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The number of controlled human infection models (CHIMs) conducted worldwide has increased considerably in recent years, although few have been conducted in low and middle-income countries (LMICs), where infectious diseases have the greatest burden. Recently Oxford University Clinical Research Unit (OUCRU) in Ho Chi Minh City (HCMC) started developi...
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Context 1
... collated themes from that meeting with themes identified through a literature review conducted between October and December 2017. This initial review was mostly based on a PubMed search using a modified PRISMA diagram ( Figure 1). Search terms used in title/abstract (added filter for "human studies") were: ...
Context 2
... on the Malawi framework and based on the discussions and the findings of our workshops, we developed a framework to guide the development of CHIM studies in Vietnam (Figure 1) 9 . This framework is based on four main concepts (Scientific, Structural, Ethical, and Cultural), each encompassing a number of different themes or considerations. ...
Citations
... This process of engagement was recommended by Ugandan stakeholders in preparation for CHI-S (Elliott et al., 2018). Similarly, other CHI studies have also recommended and conducted community engagements with the target communities in disease-endemic countries such as Zambia (Kunda-Ng'andu et al., 2021), Vietnam (Kestelyn et al., 2019), India (Vaz et al., 2019(Vaz et al., , 2020, Malawi (Kapumba et al., 2020), Kenya (Njue et al., 2018), and Gabon (Alabi et al., 2021). The studies showed that participants are able to understand the processes involved during a CHI. ...
Issues related to controlled human infection studies using Schistosoma mansoni (CHI-S) were explored to ensure the ethical and voluntary participation of potential CHI-S volunteers in an endemic setting in Uganda. We invited volunteers from a fishing community and a tertiary education community to guide the development of informed consent procedures. Consultative group discussions were held to modify educational materials on schistosomiasis, vaccines and the CHI-S model and similar discussions were held with a test group. With both groups, a mock consent process was conducted. Fourteen in-depth key informant interviews and three group discussions were held to explore perceptions towards participating in a CHI-S. Most of the participants had not heard of the CHI-S. Willingness to take part depended on understanding the study procedures and the consenting process. Close social networks were key in deciding to take part. The worry of adverse effects was cited as a possible hindrance to taking part. Volunteer time compensation was unclear for a CHI-S. Potential volunteers in these communities are willing to take part in a CHI-S. Community engagement is needed to build trust and time must be taken to share study procedures and ensure understanding of key messages.
... Our results also emphasize the previous recommendations that CHIM studies should not be started before adequate community engagement has been done and public trust has been built 34 .Findings of our study resonate with the lessons learnt during implementation of CHIM studies in other LMICs35 and the ethical framework suggested by Gordon et al in Malawi 6 .Building the capacities of Ethics Committees, researchers, regulatory bodies through workshops, interactive and engaging consultations to manage the complexities of CHIM research is an ongoing process. Countries such as Kenya, Malawi, Vietnam and Zambia show us how such capacity is built36,37 . ...
Introduction: Controlled Human Infection Model (CHIM) studies provide a unique platform for studying the pathophysiology of infectious diseases and accelerated testing of vaccines and drugs in controlled settings. However, ethical issues shroud them as the disease-causing pathogen is intentionally inoculated into healthy consenting volunteers, and effective treatment may or may not be available. We explored the perceptions of the members of institutional ethics committees (IECs) in India about CHIM studies. Methods: This qualitative exploratory study, conducted across seven sites in India, included 11 focused group discussions (FGD) and 31 in-depth interviews (IDI). A flexible approach was used with the aid of a topic guide. theory and an inductive approach. Emerging themes and sub-themes were analyzed, and major emergent themes were elucidated. Results: Seventy-two IEC members participated in the study including 21 basic medical scientists, 29 clinicians, 9 lay people, 6 legal experts and 7 social scientists. Three major themes emerged from this analysis-apprehensions about conduct of CHIM studies in India, a perceived need for CHIM studies in India and risk mitigation measures needed to protect research participants and minimize the associated risks. Conclusion: Development of a specific regulatory and ethical framework, training of research staff and ethics committee members, and ensuring specialized research infrastructure along with adequate community sensitization were considered essential before initiation of CHIM studies in India.
