Vaccines to Interrupt Malaria Transmission: Clinical Development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Highlighted in this year’s summary are results from our publications in FY2025: 1. Healy SA, Sagara I, et al. A vaccine that blocks Plasmodium falciparum transmission. 2025. NEJM Evidence. Jul;4(7):EVIDoa2400188. doi: 10.1056/EVIDoa2400188. Epub 2025 Jun 24. In 2023, we reported progress with leading malaria transmission–blocking vaccine candidates Pfs25 and Pfs230D1 formulated in Alhydrogel, showing safety, immunogenicity and confirming superior functional activity and durability of responses to Pfs230D1 over Pfs25 in Malian adults. However, we were unable to assess vaccine effectiveness likely due to low event rates, and hypothesized Pfs230D1 activity could be improved by the more potent adjuvant AS01 (the adjuvant administered with licensed vaccine RTS,S), which improved durability of Pfs25 and Pfs230D1 antibody responses in preclinical studies. In this publication, we reported a phase 1 trial in adults in Mali, including a pilot trial to assess the safety and immunogenicity of Pfs230D1-EPA and Pfs25-EPA formulated in AS01. Pilot safety participants initially enrolled into three open-label low-dose groups (5 participants per group: Pfs25 [16 μg]; Pfs230D1 [13 μg]; and coadministration [16 μg+13 μg]). Thereafter, pilot-safety participants (10 participants per group) were sequentially randomly assigned (1:1:1) to double-blind, high-dose, single-antigen groups (Pfs25 [47 μg]; Pfs230D1 [40 μg]) or the comparator (Engerix-B, GlaxoSmithKline), followed by high-dose coadministration (47 μg+40 μg) or the comparator (1:1). The vaccine was administered on a 0-, 1-, and 6-month schedule. Safety follow-up continued 6 months post–dose 3 with optional immunogenicity follow-up through 12 months post–dose 3. Individual pilot safety groups were assessed by Standard Membrane Feeding Assay (SMFA) to determine if the combination of antigens increased activity. Median transmission-reducing activity and transmission-blocking activity values post–doses 2 and 3 were lower in Pfs25 groups, and combination groups did not demonstrate higher activity versus Pfs230D1-alone groups. Based on the superior activity of Alhydrogel-adjuvanted Pfs230D1-EPA versus Pfs25-EPA, alongside the pilot-safety immunogenicity data presented here, we elected to assess only Pfs230D1-EPA/AS01 in the main phase. In the main phase trial, Pfs230D1 full-dosing regimen was associated with a 24.6% reduction in the proportion of transmitting participants, a 73.3% reduction in the proportion of positive DSFs, a 77.3% reduction in the proportion of infected mosquitoes, and a 79.6% reduction in the average oocyst count (from positive DSF assays only). The results of this trial mark a major advance for TBVs, reporting the first demonstration of efficacy to reduce transmission to mosquitoes, and establishing Pfs230D1 as the clear leading TBV candidate over Pfs25. 2. Golden A, et al. Analytical sensitivity analysis and clinical impact modeling of Rapigen rapid diagnostic tests for malaria. 2024. AJTMH. Sep 3; tpmd240003. doi: 10.4269/ajtmh.24-0003. Laboratory benchmarking allows objective analysis of the analytical performance of malaria rapid diagnostic tests (RDTs). Based on research led by our collaborating partners, we reported the analytical detection limits of the Rapigen BIOCREDIT Malaria Ag Pf/Pv (pLDH/pLDH), the Rapigen BIOCREDIT Malaria Ag Pf (pLDH/HRPII), and two best-in-class WHO-prequalified comparator RDTs, generated using standardized panels containing recombinant antigen, in vitro cultured parasites, international standards, and clinical samples. Detection limit antigen concentrations of HRP2, PfLDH, and PvLDH were determined for the Rapigen and comparator RDTs, and detection of antigens in international units (IU)/mL was also evaluated. Rapigen RDTs were predicted to have improved detection of asymptomatic cases and infections with parasites carrying hrp2 deletions through more sensitive PfLDH detection. Through the benchmarking and simulation of clinical sensitivity, we presented a method for rapidly assessing the ability of new RDTs to meet clinical needs using high-sensitivity antigen distribution data. In addition to these publications, we have closed databases for the following trials of Pfs25 and Pfs230 listed under these protocol titles: • NIAID protocol 17-I-N006 (closed) Phase 1 Dose Escalating, Double-Blind, Randomized Comparator Controlled Trial of the Safety and Immunogenicity of Pfs25M-EPA/AS01 and Pfs230D1M-EPA/AS01 Vaccines, Transmission Blocking Vaccines against Plasmodium falciparum, at Full and Fractional Dosing in Adults in Mali o manuscript published by NEJM Evidence • NIAID protocol 19-I-N086: Safety, Immunogenicity and Efficacy of Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine against Plasmodium falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali o manuscript in progress We have also seen progress in additional trials of Pfs230 vaccines, including a multistage combination vaccine of Pfs230D1+R1, listed below under these protocol titles: • NIAID Protocol 000576: Phase 1, Dose-Escalating, Double-Blind, Randomized, Comparator-Controlled Trial of the Safety, Tolerability, and Immunogenicity of the Transmission-Blocking Vaccine Pfs230D1‑EPA/Matrix-M™ against Plasmodium falciparum in Adults in Mali o manuscript in progress • ISRCTN13649456 USTTB EC: 2022/84/CE/USTTB: Phase 1 Dose-escalating, Randomized, Comparator-Controlled Trial of the Safety, Tolerability, and Immunogenicity of the Co-administration of Transmission-blocking Vaccines (R0.6C-AlOH/ Matrix- M™ with Pfs230D1 EPA/Matrix-M™) and Individual Comparators (R0.6C-AlOH/ Matrix-M™; ProC6C-AlOH/ Matrix-M™ and Pfs230D1 EPA/Matrix-M™) Against Pf in Adults in Mali TBVax2 • FMPOS Protocol: 2024/122/CE/USTTB: Phase 1 Randomized, Double-blind Dose-escalating Study of Pfs230D1 in Combination with R21 in Matrix-M in Healthy African Adults We advanced clinical development of a TBV against P. vivax. A first-in-human phase 1 study of Pvs230D1-EPA/Matrix-M is underway at the NIH Clinical Center with the primary objective of assessing safety. A total of 30 malaria-naïve adults were enrolled in 2024, divided equally into 3 dose groups based on the amount of Pvs230D1 antigen (low, intermediate, high). The vaccine was well-tolerated with study-related AEs predominantly being of mild to moderate severity. Exploratory objectives including immunogenicity have also been assessed, with high levels of anti-Pvs230D1 antibodies measured by ELISA from all 3 dose groups through 6 months post the vaccination series. Functional assessment of the vaccine-induced antibodies is underway using membrane feeding assays. A blood-stage P. vivax controlled human malaria infection (CHMI) model is being developed at the NIIH Clinical center. In the model, healthy, malaria-naïve volunteers receive intravenous injection of challenge agent which consists of donated red blood cells containing P. vivax. After approximately 1 week the volunteers become parasitemic and undergo transmission studies including direct skin feeds (DSFs) and membrane feeding assays (MFAs) to assess transmission of gametocytes to Anopheles mosquitoes. The study began enrollment in February of 2025 and thus far seven volunteers have safely undergone the CHMI procedure. High levels of transmission in both DSFs and MFAs have been observed making the model appropriate for future evaluation of transmission blocking vaccines or other interventions.