Deliberately infecting healthy volunteers with malaria parasites: Perceptions and experiences of participants and other stakeholders in a Kenyan‐based malaria infection study

Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders’ perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in‐depth interviews and non‐participant observation. Sixty‐nine participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive‐deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff. Volunteers’ experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context.


Funding information
We would like to acknowledge the Wellcome Trust and the Brocher Foundation for facilitating a research conference on the ethics of CHI models. This work was funded by a Making a Difference Grant from the Greenwall Foundation. Wellcome Trust; Brocher Foundation; Greenwall Foundation, Grant/Award Number: Making a Difference Grant. This empirical ethics study was supported by a Wellcome Trust grant (107499); which funded the CHMI study, Wellcome Trust Core fund grant number 203077 and the Global Health Bioethics Network which is supported by a Wellcome Trust Strategic Award 096527. All the authors are supported by grants from Wellcome Trust. IJ is supported by a Wellcome Trust Core fund grant number OXF-COR04-2321 and DK is supported by Wellcome Trust fellowship grant number 205419-Z-16-Z.
[Correction added on 28 August 2020, after first online publication: The funding information has been updated.] Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders' perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in-depth interviews and non-participant observation. Sixty-nine participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive-deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff.
Volunteers' experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context.

K E Y W O R D S
Africa, challenge studies, controlled human infection studies, deliberate infection, developing countries, ethics 1 | INTRODUC TI ON

| Controlled human malaria infection in endemic areas in low-to middle-income countries (LMICs)
Controlled human malaria infection (CHMI) studies involve deliberately infecting healthy volunteers with malaria pathogens under controlled conditions to observe the natural history of the pathogen or to test drug or vaccine efficacy. 1 Volunteers are then observed and monitored closely to facilitate a detailed evaluation of parasite growth dynamics and immunological responses to malaria infection. 2 Deliberate infection allows the studying of early stages of infection which is otherwise difficult to assess, given that malaria infections are mostly asymptomatic at these early stages, adding to the social value of CHMI. 3 Given these features, CHMI studies have increasingly been seen as an important scientific tool in malaria control and elimination. 4 While controlled human infection (CHI) studies intrinsically carry different levels and forms of risk depending on the pathogen under study, many have had a good safety record due to the stringent research practices followed; studies are conducted under carefully controlled conditions where the type of pathogen, dosage, route and timing of administration are carefully planned to minimise probability of serious harm. 5 Volunteers' health and wellbeing are closely monitored by qualified clinical staff and volunteers are immediately treated should they become symptomatic or feel unwell. 6 Additionally, pathogens used in CHI studies have been either self-limiting or readily controlled with appropriate low-risk treatments that are made immediately available to volunteers. 7 Risks that CHI studies pose are further mitigated through health screening prior to enrolment. 8 Where CHI studies have potential third-party risks or safety issues, volunteers maybe be provided with prolonged residential or in-patient accommodation. 9 CHMI studies have been increasingly conducted in malaria-endemic settings in LMICs in response to the need for more effective vaccines and therapies in areas where malaria is an important public health burden. 10 A faster turn-around of results and the involvement of smaller number of volunteers in CHI studies offer important advantages over traditional clinical trials. 11 The social value of CHMI studies conducted in malaria endemic settings is argued on the basis of the high burden of malaria disease and deaths in these settings; relatively modest efficacy of recently developed malaria vaccines; 12 and the view that CHMI studies may present less risk or harm to volunteers in these settings who have prior exposure to the infection, including through higher innate resistance to the pathogen as a result of naturally acquired or genetic resistance. 13

| The study site and 'parent' CHMI study in Kenya
The This programme of research has involved three phases, with Phase 1 conducted in Nairobi and Phases 2 and 3 at the KWTRP main hub in Kilifi. Each phase included a set of CHMI volunteers that were followed up to completion of their study participation before another phase was initiated. Phase 1 was a 'proof of concept' study in a setting where almost no malaria transmission occurs, and involved a small group of medical students. 24 Phase 2 included volunteers from areas of low and moderate malaria transmission in Kilifi, and Phase 3 involved Kilifi residents as well as volunteers from a high malaria transmission area in Kisumu in Western Kenya. 25 Figure 1 shows the geographic positioning of these sites. The first study on social and ethical aspects of CHMI SIKA was conducted during Phase 2. 26 The qualitative study reported on in this paper was conducted within Phase 3, at which point, a total of 161 healthy volunteers had been recruited across the programme, aged between 18 and 45 years and with prior exposure and varying levels of immunity to malaria.
During CHMI SIKA Phase 3, volunteers found healthy on screening and who demonstrated understanding of the study were enrolled. 27 An intravenous injection of Plasmodium falciparum sporozoites was administered on the day of enrolment into the study and volunteers admitted into an adapted residential facility at a nearby university. A 3-day course of malaria treatment was given to those for whom (i) the density of infection exceeded a threshold (500 parasites per µl 28 ) with or without symptoms, (ii) had symptoms and a blood film examination 16   showed evidence of malaria infection, or (iii) no symptoms had developed by the study end-point at 21 days. Overall volunteers were in residency at the university for between 15 and 24 days. The volunteers were reviewed at the research centre 35 days post-infection.

