Reproduced from an online seminar presentation, made in collaboration with TOPRA and hVIVO, given on 21 June 2022 by Bruno Speder from hVIVO.

 

Regulatory Rapporteur

 

February 2023   |   Volume 20   |   No.2

 

Despite advancement in global pharmaceutical research, nearly one billion individuals are affected by tropical diseases yearly, according to World Health Organization. The development of new treatments for tropical diseases remains difficult and this report will explore how human challenge trials can support the development of treatments and vaccines for these diseases and accelerate their regulatory approval.[1]

A number of regulatory agencies have put in place programmes to stimulate the development of therapeutics for tropical diseases, for example, the FDA `Neglected Tropical Disease Priority Review Voucher Program’.[2] Under this system, a company that receives approval for a product to treat or prevent a neglected tropical disease receives a `Priority Review Voucher`. With this voucher, the company can, for a drug or vaccine of their choice, request a review under FDA’s Priority Review Designation pathway. This pathway enables FDA review of an NDA / BLA in just six months instead of the standard ten-month time period.

A number of regulatory agencies have put in place programmes to stimulate the development of therapeutics for tropical diseases

The system aims to stimulate the development of compounds for a number of neglected tropical diseases, as the FDA’s priority review process can be extremely beneficial for companies, enabling them to market their product more quickly and begin recouping their often-considerable development costs. The priority voucher can also be sold to a third party, which has created an extensive secondary market. Since its inception, a number of additional tropical diseases have been added to the list by the US Congress.[3]

Human challenge trials (HCT)

A further incentive for tropical medicine development and registration has been health authority acceptance of novel human challenge trials (HCT) and Controlled Human Infection Models (CHIM).

In human challenge trials (HCT) or Controlled Human Infection Models (CHIM), healthy volunteers are administered a well-characterised pathogenic or virulent strain of a challenge agent in combination with a vaccine or antiviral. The challenge agent can be a virus (ie, influenza), bacteria (ie, cholera) or a parasite (ie, malaria).

The use of HCTs 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.[4] HCT have since then been used in a wide range of tropical diseases like cholera, dengue, malaria and typhoid.[5][6]The malaria challenge model is one of the most widely used challenge models, with more then 2000 volunteers enrolled in malaria challenge trials to date.[7]

The WHO has published guidance detailing the use of human challenge trials in vaccine development.[8][9]During the COVID-19 pandemic, the WHO published additional guidance on considerations around COVID-19 human challenge trials.[10][11]

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

  • When there is no appropriate non-clinical 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 field efficacy trials are not feasible.

Data from CHIM trials have traditionally been accepted by regulators as supportive for the following:

  • As proof-of-concept trials where protective or curative efficacy is being assessed.
  • As a method for determining optimal dosage (to identify the correct individual dose, dose range, or schedule for field studies).
  • ‘Preliminary clinical evidence’ in the framework of Fast Track and Breakthrough designation by the FDA.

A number of examples of Controlled Human Infection Models (CHIM) have been used in the development and registration of vaccines.

Down selection of vaccine candidates in malaria vaccine development

Controlled Human Malaria Infection (CHMI) studies have been used since the early 20th 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, depending on the mode of action of the vaccine candidate.[12]

CHMI studies have been used to down-select malarial vaccine candidates and are now an integral part of the malaria vaccine development cycle.[13] Mosquirix (RTS,S) is currently the only licensed malaria vaccine. A Phase 2 CHMI efficacy trial enabled the initiation of the phase 3 field trials conducted in over 15,000 infants and young children in Africa.[14] Based on the phase 3 vaccine efficacy of RTS,S/AS01, the vaccine was licensed and in 2019 a pilot programme supported by the WHO has been initiated in Ghana, Kenya and Malawi to vaccinate 360,000 children per year in selected areas in these countries.

CHMI studies have been used to down-select malarial vaccine candidates and are now an integral part of the malaria vaccine development cycle

Since 2009, the standardisation of CHMI models has been emphasised by the WHO and other international organisations such as the Program for Appropriate Technology in Health (PATH).[15] The standardisation of these models will allow for benchmarking and comparing different drugs / vaccines, but also help regulators and developers in the interpretation of these CHMI results.

WHO pre-qualification of typhoid vaccine

In the past decade, typhoid conjugate vaccines were developed and found to be safe and immunogenic in infants, children and adults. These novel vaccines remove the poorly immunogenic in young children and need for repeat dosing originally associated with Vi polysaccharide typhoid vaccines.

