Ethical Issues Surrounding Controlled Human Infection Challenge Studies in Endemic Low-and-Middle-Income Countries

1. Introduction

• Controlled Human Infection (CHI) Studies:
  • Involve intentional exposure to pathogens to test vaccines/therapeutics, study disease natural history, or develop infection models.
  • Controlled environment with controlled selection/production of pathogen strain, infection timing, route, dose, and subject selection.
• Advantages of CHIs:
  • Faster, smaller, and cheaper than field trials.
  • Fewer participants required compared to field trials.
  • Unique insights into host-pathogen interactions.
• Ethical Considerations:
  • Despite historical unethical research, modern CHIs are conducted with ethical oversight.
  • Only a small percentage of CHIs are conducted in LMICs despite their disease burden.

2. Study Design and Methods

2.1 Literature Review

• Focused on identifying primary scientific papers, historical examples, regulatory documents, and bioethical analyses relevant to CHIs in LMICs.

2.2 Qualitative Interviews

• Conducted with 45 participants, including scientists, ethicists, and regulatory representatives.
• Participants were recruited based on involvement in LMIC CHIs, expertise, and through snowball sampling.
• Data were coded to identify themes and sub-themes used to inform the final report.

2.3 Synthesis and Validity Checking

• Findings synthesized from literature review and interview data.
• Draft report shared for feedback and validity assessment.

3. Ethical Issues Related to Endemic LMIC CHIs

3.1 The Case for CHIs in Endemic Settings

• CHIs could be more scientifically valid and relevant to at-risk populations in endemic LMICs.
• Participants in endemic regions may benefit directly from research participation.
• Building local research capacity addresses neglected diseases endemic to LMICs.

3.2 Specific Implications of Ethical Considerations

3.2.1 Potential Individual Benefits for Participants

• Participants in endemic settings may benefit from CHIs by gaining immunity or receiving comprehensive medical care.

3.2.2 Risks to Participants

• Risks might be higher in regions with inadequate healthcare infrastructure but can be mitigated with proper study designs.
• Some participants may face lower risk due to acquired immunity or genetic resistance.

3.2.3 Third-Party Risks

• CHIs may pose risk to third parties; reducing these risks involves infection control and isolation protocols.
• Third-party risks vary with mode of disease transmission and require community engagement.

3.2.4 Consent

• Informed consent processes can be complex; recruiting less educated individuals may still be ethical with adequate consent processes.
• Familiarity with the disease in endemic settings can motivate participation.

3.2.5 Payment

• Payment considerations are complex, particularly in LMICs with economic disadvantage.
• Payment should compensate for burdens and involve local community consultation.

3.2.6 Community Engagement and Public Acceptability

• Community acceptance is crucial for ethical CHIs; engagement should be a two-way process to understand community perspectives.

4. Conclusions

• Ethical and scientific reasons support conducting CHIs in endemic LMICs.
• Endemic-region CHIs may offer more relevant results and favorable risk-benefit profiles.
• Payment and consent in LMICs require careful consideration.
• Community engagement ensures the acceptability and sustainability of CHIs.

Acknowledgments

• Supported by the Wellcome Trust and others; thank you to contributors and workshop participants.

Conflict of Interest

• Authors involved in WHO guidance on ethics of human challenge studies.