In this section, we present our findings under three broad headings. First, we describe stakeholders’ views on the acceptability of pneumococcal HIS, including perceived benefits, concerns, and views about whether, overall pneumococcal HIS might be acceptable and ethical in Malawi. Second, we report stakeholders’ suggestions on the requirements for pneumococcal HIS to be acceptable, including appropriate models of consent, fair selection of research participants, and availability of medical support. Third, we describe views on HIS for other diseases beyond pneumococcus, to consider acceptability of HIS that require different procedures.
3.1 Views on the acceptability of pneumococcal HIS research in Malawi
3.1.1 Perceived benefits of HIS
All stakeholder groups saw potential benefits of pneumococcal HIS research in Malawi, centred on the potential to improve population health. Within this, key issues included the high burden of pneumococcal disease and the value for a vaccine suited to the Malawi population.
In relation to pneumococcal disease, almost all stakeholders focused on pneumonia rather than other types of pneumococcal disease (only medical students mentioned sepsis). Stakeholders noted the high incidence and severity of pneumonia disease and suggested that developing a vaccine would protect people from ill health.
“I think it is welcome, because pneumonia takes a lot of lives […] a vaccine to prevent pneumonia is really needed.” (Religious Leader, FGD6)
A vaccine developed specifically for the Malawi context was considered valuable given differences in genetic background and environmental context.
“It’s indeed right to conduct the research […] the drugs we have here were developed in Europe and maybe because of differences in climate and our bodies, those drugs don’t work here” (Chief, FGD4)
“These studies have been done in a setting like the UK but it’s different from here, isn’t it? Here there is a number of things such as genetic and environmental factors that may have a bearing on how people respond to pathogens” (Senior clinician, KII)
While these benefits were mentioned by many stakeholders, some raised questions about the potential value of HIS research. In particular, while community participants seemed confident that HIS would deliver solutions for population health, a few key informants expressed uncertainty about the likely impact of pneumococcal HIS, perhaps reflecting awareness of both the unpredictability of research and the need to prioritise among competing research agendas.
“I am just interested to know why you want to do a HIS study on pneumococcus now in Malawi. We know that yes, streptococcus pneumoniae is a big problem, […], so what’s changed for this to come up now? […] what will be its impact?” (Senior clinician, KII)
3.1.2 Perceived concerns about HIS
While stakeholders saw HIS as having potential benefits, they also had concerns. Key issues emphasised by all stakeholder groups were safety and community reactions.
188.8.131.52 Participant safety
On safety, deliberate infection was initially perceived as carrying significant risks by many stakeholders. However, when we explained the focus on pneumococcal carriage (that is, only observing ability of the bacteria to live in the nose rather than causing pneumonia or other pneumococcal diseases), the prevalence of carriage and that there is low rate of adverse events in similar HIS in the UK, many stakeholders were reassured about safety.
“If you are just monitoring whether someone has it in their nose without it necessarily affecting that person, then you aren’t causing any harm for people to be scared” (Religious leader, FGD6-Fup)
“I don’t think it will have any risks and I don't think it’s as intense as I thought before […] with how you have explained that you’re just looking at carriage, I think it’s safer” (Frontline research staff, FGD1-Fup)
Nevertheless, safety concerns remained among some stakeholders, particularly those involved in medical care and research. Key issues were the unpredictability of individual biological reactions to the pneumococcus and limited healthcare facilities to manage severe adverse events in Malawi.
“People react differently to those agents, maybe because of their difference in biology, so just in case someone experiences the infection, and dies, […] so as researchers, how prepared are you to handle such…?” (Medical student, FGD5-Fup)
“Obviously you would want to do it in a setting whereby if a participant is sick, you are able to give all the treatment that is necessary, such as High Dependency Unit care or Intensive Care Unit. But in Malawi it’s a bit tricky because we already struggle with resources to take care of patients that are very sick.” (Senior clinician, KII)
Even when participants felt procedures were largely safe, some were concerned about the psychological impact of participation in HIS related to fear of infection.
