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

Abstract

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.

Development of whole sporozoite malaria vaccines

“…in four doses in 10 μL (total 25,000 PfSPZ), achieving infectivity in 10 of 11 subjects [98] and also in Kenya, where 25,000 PfSPZ administered i.m. achieved nearly 100% infectivity, with a single failure in a subject with the highest anti-blood stage antibody levels measured by ELISA [99]. One conclusion was that i.v.…”

Workshop report: Malaria vaccine development in Europe–preparing for the future

“…Several CHMI studies are underway or have been completed in malaria-endemic regions [41,42] but more research is required to characterise the interaction between injected sporozoites and the pre-existing natural immunity. CHMI models could be used in populations with prior exposure to the parasite or with locally sourced parasite isolates or clones and/or local infected mosquitoes, although standardisation may be challenging in this context.…”

“…Current CHMI protocols to test vaccine efficacy are based on challenge by inoculation of asexual P. falciparum blood-stages [36][37][38], and of sporozoites either by controlled mosquito bites [6] or direct intravenous administration (DVI) [39][40][41][42][43].…”

Recent Developments in Malaria Vaccinology

“…This will significantly speed up malaria vaccine research e enabling CHMI studies to occur in more centres and in malaria-endemic target populations. Future CHMI studies in malaria-exposed individuals will also greatly facilitate studies of natural immunity (Hodgson et al, 2014b) and facilitate the development of diagnostics for malaria or new antimalarial interventions, as CHMI has been proven to be a very powerful tool to investigate the underlying mechanisms of innate or acquired immunity against malaria. The development of new challenging parasite strains (like the Nijmegen P. falciparum strain NF135.C10), which are genetically distinct to the predominantly used NF54/3D7 clone challenge strain, will complement and expand the existing small repertoire of CHMI parasite strains .…”