In the halls of European research institutions, the Controlled Human Infection (CHI) Model has been tested, refined, and trusted. Scientists in places like the Netherlands have used it to simulate infections in volunteers, healthy individuals deliberately exposed to a pathogen under tightly controlled conditions. Findings from these studies have fast-tracked vaccine development, contributing to vaccines such as those for malaria, cholera, and typhoid that are in the market. However, what happens when a model designed in a non-endemic region is transferred to a setting where the disease is part of everyday life?

In Uganda, researchers at the Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit are taking on that challenge. The goal is ambitious yet clear, to adapt the CHI for Schistosoma mansoni, the parasitic worm responsible for schistosomiasis that affects millions across sub-Saharan Africa. Unlike in Europe, where volunteers have never encountered S. mansoni before, Ugandan participants may have been exposed to the parasite before and after birth. This distinction presents both a challenge and an opportunity: how do you study an infection in a population where partial immunity might already exist? In addition, could this context bring researchers closer to a viable vaccine?

A model in transition

The first CHI models for schistosomiasis have been successful at the Leiden University Medical Center (LUMC) in the Netherlands. The Dutch experience with CHI offered valuable proof of concept that researchers could safely and ethically infect volunteers, track immune responses, and prepare to test vaccine candidates. On the other hand, the conditions in Uganda are starkly different. Schistosomiasis in Uganda is a daily struggle for communities living near freshwater lakes and rivers. The stakes are higher, the ethical considerations more complex, and the urgency far greater.

Professor Alison Elliott, the Principal Investigator on the Ugandan Controlled Human Infection Study (CHI-S), explains…

"In the Netherlands, CHIM participants are given a precise dose of S. mansoni larvae under controlled laboratory conditions. In Uganda, however, there is an added layer of complexity: how do your account for the exposure history of participants? It is expected that someone has been exposed before will react differently from someone encountering the parasite for the first time."

Understanding these differences is precisely why Uganda’s CHI-S is so important. By testing vaccine candidates in an endemic setting where the vaccines are needed the most, researchers can determine how effective they truly are before deploying them at scale.

Ethical, logistical, and scientific hurdles

The journey to establishing Uganda’s CHI-S is not without obstacles. Ethical concerns loom large: can researchers justify deliberately infecting people with a disease they are trying to eliminate? The answer lies in rigorous safeguards, potential participants are regularly informed about the study and reassured through community meetings and discussions that they shall receive the safest dose, be constantly monitored, and treat as per the protocol.

Then there are logistical challenges. Research facilities at our collaborator the LUMC are well established but the Unit, in partnership with the Vector Control Division of Uganda’s Ministry of Health, has built capacity from the ground up. Specialized laboratories, training and retraining personnel, and seeking regulatory approvals continue to require time and investment. Yet, in overcoming these challenges, Uganda will not only establish a CHI; it will lay the foundation for cutting-edge biomedical research to thrive in Africa, and reduce the reliance on Western institutions.

What success would mean

If the CHI-S succeeds, its impact will extend far beyond schistosomiasis research. It will prove that complex biomedical models can be adapted to different African contexts, different diseases and other uses such as testing new drugs. It will empower local scientists, ensuring that the continent is not just a participant in global health research but a leader in it.

The CHI-S is a project in the MRC/UVRI and LSHTM Uganda Research Unit’s vaccine research theme. Read more about vaccine research at the Unit.

In a bid to develop the technical capacity of Ugandan researchers to produce the infectious challenge for CHI-S in Uganda, training of a laboratory scientist from the MRC/UVRI-LSHTM Uganda was undertaken at the LUMC in the Netherlands. During this visit, the laboratory scientist received training on the routine laboratory activities for maintaining the schistosome life-cycle, diagnostic technique used in the CHI-S model and was able to take account of the laboratory facility, equipment and materials needed for the set-up of the CHI-S in Uganda.

This was the second of the joint CHHI workshops held annually to share updates on the CHI-S Uganda, Hook-worm CHI in Gabon and the LUMC CHI model. The CHHI consortium comprising of the three research institutions: LUMC in the Netherlands, CERMEL in Gabon and UVRI in Uganda, is under the purview of the WOTRO project whose main aim is to facilitate the preparatory work for the transfer and establishment of CHHIs in Africa.

The 2021 joint workshop was held virtually, due to the COVID-19 related travel-restrictions, and was hosted by the CHI-S Uganda team. In attendance were: researchers/members of the CHHI consortium (laboratory scientists, social/behavioural scientists, research ethicists, Principle investigators of the WOTRO and CHHI projects, research clinicians, PhD and post-doc students); a representative of Uganda’s national regulatory body, the UNCST; a representative of the Vector Control Division at Ministry of Health-Uganda (VCD-MoH); and a representative of the HIV-VAC project.

The participants shared updates on the milestones so far achieved and the challenges facing the on-going preparatory work for the CHI projects in Uganda and Gabon; experiences and findings on the completed CHI studies at LUMC; and updates on the on-going CHI studies at LUMC. Opportunities for funding, training, publications and research collaboration were also identified and discussed. Additionally, the HIC-VAC network manager gave a presentation on the aims, funding and training opportunities that the CHHI consortium can leverage from the HIC-VAC project. A representative of the national research regulation, UNCST, in attendance presented about the “research regulatory landscape in Uganda”. The two-day workshop was concluded with drawing plans and way-forward for the next phase of the CHHI in Africa studies

A stakeholders’ meeting was held in December 2017 at Uganda Virus Research Institute (UVRI) with research regulators, community representatives, researchers and policy makers to explore the possibility of establishing a Controlled Human Infection model for Schistosomiasis (CHI-S) in Uganda. Substantial support was expressed for the establishment of CHI-S, especially by the representatives of schistosomiasis-affected communities who emphasized the urgent need for an effective vaccine and urged the research community not to delay the development process.