“That psychological part of knowing for sure I have been infected - I think they could not interact normally or be as productive as they could, because they would have that psychological mind-set that ‘I may be sick, let me restrict myself’.” (District Health Management, KII)
184.108.40.206 Negative community reactions
Partly linked to this concern about fear, all stakeholder groups expressed concern about negative community reactions to HIS, believing communities would see HIS research as high-risk and that misconceptions and rumours were likely. For example, participants mentioned potential for rumours about the purpose of deliberate infection, links to witchcraft and the intentions of non-Malawian researchers, particularly because MLW may be seen as a foreign institution.
This concern about community reactions partly reflected the context of recent rumours around ‘bloodsucking’ in Malawi: in 2017, there were widespread rumours about bloodsuckers, with related community violence and some disruption to community based research [25, 26]. This recent experience heightened sensitivity to potential community distrust:
“There are concerns, people don’t trust their fellow humans. [or] believe that an organisation has come to help, for example the issue of blood suckers. So to just enter a village without proper communication, I tell you - you can be chased away.” (Religious leader, FGD6)
Potential community distrust of HIS was seen by all stakeholder groups as likely to limit recruitment of HIS volunteers.
“Recruiting participants could be a problem in most communities due to misunderstanding the information and not completely trusting the people who conduct the research.” (Religious leader, FGD6)
In addition, frontline researchers saw the potential for rumour as carrying risks for MLW’s reputation and for the safety of frontline staff in other studies.
“For those who go into the community, like the field workers, or even the hospital based research staff, their security and safety […] have you thought about the safety?” (Frontline research staff, FGD2)
“We are trying hard to build…we have established community trust, of which we can say that we are not 100% good; we have got some areas where we are also lacking, and we are trying hard to maintain that. So, bringing in HIS […] we might end up ruining the trust that people have” (Frontline research staff, FGD2)
3.1.3 Reflections on the overall acceptability of pneumococcal HIS
As illustrated in the previous sections, many participants described both benefits and concerns around pneumococcal HIS. To understand overall acceptability, participants were asked whether they thought HIS research should go ahead in Malawi. Most felt HIS would be acceptable provided researchers addressed certain important conditions (conditions we explain below). Views ranged from high levels of enthusiasm to more uncertainty but with willingness to consider that HIS could be appropriate.
“Had it been there were these studies done before, maybe I would have said ‘Yeah it’s OK, this can be done’. But…I am on the 50-50, yes or no because it’s the very first time and I am thinking ‘how are they going to handle issues of safety?’” (REC member, KII)
“As a Malawian citizen I believe this research is really necessary, because people in our country are struggling […] in our hospitals, doctors try to save lives but lives are being lost. Now researchers have suggested new methods that can be tried to save lives.” (CAG member, FGD3-Fup)
Positive overall views of HIS were often related to awareness that many existing medicines were developed through research with a few people for later public use. Research was therefore considered a normal and necessary step to improving population health, and so acceptable even if it may involve risks and burdens for some individuals.
This same idea of benefit for the greater good was reflected in discussions explicitly about the ethics of HIS, and specifically whether HIS research would meet principles of justice and ensuring a ‘fair offer’ for participants, with risks and burdens of HIS adequately balanced by the benefits . Many stakeholders emphasised that some risk or burden for participants was outweighed by the potential for population health benefit, or discussed the positive aim behind HIS:
“I feel it is a fair thing … you would get vaccines developed quickly from a small number of volunteers which can benefit the population […] so I feel like it has all those benefits that could outweigh the negative parts.” (District health management, KII)
Some staff, community leaders and medical students shared these sentiments.
However, views here varied, and a few stakeholders were concerned about lack of individual benefit:
“It sounds to me like the benefit is more for the study than the participants, I can’t see what they have to benefit, rather than contributing to whatever vaccine may be developed in the long term.” (Senior Clinician, KII)
To promote an adequate balance of benefits and burdens, participants identified a range of conditions and procedures needed to address concerns around safety and community reactions and ensure pneumococcal HIS was ethical and acceptable. These conditions are discussed below.
3.2 Conditions required for the acceptability of pneumococcal HIS
As reported in the previous section, views on the ethical acceptability of pneumococcal HIS in Malawi were sophisticated and varied, suggesting that HIS might be acceptable under some conditions but not others. In this section we report on stakeholders’ views on what they considered to be the requirements for ethical and acceptable pneumococcal HIS.
