• Olivia A C Lamers, Blandine M D Franke-Fayard, KoopmanJan Pieter RJPRFrom Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden (O.A.C.L., B.M.D.F-.F., J.P.R.K., G.V.T.R., J.J.J., S.C.C.-M., F.J.A.G., H.M.B.-R., E.I., E.C., E.W., E.L.H., R.M., C.J.J., M.R.), and th, Geert V T Roozen, Jacqueline J Janse, Severine C Chevalley-Maurel, Fiona J A Geurten, Helena M de Bes-Roeleveld, Eva Iliopoulou, Emil Colstrup, Els Wessels, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Wouter Graumans, Thabitha R Stoter, Benjamin G Mordmüller, Emma L Houlder, Teun Bousema, Rajagopal Murugan, Matthew B B McCall, Chris J Janse, and Meta Roestenberg.
• From Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden (O.A.C.L., B.M.D.F-.F., J.P.R.K., G.V.T.R., J.J.J., S.C.C.-M., F.J.A.G., H.M.B.-R., E.I., E.C., E.W., E.L.H., R.M., C.J.J., M.R.), and the Department of Medical Microbiology, Radboud University Medical Center, Nijmegen (G.-J.G., M.V.-B., W.G., T.R.S., B.G.M., T.B., M.B.B.M.) - both in the Netherlands.
• N. Engl. J. Med. 2024 Nov 21; 391 (20): 191319231913-1923.

BackgroundCurrently licensed and approved malaria subunit vaccines provide modest, short-lived protection against malaria. Immunization with live-attenuated Plasmodium falciparum malaria parasites is an alternative vaccination strategy that has potential to improve protection.MethodsWe conducted a double-blind, controlled clinical trial to evaluate the safety, side-effect profile, and efficacy of immunization, by means of mosquito bites, with a second-generation genetically attenuated parasite (GA2) - a mei2 single knockout P. falciparum NF54 parasite (sporozoite form) with extended development into the liver stage. After an open-label dose-escalation safety phase in which participants were exposed to the bites of 15 or 50 infected mosquitoes (stage A), healthy adults who had not had malaria were randomly assigned to be exposed to 50 mosquito bites per immunization of GA2, an early-arresting parasite (GA1), or placebo (bites from uninfected mosquitoes) (stage B). After the completion of three immunization sessions with 50 mosquito bites per session, we compared the protective efficacy of GA2 against homologous P. falciparum controlled human malaria infection with that of GA1 and placebo. The primary end points were the number and severity of adverse events (in stages A and B) and blood-stage parasitemia greater than 100 P. falciparum parasites per milliliter after bites from GA2-infected mosquitoes (in stage A) and after controlled human malaria infection (in stage B).ResultsAdverse events were similar across the trial groups. Protective efficacy against subsequent controlled human malaria infection was observed in 8 of 9 participants (89%) in the GA2 group, in 1 of 8 participants (13%) in the GA1 group, and in 0 of 3 participants in the placebo group. A significantly higher frequency of P. falciparum-specific polyfunctional CD4+ and Vδ2+ γδ T cells were observed among participants who received GA2 than among those who received GA1, whereas GA2 and GA1 induced similar antibody titers targeting the P. falciparum circumsporozoite protein.ConclusionsIn this small trial, GA2 was associated with a favorable immune induction profile and protective efficacy, findings that warrant further evaluation. (Funded by the Bontius Foundation; ClinicalTrials.gov number, NCT04577066.).Copyright © 2024 Massachusetts Medical Society.

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