Lessons learnt from the first controlled human malaria infection study conducted in Nairobi, Kenya

Abstract

Background: Controlled human malaria infection (CHMI) studies, in which healthy volunteers are infected with Plasmodium falciparum to assess the efficacy of novel malaria vaccines and drugs, have become a vital tool to accelerate vaccine and drug development. CHMI studies provide a cost-effective and expeditious way to circumvent the use of large-scale field efficacy studies to deselect intervention candidates. However, to date few modern CHMI studies have been performed in malaria-endemic countries.

Methods: An open-label, randomized pilot CHMI study was conducted using aseptic, purified, cryopreserved, infectious P. falciparum sporozoites (SPZ) (Sanaria® PfSPZ Challenge) administered intramuscularly (IM) to healthy Kenyan adults (n = 28) with varying degrees of prior exposure to P. falciparum. The purpose of the study was to establish the PfSPZ Challenge CHMI model in a Kenyan setting with the aim of increasing the international capacity for efficacy testing of malaria vaccines and drugs, and allowing earlier assessment of efficacy in a population for which interventions are being developed. This was part of the EDCTP-funded capacity development of the CHMI platform in Africa.

Discussion: This paper discusses in detail lessons learnt from conducting the first CHMI study in Kenya. Issues pertinent to the African setting, including community sensitization, consent and recruitment are considered. Detailed reasoning regarding the study design (for example, dose and route of administration of PfSPZ Challenge, criteria for grouping volunteers according to prior exposure to malaria and duration of follow-up post CHMI) are given and changes other centres may want to consider for future studies are suggested.

Conclusions: Performing CHMI studies in an African setting presents unique but surmountable challenges and offers great opportunity for acceleration of malaria vaccine and drug development. The reflections in this paper aim to aid other centres and partners intending to use the CHMI model in Africa.

Figure 1

Study design and volunteer recruitment. 118 participants were excluded following screening. For reasons see Figure 2. In each group, the total dose of sporozoites was split between two injection sites and administered as two 50 μL injections, one in each deltoid.

Figure 2

Primary reasons for exclusion of volunteers. Of some individuals met multiple exclusion criteria. This figure illustrates the primary reason for exclusion for each volunteer. ‘HIV’ = human immunodeficiency virus; ‘ECG’ = electrocardiogram; ‘PCR’ = polymerase chain reaction for P. falciparum; ‘ALT’ = Alanine transaminase; ‘Homo α thal’ = Homozygous α thalassemia; ‘Hetero α thal’ = Heterozygous α thalassemia; βHCG = β Human Chorionic Gonadotropin.

Figure 3

Anti-schizont antibody ELISA absolute OD readings measured at screening. Serum diluted 1:1,000. Negative controls = OD readings from UK malaria-naïve adults (n = 30). Positive controls = OD readings from hyperimmune Kenyan adults living in malaria-endemic regions (n = 6). Minimal exposure = subjects enrolled in Groups 1, 3 and 5 (n = 14). Definite exposure = subjects enrolled in Groups 2, 4 and 6 (n = 14). Screened subjects = all volunteers that had blood drawn at screening (n = 145). Median values represented by lines through each dataset.

Figure 4

qPCR results post-challenge for Volunteer 110, Group 2. Long dashed line = lower limit of detection (i.e., a probability of > 50% of ≥ 1 positive result among three replicate PCR reactions) for qPCR assay (5 parasites/mL). Short dashed line = lower limit of quantification (defined as %CV < 20%) for qPCR assay (20 parasites/mL).