3.2.1 Voluntary and informed consent
All stakeholder groups highlighted voluntary and informed consent as a key condition affecting acceptability of HIS. The priority placed on informed consent was evident in discussion about whether a pneumococcal HIS as MARVELS was just and constituted a ‘fair offer’ for participants. Those stakeholders who viewed the MARVELS study as ethically acceptable often emphasised the informed voluntary consent process as a basis for this judgement.
“That is justice because the participant will be informed, they have got the information and volunteered. If someone is volunteering, it means there is justice between you and them.” (Chief, FGD4-Fup)
“A good and thorough information I think will balance [the benefit and burden], where they will get the right information, and it has to be exactly what is going to happen.” (REC member, KII)
As these quotes show, discussion about informed consent emphasised both full understanding and voluntary decision making. Both aspects would be expected in most health research, but participants emphasised that explanations should be particularly clear and open with HIS, given concerns about community misconceptions, perceived potential for risk from deliberate infection and complexity of information.
“They really need people who have got a strong understanding of things […] this time we are actually introducing a foreign body in the human body, right? So, this thing, it needs somebody to have a clear type of understanding.” (Frontline Research staff, FGD2)
While the overall emphasis was on transparency, a small number of participants raised concerns that initial description of HIS procedures might cause alarm if handled badly. One CAG member, for example, suggested that people should not be told that HIS involved introducing bacteria as people would see this negatively, although other CAG members disagreed and emphasised the need for openness. One medical student expressed uncertainty about how to balance openness and avoiding concern, given that the idea of being infected may cause fear:
“We want the person to be informed, but then I think we need to be careful with these details because we may end up scaring people. […] I don’t know how we can put it because we need to find a balance between keeping them informed and then not scaring them away, because it’s really scary.” (Medical Student, FGD5-Fup)
Involvement of family members in consent was discussed by many stakeholders, reflecting a concern not to harm family relationships or household livelihoods and dominant norms around permission from family members, particularly for women. Again, enabling discussion with family is standard practice for consent in health research, but it was particularly emphasised for MARVELS because the planned three-day residential stay would take participants away from home
“People at home are supposed to agree with you so they are aware where the participant is and what is happening.” (CAG member, FGD3)
Scope for withdrawal was also an aspect of consent with more specific implications in HIS research. Some medical students and research staff raised questions about permission to withdraw given the need to take antibiotics to clear any infection and saw this permission as important for voluntary consent.
“Maybe the person has volunteered himself, and then you have injected, you have started medications, maybe the medications are supposed to run maybe for the week. And then in the consent we have a part where it says the person can accept but at any time can withdraw. What if the medications haven’t yet finished, but the person maybe didn’t understand, and says I can’t continue, and you can’t say “no you have to, you have to!” What can happen in that situation?” (Frontline Research staff, FGD1)
Research staff felt safety and the right to withdraw could be balanced through sufficient explanation and ensuring participants fully understood planned procedures:
“We will explain to them that we will give you the bacteria and after that we will see if it can go by itself, but if it doesn’t and you have fever or whatever, we will be giving you some medication. So, if you withdraw, maybe if something can happen at home, there will be no problem. You can get this medication if you are not willing to continue.” (Frontline Research Staff, FGD1-Fup)
The perceived importance of informed and voluntary consent had implications for views about acceptable recruitment approaches. The MARVELS team were considering using flyers or adverts distributed through places such as college notice boards or social media, with phone numbers to contact for further information. Stakeholders welcomed this approach as avoiding pressure to take part (perhaps in contrast to the more typical of face to face recruitment in communities).
“I support the flyers, they are really good because when one reads it properly, they will be able to make a decision to say ‘aaah, I think I should take part in this research’, because they will read everything for themselves unlike just being told.” (CAG member, FGD3-Fup)
“I think it [use of flyers] will be of advantage, because people will come on their own will, we'll not coerce them to join the study.” (Frontline Research staff, FGD2-Fup)
Beyond specific procedures for recruitment and consent, the value placed on informed and voluntary participation also affected views on other procedures, particularly inclusion criteria and compensation as discussed below.