... Our results also emphasize the previous recommendations that CHIM studies should not be started before adequate community engagement has been done and public trust has been built 34 .Findings of our study resonate with the lessons learnt during implementation of CHIM studies in other LMICs35 and the ethical framework suggested by Gordon et al in Malawi 6 .Building the capacities of Ethics Committees, researchers, regulatory bodies through workshops, interactive and engaging consultations to manage the complexities of CHIM research is an ongoing process. Countries such as Kenya, Malawi, Vietnam and Zambia show us how such capacity is built36,37 . ...
Introduction: Controlled Human Infection Model (CHIM) studies provide a unique platform for studying the pathophysiology of infectious diseases and accelerated testing of vaccines and drugs in controlled settings. However, ethical issues shroud them as the disease-causing pathogen is intentionally inoculated into healthy consenting volunteers, and effective treatment may or may not be available. We explored the perceptions of the members of institutional ethics committees (IECs) in India about CHIM studies.
Methods: This qualitative exploratory study, conducted across seven sites in India, included 11 focused group discussions (FGD) and 31 in-depth interviews (IDI). A flexible approach was used with the aid of a topic guide. The data were thematically analyzed using grounded theory and an inductive approach. Emerging themes and sub-themes were analyzed, and major emergent themes were elucidated.
Results: Seventy-two IEC members participated in the study including 21 basic medical scientists, 29 clinicians, 9 lay people, 6 legal experts and 7 social scientists. Three major themes emerged from this analysis—apprehensions about conduct of CHIM studies in India, a perceived need for CHIM studies in India and risk mitigation measures needed to protect research participants and minimize the associated risks.
Conclusion: Development of a specific regulatory and ethical framework, training of research staff and ethics committee members, and ensuring specialized research infrastructure along with adequate community sensitization were considered essential before initiation of CHIM studies in India.
... The idea of intentionally infecting individuals raises questions about risks to study participants as well as risks to third parties not directly participating in due to prior infection and/or innate forms of resistance to particular pathogens (for example, genetic conditions such as sickle cell that reduce the severity of malaria) [29,[35][36][37]. Additionally, where volunteers of HCTs are deemed to already be at risk of being infected with a pathogen in daily life -that is, because they live in an endemic area -some literature suggests that this background risk reduces the marginal risk an individual would take on by participating in a HCT [23] -with the exception of pathogens such as Dengue, where multiple infections with different strains can increase the likelihood of severe disease [38,39]. Primary third-party risks are associated with transmission of the challenge strain(s) from infected participants to others, thus, our study respondents emphasized that researchers have an extensive ethical duty to third parties where such risks of being infected by research participants exists -given the potential for third party risks to undermine public trust in research. ...
... Our study respondents indicated that the burden of the disease being studied using a HCT approach should be of scientific importance to justify the risks associated with participant involvement, and the costs, including opportunity costs of the effort. Consistent with the literature, where stakeholders have cited that in a LMIC context, the science may differ as a result of endemic exposure to pathogen, vectors and co-infections, genetics, immune status and environmental factors; emphasizing that this unique combination of effects may not be correctly understood in a study conducted in HICs [24,34,38]. ...
... From the literature, there is a consensus on the lack of standard regulatory guidelines on HCTs in LMICs [40]. Currently, national guidelines for LMICs for regulatory and ethics in health-related research do not include specific instructions for reviewing HCTs, however, some stakeholders from LMICs have been drawing from the frameworks established and published for Malawi and Vietnam [38,41]. Our survey respondents detailed the importance of having clear guidelines for HCT designs and endpoints to minimize and control the risks as well as to provide indicators and criteria for NRA's and RECs to review and make informed decisions about which HCTs to approve, thus identifying research governance, and regulatory and ethical frameworks as an important critical success factor. ...