| The embedded empirical ethics study
The embedded empirical ethics study drew on a range of qualitative research methods, including in-depth interviews, focus group discussions, non-participant observations 29 and study document review. For clarity, we refer to individuals joining the qualitative study as 'study participants' while those in CHMI SIKA are described as 'volunteers'.

| Participants in the empirical ethics study
The empirical ethics study included a total of 69 participants, including CHMI SIKA volunteers (n=32), study staff (principal investigator, study clinicians and fieldworkers 30 ) (n=17) and community representatives 31 (n=20). Table 1 gives participants' sociodemographic characteristics. In summary, participants who were CHMI volunteers were aged between 19 and 45 years, community representatives' ages were from 27 to 73 years and the study staff from 30 to 48 years. More than half (53.3%) of CHMI volunteers participated in the empirical ethics study, consisting of all 15 CHMI volunteers from Kisumu and 17 of the 45 volunteers from Kilifi. The Kilifi volunteers who were not involved in the qualitative study were those who were symptomatic for malaria, on malaria treatment (and therefore preparing to exit the study) or declined to participate. 32 KEMRI community representatives were selected purposively on the basis of residing in the geographic locations from which CHMI volunteers had been recruited. All CHMI study staff were invited to participate in the empirical ethics study. Five CHMI volunteers were followed up at home 8-9 weeks after exiting the study; this group were purposively selected on the basis of diversity in their social and research experiences to include: a female household head, a female participant who had experienced severe malaria symptoms and three individuals (one female and two male) whose families had not been supportive of their participation in the CHMI study.

| Data collection
Data were collected mainly by IJ through observations, in-depth interviews (eight) and focus group discussions (10), as summarised in The tool was piloted before use and, as is typical for qualitative data collection, some of the questions were revised during data collection, informed by issues identified at debrief meetings following each interview. Most revisions were minor, for example adding prompts to clarify questions.

| Data analysis
All interviews and group discussions were audio-recorded. The data were transcribed verbatim, translated into English and managed with QSR Nvivo 10 software. Field notes were used to provide insights into the context and study-related interactions. The data analysis followed a framework analysis 38 approach, including the following steps: IJ, DK and PC reviewed and coded one transcript individually and later discussed it together, where they resolved any discrepancies in the coding and agreed on the initial coding framework. Three other transcripts were then coded by IJ and reviewed by this group to further refine the coding framework. 39 All other transcripts were then coded by IJ and discussed with DK, and categories, themes and sub-themes developed iteratively from codes, both inductively (from data) and deductively (drawing on ethics frameworks). 40 Analysis charts were then drawn for comparison across themes and participant groups.
Throughout the tool development, data collection and analysis the researchers were aware of and tried to take account of their positionality, especially with regard to their roles as KEMRI staff, and their personal views on CHMI studies. For example, as KEMRI staff, the social value as well as potential sensitivities for the CHMI research approach were well recognised. For this reason, we aimed to be as reflexive as possible during data collection and analysis about our own potential influences, paying attention to the need to maintain a neutral stance, including probes around counter-points during questioning, ensuring supportive dynamics within group discussion and working as a team to check emerging ideas and consider sources of influence. Additionally, IJ and DK had been introduced to the CHMI volunteers during screening, enrolment and study engagement activities, giving them an opportunity to build rapport prior to data collection.  our previous publication, (iii) trust in the research institution and in researchers, and (iv) trust in the protocol review processes.

| KEMRI community representatives
Almost all respondents across all groups expressed strong altruistic motivations for participation, but more so the Kisumu participants who came from a highly malaria endemic area, and felt that the outcomes of the study would be of benefit in the future both locally and internationally.
I have a passion for children and pregnant women. I wouldn't like to see pregnant mothers die and children under five who are vulnerable to malaria die just because we lack a proper vaccine to prevent malaria. And that is why I was driven to participate so that we could find a new way, I mean, a vaccine or a drug that could reduce the mortality rate, yes … That is the thing that gave we talked and I explained that we may be away for one month and if it will be our luck we will get that money and build our home. (M_38_Primary education_Tailor) Also as alluded to in earlier sections, trust in the research institution was a key influence on decision-making, given concerns about safety and the need for reassurance that KEMRI could be trusted to guarantee this.
Perceptions of trust towards KWTRP was described based on its positive reputation for research and supporting healthcare, its long-standing presence and positive relations in the community, and a belief that it would not intentionally harm people in the community. Interestingly, some volunteers had learnt about the CHMI study from relatives who had participated in earlier phases, and were reassured by this knowledge: I too did not have any doubts because in the second group my nephew was here, my brother was also here and they came and participated and went back home, the parasites were not detected and they got the dose [malaria treatment] and up to now they have not been sick and do not have any problem. (F_42_Primary education_Farmer) About a half of the respondents across all the groups, including those who had never participated in research before, also spontaneously reported trusting the research review processes in the country.
Information about the review process was included in the consent forms, was discussed during information giving and community engagement processes and a telephone number to the national research regulation office included in the consent form.

