well as refine decisions regarding payment and study design more generally. 46

| Community engagement and public acceptability
A major finding of our project was that public acceptance of locally conducted CHIs is widely considered a sine qua non of ethical

| CON CLUS IONS
There are ethical and scientific reasons in favor of conducting endemic LMIC CHIs in order to address the persistently high burden of infectious diseases in disadvantaged populations. In many cases, carefully conducted endemic LMIC CHIs will lead to results that are more relevant to high-risk target populations. Furthermore, well-designed endemic-region CHIs may have a more favorable profile of risks and benefits for participants (as compared with those in non-endemic CHIs), and potentially other benefits related to improving local research capacity. However, controversies persist regarding third-party risks, and these should be carefully assessed and minimized. Meanwhile, there was evidence of a consensus among stakeholders that payment for burdensome (LMIC) CHIs is appropriate, and recognition that blanket exclusion of less educated individuals may not, in many cases, be ethically appropriate. These findings may help to inform ongoing debates in research ethics regarding risk-benefit analysis, payment, and consent.
Finally, community consultation and social science work alongside biological scientists conducting CHIs may help to ensure the acceptability of CHIs among participants and communities and thus the ethical acceptability and sustainability of this type of research.

ACK N OWLED G M ENTS
This work was supported by the Wellcome Trust (210551/Z/18/Z).
We are grateful for the invaluable contributions of qualitative interview participants, including those who anonymously reviewed draft manuscripts of the final report for this project. We also thank at-