Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial

Background Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/ Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians.Methods We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18-50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4 center dot 5, and 16 center dot 5 of either 47 mu g Pfs25, 40 mu g Pfs230D1 or comparator (Twinrix or Menactra)-all co-administered with normal saline for blinding-or 47 mu g Pfs25 plus 40 mu g Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov, NCT02334462.Findings Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 mu g), Pfs230D1-EPA/Alhydrogel (15 mu g) or comparator, followed by Pfs25-EPA/ Alhydrogel (16 mu g) plus Pfs230D1-EPA/Alhydrogel (15 mu g) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 mu g Pfs25-EPA/Alhydrogel plus saline (n=50 [25%]; Pfs25), 40 mu g Pfs230D1-EPA/Alhydrogel plus saline (n=49 [25%]; Pfs230D1), 47 mu g Pfs25-EPA/ Alhydrogel plus 40 mu g Pfs230D1-EPA/Alhydrogel (n=50 [25%]; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 [25%]). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77 center dot 8 [95% CI 56 center dot 9-106 center dot 3], 146 center dot 4 [108 center dot 3-198 center dot 0], and 410 center dot 2 [301 center dot 6-558 center dot 0]; Pfs25 geometric mean 177 center dot 7 [130 center dot 3-242 center dot 4] and 315 center dot 7 [209 center dot 9-474 center dot 6]). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74 center dot 5% [66 center dot 6-82 center dot 5]) and Pfs25 plus Pfs230D1 (68 center dot 6% [57 center dot 3-79 center dot 8]), after the third dose and after the fourth dose (88 center dot 9% [81 center dot 7-96 center dot 2] for Pfs230D1 and 85 center dot 0% [78 center dot 4-91 center dot 5] Pfs25 plus Pfs230D1) but not for Pfs25 (58 center dot 2% [49 center dot 1-67 center dot 3] after the third dose and 58 center dot 2% [48 center dot 5-67 center dot 9] after the fourth dose). Pfs230D1 transmission-reducing activity (73 center dot 7% [64 center dot 1-83 center dot 3]) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 [3%] of 982 [-0 center dot 013 to 0 center dot 014], Pfs230D1 22 [2%] of 954 [-0 center dot 005 to 0 center dot 027], and combination 11 [1%] of 940 [-0 center dot 024 to 0 center dot 002]) did not differ from that of the comparator (22 [2%] of 974), nor did Pfs230D1 and combination groups differ (-0 center dot 024 to 0 center dot 001).Interpretation Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness.Funding Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health.Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved.