Human Challenge Trials for Tropical Diseases: Not as exotic as one might think

Introduction

Despite scientific progress made in the last decades, nearly 1 billion of individuals are affected by tropical diseases yearly, according to the World Health Organization. The development of new vaccines for tropical diseases remains difficult and this blog will showcase how human challenge trials can support the development of treatments / vaccines for these diseases.

The use of Human Challenge Trials (HCT) or Controlled Human Infection Models (CHIM) to support the development of vaccines and treatments for neglected tropical diseases is not new. One prominent example was the yellow fever experiments conducted by Walter Reed in the early 1900s that proved that yellow fever was transmitted by mosquitoes. HCT have since then been used in a wide range of tropical diseases like cholera, dengue, malaria and typhoid. The malaria challenge model has been one of the most widely used challenge models, with more than 2000 volunteers enrolled in malaria challenge trials globally to date.

Existing regulatory framework

The World Health Organization (WHO) has published a guidance detailing the use of human challenge trials in vaccine development. During the COVID-19 pandemic, the WHO published additional guidance on the considerations on COVID-19 human challenge trials.

The guidance specifies that if they are performed, human challenge trials may be of particular use:

• When there is no appropriate nonclinical model (eg, when a candidate vaccine is intended to protect against an infectious disease that is confined to humans)
• When there is no known immune correlate of protection (ICP)
• When vaccine efficacy trials are not feasible.

HCTs have been frequently used in the clinical development of vaccines for tropical diseases and supported the regulatory approval of a number of tropical disease vaccines. Two case studies will highlight the use of CHIM in the development of vaccines for tropical vaccines.

Down selection of vaccine candidates in malaria vaccine development

Controlled Human Malaria Infection (CHMI) studies have been used since the early 20^th century. In CHMI models, infection is induced either through the use of sporozoites inoculated via direct injection or through bites from infected mosquitoes or plasmodium infected blood, pending on the mode of action of the vaccine candidate.

CHMI studies have been used to down-select malarial vaccine candidates and are now an integral part of the malaria vaccine development cycle. Mosquirix (RTS,S) is currently the only licenced malaria vaccine. A phase 2 CHMI efficacy trial enabled the initiation the phase 3 field trials conducted in over 15,000 infants and young children in Africa. Based on the phase 3 vaccine efficacy of RTS,S/AS01, the vaccine was licensed and in 2019 a pilot program supported by WHO has been initiated in Ghana, Kenya and Malawi to vaccinate 360,000 children per year in selected areas in these countries.

Since 2009, standardization of CHMI models have been emphasized by the WHO and other international organizations such as PATH.

WHO pre-qualification of typhoid vaccine

Vi polysaccharide typhoid vaccines are poorly immunogenic in young children and need repeat dosing. In the past decade, typhoid conjugate vaccines were developed and found to be safe and immunogenic in infants, children and adults.

Typbar-TCV, a typhoid conjugate vaccine, was licensed in India for use based on immunogenicity higher than induced by the Vi-polysaccharide vaccine. No clinical efficacy data was generated pre-licensure. In 2016, the vaccine was in human challenge model of typhoid, In the phase 2b study, healthy adult typhoid naïve volunteers were vaccinated with a single dose of either Typbar TCV, the Vi-polysaccharide vaccine or placebo. Subjects were then challenged using a wild-type typhoid strain, making it more generalisable to natural infection than attenuated strains. Based on results from both earlier immunogenicity studies and the data on efficacy from the human challenge study, Typbar-TCV was pre-qualified by WHO in 2017 and recommended for use in endemic areas.

Conclusion

Human challenge trials play a very important and supportive role in both our understanding of disease and the testing of novel antivirals and vaccines. As the above case studies show they play an essential role in the development of vaccines for tropical diseases and form the basis of a regulatory pathway for accelerated approval in certain specific cases.

References

1. Joshi et al. Roadmap to the treatment of neglected tropical diseases: nanocarrier interventions Journal of controlled release, 2021
2. Clements AN et al.. History of the discovery of the mode of transmission of yellow fever virus J Vector Ecol. 2017
3. Metzger et al, Experimental infection in humans – historical and ethical reflections, Tropical Medicine & international Health, 2019
4. Adams-Phipps et al, A Systematic Review of Human Challenge Trials, Designs, and Safety, Medrxiv, 2022 (pre-print)
5. Roestenberg et al, Experimental infection of human volunteers, Lancet Infectious Diseases, 2018
6. WHO. Human challenge trials for vaccine development: regulatory considerations. 2016.
7. WHO. Guidelines on clinical evaluation of vaccines: regulatory expectations. Revision of WHO TRS 924, Annex 1.
8. WHO. Key criteria for the ethical acceptability of COVID-19 human challenge studies. WHO Working Group for Guidance on Human Challenge Studies in COVID-19, 2020.
9. WHO. Feasibility, potential value and limitations of establishing a closely monitored challenge model of experimental COVID-19 infection and illness in healthy young adult volunteers. Report from the WHO Advisory Group on Human Challenge Studies , 2020
10. Roestenberg et al.  Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am. J. Trop. Med. Hyg.2013
11.  Sauerwein et al. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat. Rev. Immunol. 2011
12. RTS SCTP Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015
13. Laurens et al.  A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines. Vaccine. 2012
14. Mohan et al. Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin. Infect. Dis. 2015
15. Jin et al. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet. 2017
16. WHO Typbar-TCV product overview Typbar-TCV | WHO - Prequalification of Medical Products (IVDs, Medicines, Vaccines and Immunization Devices, Vector Control) (accessed 10 January 2023)