Background
Owing to the globalization of vaccine clinical trials, as well as advances in technologies, improved research accountability, and robust regulatory and ethical scrutiny, the choice to perform human challenge trials has become evident, and one of the most significant applications of human challenge trials is the assessment of vaccine efficacy. While human challenge trials have largely been conducted in high-income countries, the concept is relatively new in many low- and middle-income countries. Thus, the aim of this study was to identify the critical success factors for conducting human challenge trials for vaccine development in low- and middle-income countries.
Methodology
Using a two-step methodology, we first carried out a systematic literature review that was centered on identifying low- and middle-income countries that are either establishing a framework for, have conducted, or are conducting human challenge trials for vaccine development; secondly, we conducted a descriptive cross-sectional survey using a standardized semi-structured online questionnaire administered to eligible stakeholders, to identify the critical success factors for conducting human challenge trials for vaccine development in low- and middle-income countries. Seventeen low- and middle-income countries were identified and included in the survey.
Results
The most cited critical success factors for conducting human challenge trials for vaccine development in low- and middle-income countries were Informed Consent, Risk Compensation and/or Reimbursement, Participant Safety and/or Public Protection, Community Engagement, Infrastructural Capacity, and Ethical and Regulatory Frameworks.
Conclusion
From an empirical perspective, this study provides a list of critical success factors that form the basic structure to guide the design and implementation of further human challenge trials in low- and middle-income countries. Further studies are needed to establish a standardized conceptual framework to aid in the review, approval and overall conduct of human challenge trials in low- and middle-income countries.
... It is evident that low-and middle-income countries (LMICs) carry the higher burden of infectious disease in comparison to high income countries [1][2][3] . Most of these infectious diseases are preventable. ...
... ✓ well placed to undertake as HIC because they have: (3,(14)(15)(16) In order to reduce the burden of participation for attendees while ensuring that they remained engaged and owned the whole process, we used a combination of methods that provided structure to guide proceedings but also the flexibility to allow attendees to share personal stories on key aspects of concern to HIS. Distribution of reading materials ahead of the meeting and didactic sessions aimed to create a common understanding on the current information on HIS implementation and ethical and regulatory issues arising. ...
Human infection studies (HIS) have generally been used as a tool in the pathway for vaccine development in high income settings. Over the last decade, this model has been implemented in LMICs with the aim of accelerating development of next generation vaccines that would perform better in these settings. However, in most LMICs, the ethics and regulatory framework for the conduct of these studies are not in place. In Zambia, these studies are yet to be conducted and thus we conducted a stakeholder engagement workshop in October 2019. We engaged with bioethicists, regulatory authority, and scientists from within Zambia and other African countries to anticipate and address foreseeable ethical and regulatory issues when conducting HIS in Zambia for the first time. The workshop largely focused on sensitizing the stakeholders on the benefits of these studies with the following main points for consideration on the implementation of these studies in Zambia: need for in-country legal framework and guidelines; need for adequate informed consent based on comprehensive understanding of the concept of HIS and study requirements; and requirements for heightened vigilance to assure participant safety including good ethical and clinical practice with regulatory, ethical, data safety, and community oversight. Additionally, the workshop emphasized the need for rigorous health screening prior to enrolment; suitable infrastructure for containment; and personnel to provide appropriate treatment including emergency resuscitation and evacuation if indicated. Specific recommendations included compensation for burden of participation; access to care and provision for study related injury (e.g. no-fault insurance); and withdrawal and exit procedures to preserve individual and community safety. Finally, the meeting concluded that researchers should actively engage key gate keepers including civic leaders such as parliamentarians, universities, researchers, potential participants and laypersons to avoid circulation of misinformation.
... Since there is no medical incentive for the participant often the primary motivation seems to be financial reward but again the literature shows that in this context altruism and contributing to research and knowledge are important motivators. 25,[29][30][31][32][33] We intend to apply this framework to planned human challenge studies involving healthy participants and, if appropriate, revise and adapt our current framework. ...
Background
Providing compensation for participants in clinical research is well established and while international guidelines exist, defining a context-specific and fair compensation for participants in low-resource settings is challenging due to ethical concerns and the lack of practical, national compensation and reimbursement frameworks.