Typbar-TCV, a typhoid conjugate vaccine, was licensed in India for use based on immunogenicity higher than that induced by the Vi-polysaccharide vaccine. No clinical efficacy data was generated pre-licensure.[16] In 2016, Typbar-TVC was tested in a typhoid human challenge model , In this phase 2b HCT study, healthy adult typhoid naïve volunteers were vaccinated with a single dose of either Typbar TCV, the Vi-polysaccharide vaccine or placebo.[17] 

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.[18]

Pivotal efficacy data in EMA / FDA marketing authorisation for cholera vaccine

Vaxchora is a live oral cholera vaccine intended to prevent cholera disease in adults and children aged from six years (18 years in the US). The vaccine is aimed at those travelling to cholera-endemic regions. It contains a weakened form of the cholera bacterium Vibrio cholerae (serogroup O1). Vaxchora received marketing authorisation valid throughout the EU in April 2020 and was approved by the FDA in June 2016.[19][20]

Developing a vaccine for cholera – in particular, one aimed at travellers – has a major challenge: performing a Phase III field trial in this population would be difficult, as both placebo and active group would need to be meaningfully exposed to cholera – in the same order of magnitude – in order to achieve a conclusive result on efficacy. To be able to demonstrate efficacy, a CHIM trial was included in the development pathway as the pivotal efficacy study, replacing a Phase III efficacy field trial. In this CHIM study, 197 healthy adults aged 18 to 45 years received a single dose of either Vaxchora (95 volunteers) or placebo (102 volunteers) and were then given infectious cholera bacteria (O1 strain).

The CHIM trial showed that Vaxchora can prevent symptoms of cholera in people coming into contact with the bacteria and provided the pivotal part of the efficacy data. In order to have a sufficiently large safety database, a main safety immunogenicity study involving 3,022 healthy adults aged 18 to 45 years was performed. Two further studies in special populations confirmed that giving Vaxchora to adults aged 46 to 64 years or to children and adolescents aged 6 to 18 years, was effective at inducing the production of antibodies against cholera bacteria.

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. The case studies above underline their essential role in the development of vaccines for tropical diseases and highlight how they form the basis of a regulatory pathway for accelerated approval in certain specific cases.

References

[1] Joshi G, Quadir SS, Yadav KS. Road map to the treatment of neglected tropical diseases: Nanocarriers interventions. J Control Release. 2021;339:51-74. doi:10.1016/j.jconrel.2021.09.020

[2] FDA. (2018) Food and Drug Administration Amendment Act (FDAAA) of 2007.

[3] Aerts C, Barrenho E, Miraldo M, Sicuri E. The Impact of the Priority Review Voucher on Research and Development for Tropical Diseases [published correction appears in Pharmaceut Med. 2022 Dec;36(6):405]. Pharmaceut Med. 2022;36(3):189-197. doi:10.1007/s40290-022-00427-x

[4] Clements AN, Harbach RE. History of the discovery of the mode of transmission of yellow fever virus. J Vector Ecol. 2017;42(2):208-222. doi:10.1111/jvec.12261

[5] Metzger WG, Ehni HJ, Kremsner PG, Mordmüller BG. Experimental infections in humans-historical and ethical reflections. Trop Med Int Health. 2019;24(12):1384-1390. doi:10.1111/tmi.13320

[6] Adams-Phipps J, Toomey D, Więcek W, et al. A Systematic Review of Human Challenge Trials, Designs, and Safety [published online ahead of print, 2022 Oct 11]. Clin Infect Dis. 2022; ciac820. doi:10.1093/cid/ciac820

[7] Roestenberg M, Hoogerwerf MA, Ferreira DM, Mordmüller B, Yazdanbakhsh M. Experimental infection of human volunteers. Lancet Infect Dis. 2018;18(10):e312-e322. doi:10.1016/S1473-3099(18)30177-4

[8] WHO. (2017) Human challenge trials for vaccine development: regulatory considerations, Annex 10, TRS No 1004.

[9] WHO. (2004) Guidelines on clinical evaluation of vaccines: regulatory expectations. Revision of WHO TRS 924, Annex 1.

[10] WHO. (2020) Key criteria for the ethical acceptability of COVID-19 human challenge studies. WHO Working Group for Guidance on Human Challenge Studies in COVID-19.

[11] WHO. (2020) 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.

[12] Roestenberg M, Bijker EM, Sim BKL, et al. Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2013;88(1):5-13. doi:10.4269/ajtmh.2012.12-0613

[13] Sauerwein RW, Roestenberg M, Moorthy VS. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol. 2011;11(1):57-64. doi:10.1038/nri2902

[14] RTS,S Clinical Trials Partnership. 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 [published correction appears in Lancet. 2015 Jul 4;386(9988):30]. Lancet. 2015;386(9988):31-45. doi:10.1016/S0140-6736(15)60721-8

[15] Laurens MB, Duncan CJ, Epstein JE, et al. A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines. Vaccine. 2012;30(36):5302-5304. doi:10.1016/j.vaccine.2012.04.088

[16] Mohan VK, Varanasi V, Singh A, 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;61(3):393-402. doi:10.1093/cid/civ295

[17] Jin C, Gibani MM, Moore M, 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;390(10111):2472-2480. doi:10.1016/S0140-6736(17)32149-9

[18] WHO Typbar-TCV product overview Typbar-TCV | WHO - Prequalification of Medical Products (IVDs, Medicines, Vaccines and Immunization Devices, Vector Control) (accessed 10 January 2023) 

[19] EMA.(2020) Vaxchora: EPAR Assessment Report.

[20] FDA. (2022) Vaxchora.

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