| Future CHI: participating and supporting
It is clear from our data that the reality of some of the burdens (for example, the levels of anxiety associated with being given an infection, the discomfort of having frequent blood sampling and the discomfort and anxiety associated with having an acute malaria infection) had not always been fully taken into account during decision-making. In future publications we aim to explore these issues in more depth, particularly around decision-making on participation in relation to risks of undue inducement, and forms and levels of physical, social and emotional burdens or harms experienced by volunteers, including longer term follow-up data.
Arguably as a 'marker' for ways in which volunteers weighed up their experiences of CHMI SIKA overall, many expressed interest in participating in future similar studies, that is, research involving deliberate infection with an acute and treatable pathogen: I think I would participate again in another exercise.
At first it was a risk taking, but now I feel I can with- to their reputation should the CHMI study cause problems in the community. Highlighting that CHMI studies were being importantly justified through their putative social value, participants strongly recommended that any vaccine candidates discovered through this route should be quickly moved into trials to accelerate the vaccine development process.

| D ISCUSS I ON
CHI studies in LMICs are relatively new, have the potential to accelerate discovery of much needed therapies including vaccines, and present a range of ethical issues, as outlined in the introduction to this paper. The potential social value of the research has been argued as a core justification for conducting CHI studies in LMIC for diseases endemic in these settings. 46  In this discussion we aim to underline findings that showed that the fact of being deliberately infected (by injection in this case) with a disease-causing organism can have an impact on volunteers that may go beyond biomedical understandings of safety but are nonetheless critical aspects of wellbeing, and have a moral importance for arguments about the acceptability of deliberate infection. In our study, deliberate infection was seen as a highly unusual research strategy amongst volunteers and the community representatives. As we have shown, and go on to discuss, the notion engendered sometimes very high levels of anxiety over the course of participation, alongside experiences of ill-health-where malaria infection followed-which were at times perceived as very severe. We note that the individual psychological experiences of excitement, anxiety and fear fluctuated strongly over the period of participation, primarily in relation to specific research activities, but also influenced by social relations between volunteers and staff. Similarly, over prolonged periods of residency, psychological and emotional burdens were common, and responded to by the study team.

| Tensions and fluctuations within emotional responses to being a volunteer in the CHMI study
In this and our earlier paper, 50

| Physical, emotional and social harms
Volunteers in CHMI SIKA who participated in our study described a range of physical, emotional and social burdens or harms associated with the period of residency required in this study. We particularly note the fluctuating nature of these harms over time and the dissonance between a theoretical understanding of the procedures in-  Decisions to join and remain in the study hinged on familiarity with malaria as a common and treatable condition, levels of compensation, altruism, observation of the experiences of earlier volunteers and trust in the expertise of the study team, the research programme, and the research review system. Volunteers' excitement of being involved in the study, and their hopes and fears in relation to this, shifted in nature, extent and focus over the course of the study, reflecting the unfamiliarity of some research processes involved.

| CON CLUS ION
Amongst those CHMI volunteers who developed malaria symptoms, some experienced severe physical discomfort; volunteers' burdens also included fluctuating but sometimes severe forms of psychological and emotional reactions across the duration of residency.
Heightened levels of anxiety occurred particularly during the injection with malaria parasites, suggesting high levels of discomfort with this CHMI study procedure. These findings highlight the importance of understanding grounded realities for volunteers over time in defining the ethical dimensions of CHI.
We argue that researchers planning for CHMI studies and reviewers should consider both the physical, social and psychological burdens of participation when assessing levels of risk for these studies. We further argue that ethics oversight of CHMI studies should take account of these issues, in deciding whether consent, engagement and the balance of benefits and harms for a given CHMI are reasonable in a given context. To address these issues, we suggest that skilled counselling services should be provided both for CHMI communication and management of emotions may be important for study staff given the extra responsibilities they take on to offer emotional support to volunteers throughout the study.

ACK N OWLED G EM ENTS
We are grateful to all participants including the CHMI volunteers in Kilifi and Kisumu, the KCR members and study staff. We appreciate the support from the wider CHMI investigator team that enabled us to embed our research in the Malaria CHMI study; supported by a Wellcome Trust grant (107499), core grant to Kilifi, Kenya (203077) the Global Health Bioethics Network that is supported by a Wellcome Trust Strategic Award (096527) The manuscript is published with the support of the Director, KEMRI.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

AUTH O R B I O G R A PH I E S
Irene Jao is a nurse and social science researcher in the Health