Methods
We reviewed Oxford University Clinical Research Unit (OUCRU) internal reimbursement documentation over a 10-y period and conducted a scoping literature review to expand our knowledge of compensation and reimbursement practices including ethical concerns. We developed a preliminary reimbursement framework that was presented to community advisory boards (CAB) and clinical investigators to assess its applicability, fairness and transparency.
Results
The main topics discussed at the workshops centered on fairness and whether the reimbursements could be perceived as financial incentives. Other decisive factors in the decision-making process were altruism and the loss of caregivers’ earnings. Investigators raised the issue of additional burdens, whereas the CAB members were focused on non-monetary elements such as the healthcare quality the patients would receive. All elements discussed were reviewed and, where possible, incorporated into the final framework.
Conclusion
Our new reimbursement framework provides a consistent, fair and transparent decision-making process and will be implemented across all future OUCRU clinical research in Vietnam.
... These views were also reinforced in recent deliberations on the feasibility and ethics of CHIMs in India, held among wider stakeholders , and also from deliberations in other countries such as Vietnam (Kestelyn et al. 2019). ...
... These perceptions not only indicate who are likely to participate in CHIM studies but provide underlying motivations and concerns about these studies being ethical or exploitative. Many of the findings that have emerged from this study support the findings of research elsewhere , Molyneux et al. 2012, Gordon et al. 2017, Bambery et al. 2016, Njue et al 2018, Kestelyn et al. 2019. As this study was qualitative-we cannot conclude that these represent the views of the public everywhere in India-and there may well be a place for an expanded study across geographies, using a quantitative tool. ...
Research using Controlled Human Infection Models is yet to be attempted in India. This study was conducted to understand the perceptions of the lay public and key opinion makers prior to the possible introduction of such studies in the country. 110 respondents from urban and rural Bangalore district were interviewed using qualitative research methods of Focus Group Discussions and In-depth Interviews. The data was analyzed using grounded theory. Safety was a key concern of the lay public, expressed in terms of fear of death. The notion of infecting a healthy volunteer , the possibility of continued effects beyond the study duration and the likelihood of vulnerable populations volunteering solely for monetary benefit, were ethical concerns. Public good outcomes such as effective treatments, targeted vaccines and prevention of diseases was necessary justification for such studies. However, the comprehension of this benefit was not clear among non-medical, non-technical respondents and suggestions to seek alternatives to CHIMs repeatedly arose. There was a great deal of deflection-with each constituency feeling that people other than themselves may be ideally suited as participants. Risk takers, those without dependents , the more health and research literate, financially sound and those with an altruistic bent of mind emerged as possible CHIM volunteers. While widespread awareness and advocacy about CHIM is essential, listening to plural voices is the first step in public engagement in ethically contentious areas. Continued engagement and inclusive deliberative processes are required to redeem the mistrust of the public in research and rebuild faith in regulatory systems.
... To understand how different forces play a role within different hosts requires dissection of the transmission process by either infecting mosquitoes with DENV isolated from humans or infecting humans with DENV isolates from mosquito. Due to ethical considerations, human challenge studies are rarely performed under this purpose (Lyons, 2014;Mammen et al., 2014;Kestelyn et al., 2019); therefore, within-human genetic variations of DENV can only be observed under epidemiological settings. In this section, we reviewed the studies applying NGS to understand the different evolutionary forces acting on mosquito vectors fed with blood meal mixed with dengue virus isolates, or viremic blood directly from dengue patients in the well-defined laboratory settings (Table 1). ...
