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

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.

Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection.

BACKGROUND: Controlled human malaria infection (CHMI) studies are a vital tool to accelerate vaccine and drug development. As CHMI trials are performed in a controlled environment, they allow unprecedented, detailed evaluation of parasite growth dynamics (PGD) and immunological responses. However, CHMI studies have not been routinely performed in malaria-endemic countries or used to investigate mechanisms of naturally-acquired immunity (NAI) to Plasmodium falciparum. METHODS: We conducted an open-label, randomized CHMI pilot-study using aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) to evaluate safety, infectivity and PGD in Kenyan adults with low to moderate prior exposure to P. falciparum (Pan African Clinical Trial Registry: PACTR20121100033272). RESULTS: All participants developed blood-stage infection confirmed by quantitative polymerase chain reaction (qPCR). However one volunteer (110) remained asymptomatic and blood-film negative until day 21 post-injection of PfSPZ Challenge. This volunteer had a reduced parasite multiplication rate (PMR) (1.3) in comparison to the other 27 volunteers (median 11.1). A significant correlation was seen between PMR and screening anti-schizont Enzyme Linked Immunosorbent Assays (ELISA) OD (p = 0.044, R = -0.384) but not when volunteer 110 was excluded from the analysis (p = 0.112, R = -0.313). CONCLUSIONS: PfSPZ Challenge is safe and infectious in malaria-endemic populations and could be used to assess the efficacy of malaria vaccines and drugs in African populations. Whilst our findings are limited by sample size, our pilot study has demonstrated for the first time that NAI may impact on PMR post-CHMI in a detectable fashion, an important finding that should be evaluated in further CHMI studies.

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers.

BACKGROUND: Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. METHODS: Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. RESULTS: The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was <150 nM. CONCLUSION: Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C(eff) of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

In vivo and in vitro efficacy of amodiaquine against Plasmodium falciparum in an area of continued use of 4-aminoquinolines in East Africa.

In light of reports of increasing resistance of parasites to amodiaquine in African countries in which Plasmodium falciparum is endemic as well as the paucity of recent in vitro sensitivity data, we assessed the in vivo and in vitro sensitivity to amodiaquine of P. falciparum isolates from 128 pediatric outpatients (0.5-10 years old) in Pingilikani, Kilifi District, Kenya, who were treated with amodiaquine (10 mg/kg/day for 3 days). The polymerase chain reaction-corrected parasitological cure rate on day 28 (by Kaplan-Meier analysis) was 82% (95% confidence interval [CI], 74%-88%). Twenty-six percent (17/66) of tested pretreatment P. falciparum field isolates had 50% in vitro growth inhibition at concentrations of N-desethyl-amodiaquine (DEAQ)-the major biologically active metabolite of amodiaquine-above the proposed resistance threshold of 60 nmol/L, but baseline median DEAQ 50% inhibitory concentration values were not associated with subsequent risk of asexual parasite recrudescence (29 nmol/L [95% CI, 23-170 nmol/L] and 34 nmol/L [95% CI, 30-46 nmol/L] for patients with and those without recrudescences, respectively). The median absolute neutrophil count dropped by 1.3 X 10(3) cells/microL (95% CI, -1.7 X 10(3) to -0.7 X 10(3) cells/microL) between days 0 and 28. The high prevalence of in vitro and in vivo resistance precludes the use of amodiaquine on its own as second-line treatment. These findings also suggest that the value of amodiaquine combinations as first- or second-line treatment in areas with similar patterns of 4-aminoquinoline resistance should be reassessed.