Authors

Discussion

Introduction: Given the recent resurgence of malaria, an effective vaccine is needed now more than ever. The only vaccine candidates that have achieved >90% protection in clinical trials consist of live attenuated sporozoites. Attenuation can be achieved by radiation, chemoprophylaxis or genetic modification. Irradiated parasites cause few side effects and abort development 1-2 days after hepatocyte invasion, yet have a lower potency than chemo-attenuated parasites. Depending on the pharmacological intervention, chemo-attenuated parasites can persist longer in the host, which may improve immunogenicity. The advantage of genetic attenuation is that parasites can be engineered to arrest at a desired timepoint, combining biosafety with increased potency. We previously tested an early-arresting (EA) genetically attenuated Plasmodium falciparum (Pf) parasite (GAP) that interrupts development 2-3 days into the liver stage. While the EA-GAP GA1 (PfNF54∆slarp∆b9) was safe and well-tolerated, its protective efficacy in malaria-naïve Dutch participants was lower than desired. We therefore created GA2 (PfNF54∆mei2), a late-arresting (LA) GAP that aborts development just before the end of the liver stage (after 6-7 days). We hypothesized that by prolonging exposure and broadening the variety of antigens presented to the immune system, immunogenicity and therefore protective efficacy would be increased.

Methods: We conducted a phase 1/2a partially double-blind placebo-controlled clinical trial, assessing the safety, tolerability and preliminary protective efficacy of GA2. Forty-three healthy male and female, non-pregnant, malaria-naïve volunteers, aged 18-35, participated in the study. The primary endpoints were the frequency and severity of adverse events (AE) and parasitaemia, assessed by 18s qPCR. Stage A was a dose-escalation study: participants were exposed once to 15 or 50 GA2-infected mosquito bites (MB). In stage B, GA2 was compared to its predecessor GA1 and a placebo. Participants were exposed to 50 GA2-, GA1-infected or uninfected MB, three times at 28-day intervals. Three weeks later, all participants underwent controlled human malaria infection (CHMI) by means of 5 MB infected with the unattenuated homologous Pf isolate (3D7).

Results: The GA2 parasite was found to be safe and well-tolerated and the frequency and severity of AEs was low and comparable across groups. No breakthrough infections occurred following GA2-administration at any dose. Immunisation with GA2 resulted in 89% protection against homologous CHMI: 8 out of 9 participants remained qPCR negative until the end of the trial. GA1 immunisation achieved a protective efficacy of 13%: 7 out of 8 participants developed parasitaemia following CHMI. Immunisation with uninfected MB offered no protection. GA2- and GA1-immunised participants exhibited a significant increase in anti-Pf circumsporozoite protein