Human challenge models: tools to accelerate the development of malaria vaccines

ABSTRACT

Introduction: Malaria challenge models, where healthy human volunteers are intentionally infected with Plasmodium species parasites under controlled conditions, can be undertaken in several well-defined ways. These challenge models enable evaluation of the kinetics of parasite growth and clearance, host-pathogen interactions and the host immune response. They can facilitate discovery of candidate diagnostic biomarkers and novel vaccine targets. As translational tools they can facilitate testing of candidate vaccines and drugs and evaluation of diagnostic tests.

Areas covered: Until recently, malaria human challenge models have been limited to only a few Plasmodium falciparum strains and used exclusively in malaria-naïve volunteers in non-endemic regions. Several recent advances include the use of alternate P. falciparum strains and other species of Plasmodia, as well as strains attenuated by chemical, radiation or genetic modification, and the conduct of studies in pre-exposed individuals. Herein, we discuss how this diversification is enabling more thorough vaccine efficacy testing and informing rational vaccine development.

Expert opinion: The ability to comprehensively evaluate vaccine efficacy in controlled settings will continue to accelerate the translation of candidate malaria vaccines to the clinic, and inform the development and optimisation of potential vaccines that would be effective against multiple strains in geographically and demographically diverse settings.

KEYWORDS:

• Malaria
• human challenge models
• vaccines
• drugs
• diagnostics
• tools

Article highlights

• Human challenge models for malaria, which involve deliberate infection of volunteers with Plasmodium species sporozoite or blood stage parasites, are an important tool for the development and efficacy testing of anti-malaria vaccines.

• Two modes of infection in human challenge models for malaria exist: sporozoite stage models initiated by infected mosquito bite or injection of cryopreserved sporozoites (PfSPZ); and blood stage models initiated by injection with parasitised red blood cells. The recently developed transmission model, where asexual blood stage parasitemia is cleared with drug treatment allowing for the development of gametocytes, represents an adaption of the latter.

• Human challenge models are diversifying. Multiple Plasmodium strains and species are now established for human challenge.

• The development of cryopreserved PfSPZ (Sanaria Inc.) is facilitating human challenge studies in non-naïve volunteers in malaria endemic areas. A  recent achievement is the application of human challenge to evaluate radiation-attenuated PfSPZ vaccine efficacy in Tanzania, a malaria endemic area.

• Human challenge models are facilitating pre-clinical development of the next generation of malaria vaccines by identifying potential: (1) vaccine candidates by large scale screening of sera from individuals with immunity and by functional antibody guided discovery and; (2) biomarkers and mechanisms of immunity to disease and vaccination.

• By focusing on the use of human challenge models to malaria endemic areas and further diversifying the challenge models available, these models will become established as integral to the vaccine development pipeline.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

M M Cooper is supported by a Postgraduate Research Scholarship from James Cook University. D L Doolan is supported by a National Health and Medical Research Council of Australia (NHMRC) Principal Research Fellowship (1137285). J S McCarthy is supported by a NHMRC Practitioner Fellowship (1135955).