The potential implementation challenges that are likely to face CHI-S studies in Uganda were also discussed and a “road-map” was drawn to ensure successful implementation. This road-map comprised of the following preparatory steps: conducting a risk assessment; development of infrastructure and technical capacity to produce the infectious challenge in Uganda; community engagement from parliamentary to grass-roots level; pilot studies to establish approaches to assuring fully informed consent and true voluntariness, and strategies for selection of volunteers who can avoid natural infection during the 12-week of CHI-S; the building of regulatory capacity; and the development of study protocols and a product dossier in close consultation with ethical and regulatory partners.

Furthermore, it was recommended that opportunity should be provided for the Uganda’s regulators and ethicist to learn more about CHI-S through visit to the Leiden in the Netherlands and engage with the Dutch collaborators. Taking into consideration the recommended preparatory steps, implementation challenges and possible solutions, and the significance of CHI-S in accelerating the development pipeline of a much needed vaccine, establishment of CHI-S in Uganda was considered both feasible and desirable. Further details on the discussions and outcome this meeting is published in AAS Open Research Journal; Elliott AM, Roestenberg M, Wajja A et al. Ethical and scientific considerations on the establishment of a controlled human infection model for schistosomiasis in Uganda: report of a stakeholders’ meeting held in Entebbe, Uganda. [version 2; peer review: 2 approved]. AAS Open Res 2018, 1:2 (https://doi.org/10.12688/aasopenres.12841.2).

The CHI-S study in Uganda is implemented under the purview of UNSCT’s National Biosafety Committee (NBC) and its institutional arm, the UVRI Institutional Biosafety Committee (IBC). The NBC was tasked with the mandate to inspect and approve the challenge production facility by the JRM committee. Subsequently, it was paramount for the CHI-S team to involve the NBC and IBC early in the process of establishing the challenge agent production facility.

The NBC chair visited the UVRI for a pre-liminary meeting to review the design, lay-out and refurbishment plans for the “CHI-S-Ug snail laboratory” on 31st Aug 2020. During this visit, the chair, joined by the IBC team was able to inspect the proposed laboratory and make recommendations before the commencement of the refurbishment. Other facilities and sites such as the proposed site for the animal house were also visited.

The refurbished of the snail laboratory has now been completed and a preliminary inspection done by the IBC representative. A field collection of fresh-water snails, the intermediate host/ vector for schistosomes, was conducted and a snail colony has now is being maintained in the laboratory. This snail colony will be used to maintain the schistosome life-cycle and thus, for production of the infection material.  The CHI-S Uganda team is now working towards addressing the additional recommendations by the IBC and to have the final inspection by the NBC done to obtain an approval and launch the laboratory for the infection material production.  

Following the road-map drawn from the stakeholders’ meeting, a protocol (including a product dossier and other relevant documents) for the CHI-S in Uganda were developed and jointly reviewed by the relevant ethical and regulatory committees in a “Joint review meeting” (JRM) held on 27th June 2019. Participants of this JRM included representatives of the Uganda National Council for Science and Technology (UNCST), National Drug Authority (NDA), Uganda National Health Research Organization (UNHRO), National Environmental Management Authority (NEMA) and the UVRI-Research Ethics Committee (UVRI-REC).

Among issues discussed in this meeting, appropriate volunteer renumeration; measures to ensure avoidance of contact with the schistosome-infested lake waters during the study period; and regulatory over-sight of the CHI-S were discussed. The JRM recommended exemption of the study from the NDA statute given that CHI-S does not employ use of an investigational drug and thus, beyond the mandate of the NDA. However, the National Biosafety Committee (NBC) was tasked to over-see the conduct of the study, mainly to inspect and approve the production facility (the CHI-S-Ug snail laboratory) and to review documents for the importation of starting-biological research materials from LUMC.

It was concluded that the establishment of CHI-S in Uganda is feasible and relevant and hence, a go-ahead was given for the submission of the study protocol to UVRI-REC, and subsequently UNCST, for ethical review and approval.

The LUMC Biosafety Officer and laboratory scientist paid a visit to the MRC/UVRI-LSHTM Uganda Research Unit from 20th - 23rd February 2020 to guide the Uganda CHI-S team on the refurbishment and set-up of the challenge agent production facility, the CHI-S-Ug snail laboratory. The two teams extensively discussed the lay-out, design, appropriate bio-safety containment level and equipping of the snail laboratory, and the planned CHI-S-Ug animal facility. 

The first preparatory step taken was to organise a visit for representatives of Uganda’s regulators and ethicists to Leiden University Medical Centre (LUMC) in the Netherlands where the first “Schistosomiasis Controlled Human Infection studies” was being conducted. The purpose of this visit was to engage with the researchers at LUMC who pioneered the CHI-S, in order to further understand and appreciate the implementation and safe-conduct of CHI-S for vaccine development.

The Uganda CHI-S team shared their experience on the regulatory framework of Uganda and the preparatory work for establishing the first CHI-S in Uganda with researchers and regulators in Lambaréné, Gabon. This activity was to provide guidance for the establishment of a Hookworm CHI study in Gabon, and share knowledge and experiences on strengthening the regulatory and legislative capacity to over-see CHI studies in Africa.

A manuscript on the proceedings of this workshop has been jointly prepared by the Gabon, LUMC and Uganda CHI teams, and is soon to be published ("Establishing a Controlled Hookworm Human Infection (CHHI) model for Africa. A report from the stakeholders meeting held in Lambaréné, Gabon, November 10-11, 2019." (AOPH-D-21-00161R1).