Dengue viral (DENV) infection results in a wide spectrum of clinical manifestations from asymptomatic, mild fever to severe hemorrhage diseases upon infection. Severe dengue is the leading cause of pediatric deaths and/or hospitalizations, which are a major public health burden in dengue-endemic or hyperendemic countries. Like other RNA viruses, DENV continues to evolve. Adaptive mutations are obscured by the major consensus sequence (so-called wild-type sequences) and can only be identified once they become the dominant viruses in the virus population, a process that can take months or years. Traditional surveillance systems still rely on Sanger consensus sequencing. However, with the recent advancement of high-throughput next-generation sequencing (NGS) technologies, the genome-wide investigation of virus population within-host and between-hosts becomes achievable. Thus, viral population sequencing by NGS can increase our understanding of the changing epidemiology and evolution of viral genomics at the molecular level. This review focuses on the studies within the recent decade utilizing NGS in different experimental and epidemiological settings to understand how the adaptive evolution of dengue variants shapes the dengue epidemic and disease severity through its transmission. We propose three types of studies that can be pursued in the future to enhance our surveillance for epidemic prediction and better medical management.
Introduction: Controlled Human Infection Model (CHIM) studies provide a unique platform for studying the pathophysiology of infectious diseases and accelerated testing of vaccines and drugs in controlled settings. However, ethical issues shroud them as the disease-causing pathogen is intentionally inoculated into healthy consenting volunteers, and effective treatment may or may not be available. We explored the perceptions of the members of institutional ethics committees (IECs) in India about CHIM studies.
Methods: This qualitative exploratory study, conducted across seven sites in India, included 11 focused group discussions (FGD) and 31 in-depth interviews (IDI). A flexible approach was used with the aid of a topic guide. The data were thematically analyzed using grounded theory and an inductive approach. Emerging themes and sub-themes were analyzed, and major emergent themes were elucidated.
Results: Seventy-two IEC members participated in the study including 21 basic medical scientists, 29 clinicians, 9 lay people, 6 legal experts and 7 social scientists. Three major themes emerged from this analysis—apprehensions about conduct of CHIM studies in India, a perceived need for CHIM studies in India and risk mitigation measures needed to protect research participants and minimize the associated risks.
Conclusion: Development of a specific regulatory and ethical framework, training of research staff and ethics committee members, and ensuring specialized research infrastructure along with adequate community sensitization were considered essential before initiation of CHIM studies in India.
Venetian quarantine 400 years ago was an important public health measure. Since 1900 this has been refined to include “challenge” or deliberate infection with pathogens be they viruses, bacteria, or parasites. Our focus is virology and ranges from the early experiments in Cuba with Yellow Fever Virus to the most widespread pathogen of our current times, COVID-19. The latter has so far caused over four million deaths worldwide and 190 million cases of the disease. Quarantine and challenge were also used to investigate the Spanish Influenza of 1918 which caused over 100 million deaths. We consider here the merits of the approach, that is the speeding up of knowledge in a practical sense leading to the more rapid licensing of vaccines and antimicrobials. At the core of quarantine and challenge initiatives is the design of the unit to allow safe confinement of the pathogen and protection of the staff. Most important though is the safety of volunteers. We can see now, as in 1900, that members of our society are prepared and willing to engage in these experiments for the public good. Our ethnology study, where the investigator observed the experiment from within the quarantine, gave us the first indication of changing attitudes amongst volunteers whilst in quarantine. These quarantine experiments, referred to as challenge studies, human infection studies, or “controlled human infection models” involve thousands of clinical samples taken over two to three weeks and can provide a wealth of immunological and molecular data on the infection itself and could allow the discovery of new targets for vaccines and therapeutics. The Yellow Fever studies from 121 years ago gave the impetus for development of a successful vaccine still used today whilst also uncovering the nature of the Yellow Fever agent, namely that it was a virus. We outline how carefully these experiments are approached and the necessity to have high quality units with self-contained air-flow along with extensive personal protective equipment for nursing and medical staff. Most important is the employment of highly trained scientific, medical and nursing staff. We face a future of emerging pathogens driven by the increasing global population, deforestation, climate change, antibiotic resistance and increased global travel. These emerging pathogens may be pathogens we currently are not aware of or have not caused outbreaks historically but could also be mutated forms of known pathogens including viruses such as influenza (H7N9, H5N1 etc.) and coronaviruses. This calls for challenge studies to be part of future pandemic preparedness as an additional tool to assist with the rapid development of broad-spectrum antimicrobials, immunomodulators and new vaccines.
