Background: 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.
Methods: 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).
Results: 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.
Conclusions: 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.).