3.2.2 Fair selection of participants
Inclusion and exclusion criteria for HIS participants were seen as an important consideration for acceptability among all stakeholder groups. Participants in focus groups and interviews were asked openly about criteria they saw as important, and for their views on criteria being considered by the MARVELS team. Views on groups of who should be either targeted for participation or excluded reflected concerns related to informed and voluntary participation, community interest and misconceptions, equitable opportunities for participation between different population groups, burden on livelihoods or other activities, and ensuring research value and validity through a sample population considered relevant and unbiased - principles that were sometimes in tension.
The health status of HIS participants was raised by all stakeholder groups as an important consideration. Stakeholders recommended excluding people with long-term or acute conditions that might increase vulnerability to pneumococcal infection, as well as people allergic to the antibiotics used to clear infection and those with other contraindications. They urged thorough screening, particularly because potential volunteers may be unaware of underlying conditions.
“I would be worried about […] people who have diseases that would lead them to be vulnerable to any sort of infection. So, people who have chronic comorbidities like a heart failure patient or somebody with chronic renal dysfunction.” (Senior clinician, KII)
“I think this research is suitable for someone who has been screened, someone who has no health problem, so that when they are infected, their body will easily fight the infection.” (CAG member, FGD3)
Views on inclusion of people with HIV were mixed, with concerns for safety but also for equity and relevance of the findings for a high-risk group. Many felt people with HIV should be excluded due to vulnerability to infections. However, some also discussed the need to ensure any resulting vaccine to be suitable for people with HIV given their susceptibility to pneumococcal infection.
“This vaccine is not only going to those who are HIV negative, […], so don’t you think that we will also need to study those who are on ART, if we give them this vaccine, how is it going to work? Or like are we not leaving them aside? (Frontline research staff, FGD1)
As one way to balance these concerns for safety, equity and relevance, senior clinicians felt people with HIV might potentially be included if they were virally supressed, though they felt more information was needed to make this decision:
“In my view, I don’t necessarily see that as a severe contraindication, if we have evidence that they have an undetectable viral load, but I don’t know” (Senior Clinician, KII)
Beyond criteria around health, stakeholders discussed three criteria under consideration by the MARVELS team: restricting participation to medical students, people fluent in English and those with higher levels of education. The MARVELS team proposed these criteria to ensure potential participants could fully understand study information and to facilitate discussion with MARVELS clinicians, some of whom are British and without fluent Chichewa. Stakeholders saw potential benefits of these criteria for informed consent, and some supported restricting participation to these groups.
“I think the idea of involving medical students will be better because considering the…. understanding the concept, it’s easier for us (medical students), but for people out there it’s not going to be easy.” (Medical student, FGD5)
However, many stakeholders thought focusing only on these groups would be inequitable and deny opportunities for participation to others.
“If we say that participants should be determined by a certain level of education, we are being biased. Someone may be able to understand but not be educated to the standards you want.” (Chief, FGD4)
A further concern was that restricting participation might affect community views of the relevance of the research if participation was later expanded, or of the resulting vaccine.
“If you focus only on educated people, there will be a lot of questions around equity, whether the findings can be trusted, safety of volunteers and being unsure if the research has even started. It would be better to recruit some educated and some uneducated people, so the results represent both sides.” (CAG member, FGD3-Fup)
To address these concerns, some suggested broadening the sample, and involving Malawian clinicians in the research team or using translators to enable communication, as they had seen with other studies or in hospitals where translators assist English-speaking clinicians.
3.2.3 Adequate medical care
Medical support to ensure participant safety was viewed as critical for acceptability of pneumococcal HIS research in Malawi. Key discussions related to provision of adequate healthcare, the planned residential stay and other measures designed to ensure safety.
220.127.116.11 Healthcare facilities
Stakeholders emphasised the need for high quality healthcare facilities and procedures of the same standard as those in HIC:
“The standard should be better than the ones used in Liverpool, because in Liverpool obviously they have more resources for controlling […] let’s say things get out of hand, as compared to here, we do not have a lot of resources that can help us to control. So, monitoring will have to be of the best standard.” (Medical student, FGD5)
Participants also emphasised the importance of adequate laboratory facilities, and experienced staff with the skills to support volunteers if they develop an infection. These technical and ‘backroom’ aspects were mentioned particularly by stakeholders from medical and research settings.
