A genetically engineered Plasmodium falciparum parasite vaccine provides protection from controlled human malaria infection

Abstract

Genetically engineered live Plasmodium falciparum sporozoites constitute a potential platform for creating consistently attenuated, genetically defined, whole-parasite vaccines against malaria through targeted gene deletions. Such genetically attenuated parasites (GAPs) do not require attenuation by irradiation or concomitant drug treatment. We previously developed a P. falciparum (Pf) GAP with deletions in P52 , P36 , and SAP1 genes (PfGAP3KO) and demonstrated its safety and immunogenicity in humans. Here, we further assessed safety, tolerability, and immunogenicity of the PfGAP3KO vaccine and tested its efficacy against controlled human malaria infection (CHMI) in malaria-naïve subjects. The vaccine was delivered by three ( n = 6) or five ( n = 8) immunizations with ~200 PfGAP3KO-infected mosquito bites per immunization. PfGAP3KO was safe and well tolerated with no breakthrough P. falciparum blood stage infections. Vaccine-related adverse events were predominately localized urticaria related to the numerous mosquito bites administered per vaccination. CHMI via bites with mosquitoes carrying fully infectious Pf NF54 parasites was carried out 1 month after the last immunization. Half of the study participants who received either three or five PfGAP3KO immunizations remained P. falciparum blood stage negative, as shown by a lack of detection of Plasmodium 18 S rRNA in the blood for 28 days after CHMI. Six protected study participants received a second CHMI 6 months later, and one remained completely protected. Thus, the PfGAP3KO vaccine was safe and immunogenic and was capable of inducing protection against sporozoite infection. These results warrant further evaluation of PfGAP3KO vaccine efficacy in dose-range finding trials with an injectable formulation.

A conservedPlasmodiumprotein that localizes to liver stage nuclei is critical for late liver stage development

“…Genetic attenuation of Pf malaria parasites leading to liver stage arrest forms the basis of a vaccination platform that provides protection from parasite challenge 25, 26, 42 but the discovery of genes for specific liver stage attenuation has been difficult. The present study uncovers a novel gene deletion in both the rodent malaria parasite Py and the human malaria parasite Pf, that causes the creation of a LARC GAP.…”

“…The copyright holder for this preprint this version posted December 14, 2022. ; https://doi.org/10.1101/2022.12.13.519845 doi: bioRxiv preprint liver stage development are deleted from the parasite genome to create genetically attenuated parasites (GAP) 10,25,26 . With respect to irradiated sporozoites, vialed, aseptic, irradiated, cryopreserved Pf NF54 strain sporozoites have been extensively used for intravenous vaccination and numerous successful clinical trials have been carried both in malaria-naïve individuals and in endemic regions of Africa [5][6][7][8][27][28][29] .…”

“…Attenuation is currently achieved in one of three ways -(i) irradiation of sporozoites that then arrest development into liver stages soon after hepatocyte invasion 6,22 , (ii) chemoprophylaxis that kills the liver stage parasite during liver stage development or after the liver stage-to-blood stage transition 23,24 and (iii) genetic attenuation where genes essential for liver stage development are deleted from the parasite genome to create genetically attenuated parasites (GAP) 10,25,26 . With respect to irradiated sporozoites, vialed, aseptic, irradiated, cryopreserved Pf NF54 strain sporozoites have been extensively used for intravenous vaccination and numerous successful clinical trials have been carried both in malaria-naïve individuals and in endemic regions of Africa [5][6][7][8][27][28][29] .…”

“…Pf GAP3KO was shown to be safe and completely attenuated in a pre-clinical trial 41 . Furthermore, in a first-in-human clinical trial where Pf GAP3KO vaccination was administered by infectious mosquito bite, provided 50% sterile protection from a controlled human malaria infection (CHMI) by the administration of five infectious bites from mosquitoes harboring wildtype Pf NF54 25 . The additional EARD GAP candidate, PfSPZ-GA1, composed of aseptic, purified, cryopreserved sporozoites has also completed its first in-human clinical trials 42 .…”

Five decades of clinical assessment of whole-sporozoite malaria vaccines

“…CHMI was carried out by the bites of PfNF54-infected mosquitoes either 4 weeks after the last immunization of the 6 volunteers in each of study arms 1 and 2, or 26 weeks after the first CHMI for study participants in both study arms who did not have any detectable Pf infection after the first CHMI. The vaccine protected 50% of the volunteers in either study arm after the first CHMI, and protected 1 of the 6 volunteers who undertook the second CHMI ( 93 ).…”