Malaria clinical trials at University of California Health

This is a Phase 2 clinical trial of Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) vaccine (Sanaria® PfSPZ-LARC2 Vaccine). It represents the next step in the development of this vaccine toward licensure, following a successful Phase 1 program in which the vaccine was shown to be safe (fully attenuated), well tolerated and immunogenic in malaria-exposed 1- to 45-year-olds in Burkina Faso (BFSPZL1 trial) and in malaria-naive adults in the US (USSPZL1 trial). Protection data will be available in March 2026 from the USSPZL1 trial, but these data will be from malaria-naive adults undergoing controlled human malaria infection (CHMI), representing (1) a different population with respect to immune status compared to malaria-exposed African adults, and (2) a one-time malaria exposure to a single malaria strain, compared to the ongoing, heterogeneous infection risk in nature. It is therefore important to assess field efficacy in Africa as soon as possible, to ascertain the potential value of PfSPZ-LARC2 Vaccine in addressing the World Health Organization's (WHO's) call for vaccines with high efficacy (>90%) against Pf infection naturally transmitted in endemic populations, with a focus on high burden sub-Saharan countries. PfSPZ-LARC2 Vaccine is especially promising because of data in malaria-naive adults showing that a biosimilar LARC vaccine called GA2 (aka LARC1) provided 90% vaccine efficacy (VE) against CHMI after administration of a single dose by mosquito bite, as recently published by the Leiden University Medical Center. The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double deletion of the genes encoding the Mei2 and LINUP proteins, both of which are required for transition from liver to blood stage malaria. As a result, mei2-/linup- parasites undergo developmental arrest in the late liver stages without releasing merozoites into the blood stream. No blood stage parasites are produced, either asexual or sexual, and the parasite life cycle does not progress. Because Pf parasites with the LARC phenotype replicate in the liver before disintegrating, they amplify and diversify parasite protein expression and are expected to be a potent immunogen to induce anti-malarial immunity, equaling or exceeding the potency and efficacy of the replication-competent chemo-attenuated Sanaria® PfSPZ-CVac (chloroquine) vaccine approach. Because the parasites are intrinsically attenuated, they are expected to be safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine, to the replication deficient, early arresting PfSPZ-GA1 Vaccine, and to the single-gene(mei2)-deleted GA2 (LARC1) parasites tested at the Leiden University Medical Center that provided 90% protection against CHMI after a single dose as described above. In summary, the late liver stage arresting replication competent, genetically attenuated PfSPZ-LARC2 Vaccine should combine the best-in-class immunogenic potency and protective efficacy of replicating PfSPZ-CVac (chloroquine) with the excellent safety and tolerability of the early arresting, non-replicating radiation attenuated PfSPZ Vaccine, genetically attenuated PfSPZ-GA1 Vaccine, and genetically attenuated GA2 vaccine. High level efficacy against naturally transmitted Pf in this trial will set the stage for Phase 3 testing and licensure. It will be complimentary to data from other planned trials to establish the following target populations: 1) women of child-bearing potential and pregnant women, to prevent pregnancy malaria; 2) children, to prevent pediatric malaria; and, eventually, 3) entire populations, to halt transmission and achieve regional malaria elimination. This development path aimed at endemic populations is being pursued in parallel with studies in malaria-naive individuals aiming to concurrently license a high efficacy malaria vaccine for travelers from non-malaria endemic to malaria-endemic areas.