“It’s fine to do it but after we have made sure that everything is in place, we have a laboratory that is of high quality, the inoculum will be kept there safe, we have the expertise.” (Senior clinician, KII)
As well as staff with experience in HIS and pneumococcus, some participants mentioned the need to involve local staff for both, building research capacity and because of their existing trust by participants.
“You need to include local clinicians. Clinicians who are well known by people and who also should develop skills in carrying out that type of study.” (REC member, KII)
18.104.22.168 Residential stay
As previously described, the MARVELS team plans a three-night residential stay for participants following inoculation at an accommodation which is located close proximity to one of Blantyre’s private hospitals. This residential stay was generally welcomed by stakeholders as important for safety, allowing easy access to medical care and the research team.
“It’s good you thought of arranging the residential stay to protect participants, because they will be close to Mwaiwathu hospital (private hospital in Blantyre). It will be safe for participants.” (Chief, FGD4)
However, while the residential stay was welcomed for medical support, there were some concerns about the impacts on household members left behind, and community participants in particular worried about the impact on livelihoods if the breadwinner is away from home. Some participants also mentioned that people may dislike being away from home or feel trapped in the hostel.
Views on an alternative non-residential option were mixed. Some felt this could not be considered for initial HIS studies, but others felt a non-residential option should be allowed, particularly if volunteers live close to the hospital or have good transport and communication access in case of adverse events.
“I think if the person stays in the city or has a car it won’t be difficult; if they face any problem, they can rush to the hospital straight away.” (CAG member, FGD3-Fup)
22.214.171.124 Additional safety measures
Several additional measures were proposed by the MARVELS team as part of a package of medical support, largely following procedures used with pneumococcus HIS in the UK. This included providing an emergency package of antibiotics and a thermometer, so that participants could take their temperature daily to monitor reactions to inoculation and treat themselves in case they could not access medical care in an emergency. Stakeholders generally saw this package as useful. However, many raised concerns about limited understanding of thermometer use and improper use of antibiotics, particularly among volunteers with less education or no medical training.
“If it’s the medical students then it’s OK, but if it’s not, it’s better they just come to be checked […] if he is not that well educated, if they just feel a fever, you are not sure that they will actually take the drugs as they have been advised…some may even overdose.” (Frontline Research staff, FGD2-Fup)
“Our friends in the UK are more advanced; they know how to use a thermometer, whereas someone from Malawi doesn’t know how it’s properly used.” (CAG member, FGD3-Fup)
To address this potential for misunderstanding, stakeholders suggested clear explanations for HIS volunteers about how and when to take the drugs, or follow-up visits at home by the research team to monitor antibiotic use.
Other medical support procedures proposed by the MARVELS team were generally seen as adequate, including 24-hour access to a study doctor, availability of a research team member at the residential hostel, a sequence of monitoring visits to check for symptoms, and daily phone contact by the study doctor. With these procedures in place, most stakeholders felt reassured about safety.
“There is protection. If they see that a participant’s health has changed, they will rush them to the hospital, showing that there is help. So, we cannot have any concerns.” (Chief, FGD4)
3.2.4 Compensation and reimbursement
Compensation of volunteers participating in HIS research was identified by all stakeholder groups as important for acceptability. Within this, many participants mentioned reimbursing HIS volunteers for transport costs (for example, to attend monitoring check-ups at the hospital), and compensation for time away from income generating activity. The latter was particularly important given the three-day residential stay.
“If he earns 2,000 a day [about £2], then that 2,000, you need to cover it for those days he participates in your study” (CAG member, FGD3-Fup)
Stakeholders also discussed compensation for risk. Some felt compensation for HIS participation would be higher than for other studies as they perceived HIS as higher risk:
“For the HIS I am sure we would go for a bit higher looking at the risks associated.” (REC member, KII)
However, others thought compensation should be similar to other studies, to avoid reducing recruitment for other studies or creating undue inducement. Concerns about undue inducement were mentioned by several stakeholders and considered a particular risk for less educated or lower-income groups.
“Here in Malawi, we have a lot of people who are poor, and poverty might be one reason they join the study, because of the incentives. They completely don’t understand the study, but because they want to make ends meet, they’ll just join.” (Medical student, FGD5)
Views on the amount of reimbursement and compensation varied widely, with suggested figures ranging from 15,000 [about £15] to 300,000 [about £300] for the 3-day residential stay, plus additional amounts covering transport for hospital visits. Often stakeholders found it hard to indicate specific amounts and suggested that compensation be determined by researchers based on standard practice and guidance.
