A Vaccine to Block Plasmodium falciparum Transmission

Malaria vaccines that target parasite development in mosquitoes offer a strategy to block disease transmission and support control, elimination, and eradication. In this article, we evaluate Pfs230D1-exoprotein A (EPA) and Pfs25-EPA for safety, immunogenicity, and field efficacy in Malian adults. We first conducted a comparator-controlled, dose-escalating pilot safety trial, assessing Pfs25-EPA (16 vs. 47 μg) and Pfs230D1-EPA (13 vs. 40 μg), and their combinations, each formulated in the adjuvant AS01, at a 0-, 1-, and 6-month schedule. We then conducted a randomized, double-blind, comparator-controlled main trial to evaluate two Pfs230D1-EPA/AS01 regimens on a 0-, 1-, 4-, 16-month schedule. Pfs230D1-full, consisting of 40 μg of Pfs230D1-EPA plus 50 μg of AS01 for each dose, versus Pfs230D1-fractional, identical to Pfs230D1-full except for the third dose that used 8 μg of Pfs230D1-EPA and 10 μg of AS01. Primary end points were safety and reactogenicity (as-treated population), and secondary end points (as-randomly-assigned population) were immunogenicity by enzyme-linked immunosorbent assay, serum activity by mosquito standard membrane feeding assay (SMFA), and efficacy by direct skin feeding assay (DSF). In the pilot safety trial, 65 participants received injections (45 Pfs230D1 and/or Pfs25; 20 comparator). In the main phase, 236 participants received injections (56 Pfs230D1-full; 61 Pfs230D1-fractional; 119 comparator). No serious adverse events (SAEs) occurred in vaccinees in the pilot or main phase. Pfs230D1-full and Pfs230D1-fractional regimens induced antibody responses and transmission-reducing activity (based on SMFA) detectable up to approximately 1 year post-vaccination 3. Primary efficacy analysis showed combined Pfs230D1-full and Pfs230D1-fractional groups were not associated with reductions in mosquito positivity rate in the first 6 weeks of year 1 (efficacy, -1.55; 95% confidence interval [CI], -11.05 to 0.46). In the Pfs230D1-full group, DSF positivity was lower by 72.5% (95% CI, 30.4 to 89.1), and the proportion of infected mosquitoes was lower by 77.3% (95% CI, 19.5 to 93.6) over two transmission seasons. In this trial, Pfs230D1-EPA/AS01 regimens did not result in SAEs and generated antibody responses and functional activity that persisted for up to 1 year postvaccination. Although the primary efficacy estimate did not demonstrate a reduction in parasite transmission during the first 6 weeks of follow-up, the full dosing regimen was associated with reduced transmission events and infected mosquitoes over 2 years. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov ID, NCT02942277.).