Phase i trial of pfs25-EPA/Alhydrogel® a transmission blocking vaccine against falciparum malaria in healthy malaria-naïve adults

We describe the results of a phase I dose-escalating clinical trial to assess the safety and immunogenicity of the transmission blocking vaccine Pfs25-EPA/Alhydrogel®. Pfs25 has previously been shown to induce antibody which inhibits parasite development in a standard membrane feeding assay (SMFA), but an immunogenic formulation safe for human use has been lacking. EPA as a conjugate has been shown to enhance immunogenicity and to be safe in humans. Pfs25 and EPA were chemically conjugated and adjuvanted with Alhydrogel. 30 subjects have received up to three doses of 8, 16 (at 0 and 2 months) or 47-μg of Pfs25 at 0, 2 and 4 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity. No vaccine related serious adverse events occurred. The most common solicited adverse event was pain at the injection site, and the frequency of adverse events decreased with each successive dose of vaccine. A decrease in hemoglobin was seen in 8 of 30 subjects after the first vaccination, in 11 of 26 subjects after the second and 2 of 15 after the third vaccination. The majority of these were mild in nature, a few were moderate, and most were in subjects who had a previous history of low hemoglobins or anemia and were judged to be unrelated to vaccination. The vaccine was more immunogenic with each successive dose. Geometric mean antibody levels in the 47 μg dose group were 92 EU (95% CI 55, 155) and 228 EU (95% CI 151, 344) after the second and third vaccinations respectively. Sixteen of 17 subjects in the 47 μg dose group had detectable antibody response after 2 vaccinations; 15/15 had responses after 3 vaccinations. Transmission blocking activity correlates with antibody titer, as demonstrated by SMFA. The data to date demonstrate that Pfs25-EPA/Alhydrogel® is well tolerated, increasingly immunogenic with each dose, and induces antibodies which inhibit parasite development in the mosquito.