“I feel like every organisation has its way of providing incentives and it would also be best to look [at] what do other organisations recommend on the type of incentives you can give to someone when you are involving his life and his health.” (Medical Student, FGD5)
In relation to how reimbursement and compensation should be given to volunteers, most stakeholders felt it should be spaced throughout the study, to cover costs as they arise and so reduce burden, and to support retention.
As well as compensation for time and burden, stakeholders indicated the importance of insurance and compensation in the event of severe adverse events.
“As long as there is an agreement that you will take care of everything if the volunteers fall sick or die while participating, then we don’t have concerns.” (Chief, FGD4-Fup)
Stakeholders emphasised the need for careful review and approval of any HIS in Malawi by research ethics committees (RECs) and other regulatory bodies such as pharmacy, medicine and poisons body (PMPB), to protect the safety of participants:
“They have to give approvals to show that they have met the standards and they are not bringing any kind of harm to these people.” (Medical student, FGD-Fup)
However, participants involved in medical care and research expressed concerns over lack of standard regulatory guidelines on HIS to guide the local regulatory bodies.
“But also making sure that there are clear guidelines from the regulators […] because this will be a first study. I don’t know if our regulators have got guidelines to conduct this type of research” (Senior Clinician, KII)
3.2.6 Community engagement
Community engagement was considered by all stakeholders as key component if HIS research is to be accepted in Malawi. As previously described, the potential for negative community reactions and distrust in HIS was a key concern for all stakeholder groups. However, many emphasised that adequate community engagement to promote understanding could overcome this concern:
“There should be enough awareness raising among everyone, so they know the importance of HIS. This will ensure they understand what will happen in the study and they will be able to explain to other people who might be creating stories about it.” (Religious leader, FGD6)
Comments on community engagement focused on raising awareness, sharing information about HIS and providing an opportunity for people to ask questions. However, a few stakeholders also mentioned more two-way engagement with community input to HIS design, particularly seeking feedback from participants once HIS research begins.
On approaches for community engagement, participants suggested a range of channels, including working with chiefs, community opinion leaders and the media to reach potential participants and wider communities.
“I think the channels to use are chiefs, CAG members, or churches. […] even radio and TV stations so that many people hear the information.” (CAG member, FGD3-Fup)
Community stakeholders also emphasised the presence of a HIS scientist during any community engagement activity to respond to any questions and give clear information.
“You may face challenges with lots of questions. As we (chiefs) are holding meetings, you [the scientist] should be present to explain things to people clearly.” (Chief, FGD)
3.3 The acceptability of other types of HIS beyond pneumococcal studies
The views above relate to HIS focused on pneumococcal carriage. Participants were also asked for views on the acceptability of HIS for other diseases that require different procedures. Stakeholders had mixed views about the acceptability of other types of HIS, particularly HIS such as malaria or typhoid that are more likely to cause symptoms or require a longer residential stay or quarantine.
The higher likelihood of developing symptoms was seen by some stakeholders as a concern for safety, although others felt it could be justified by the high burden of the disease considered (for example malaria) and acceptable with adequate medical support including close monitoring.
“I think people will be more scared of the higher risks. But still more it’s worth doing it because like I said about malaria, there are a lot of people who are affected by malaria” (Medical student, FGD-Fup)
A longer residential stay or quarantine was considered positive for safety (including protecting participants, and stopping spread of infection to the public), but stakeholders mentioned potential negative impacts on family and livelihoods and concerns around participant comfort. Reasonable compensation and clear information on the procedures were identified as preconditions for acceptability.
“Let’s say the man is a breadwinner at home – staying for 20 days is difficult. […]. In that situation, you will provide not only transport but consider an amount to match the income he is missing.” (CAG member, FGD-Fup)
Several stakeholders suggested starting with pneumococcus and then gradually expanding to other, potentially more challenging, diseases if initial HIS go smoothly and produce useful findings.
“Because this is just the first HIS research starting in Malawi, it might be a bit risky in general; but I think as we go along we will see that maybe it’s going on well with the experience and there will be no problems with other types.” (Frontline research staff, FGD-Fup).