Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity

Abstract

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.

Human challenge trials in vaccine development

“…For instance, in malaria, the primary targets for malarial vaccines are children and young infants whereas CHMI studies are carried out in healthy adults. Similarly, historically most challenge studies, have enrolled participants who have no prior history of exposure to challenge agent, however that is changing with more such studies being carried out in endemic regions and allowing for selection of participants who have had pre-exposure [ 24 ]. The route of infection, the dose of the challenge agent use might not appropriately mimic the natural course of infection and hence this might affect the interpretations drawn from such studies [ 8 ].…”

“…This has allowed the CHMI models to be more widely used, including in endemic regions in Africa [ 23 ]. Conducting CHMI studies in endemic settings can help understand the effects of pre-exposure and immunity which is not feasible in non-endemic settings [ 24 ].…”

Exploring willingness to participate in future Human Infection Studies in Lusaka, Zambia: A nested qualitative exploratory study

“…Infection control measures at the facility further contain the pathogen thus preventing and protecting third parties from getting unwanted infections. Similar to requirements reported from Kenya [18], facilities need to cater to more than medical concerns to include comfort, entertainment, family visitations (if possible), and provision to meet pressing worldly obligations such as examinations and funerals. These provisions bring with them considerations of measures that protect participants from infections carried by visitors and the visitors, infection from the facility [6].…”

Case Studies: Challenge Studies in Low- and Middle-Income Countries

“…The Kenyan study was conducted in Nairobi, a non-endemic part of the country and the investigators found it difficult to recruit as many semi-and/or highly-immune individuals as they had planned, largely because of a lack of exposure to prior infection in the local population in Nairobi (the research group have since begun conducting HCS in and/or recruiting from more endemic parts of Kenya (Kapulu et al 2018)). In contrast, the Tanzanian and Gabonese studies took place in endemic areas and were able to recruit semi-immune individuals (and/or those with innate resistance to malaria) more easily.…”