Advancing Global Health through Development and Clinical Trials Partnerships: A Randomized, Placebo-Controlled, Double-Blind Assessment of Safety, Tolerability, and Immunogenicity of PfSPZ Vaccine for Malaria in Healthy Equatoguinean Men

Abstract

Equatorial Guinea (EG) has implemented a successful malaria control program on Bioko Island. A highly effective vaccine would be an ideal complement to this effort and could lead to halting transmission and eliminating malaria. Sanaria® PfSPZ Vaccine (Plasmodium falciparum sporozoite Vaccine) is being developed for this purpose. To begin the process of establishing the efficacy of and implementing a PfSPZ Vaccine mass vaccination program in EG, we decided to conduct a series of clinical trials of PfSPZ Vaccine on Bioko Island. Because no clinical trial had ever been conducted in EG, we first successfully established the ethical, regulatory, quality, and clinical foundation for conducting trials. We now report the safety, tolerability, and immunogenicity results of the first clinical trial in the history of the country. Thirty adult males were randomized in the ratio 2:1 to receive three doses of 2.7 × 105 PfSPZ of PfSPZ Vaccine (N = 20) or normal saline placebo (N = 10) by direct venous inoculation at 8-week intervals. The vaccine was safe and well tolerated. Seventy percent, 65%, and 45% of vaccinees developed antibodies to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) by enzyme-linked immunosorbent assay, PfSPZ by automated immunofluorescence assay, and PfSPZ by inhibition of sporozoite invasion assay, respectively. Antibody responses were significantly lower than responses in U.S. adults who received the same dosage regimen, but not significantly different than responses in young adult Malians. Based on these results, a clinical trial enrolling 135 subjects aged 6 months to 65 years has been initiated in EG; it includes PfSPZ Vaccine and first assessment in Africa of PfSPZ-CVac. ClinicalTrials.gov identifier: NCT02418962.

Figures

Figure 1.

Consort diagram for EGSPZV1 clinical trial.

Figure 2.

Comparison of adverse events (AEs) in volunteers receiving normal saline (NS) and PfSPZ Vaccine. The percent of volunteers with a specific AE is depicted. Only a single volunteer had any individual AE after each immunization (maximum of 1/10 [10%] for NS and 1/20 [5%] for PfSPZ Vaccine). ¥, €, £, β are individual volunteers. This figure appears in color at www.ajtmh.org.

Figure 3.

Antibody responses 2 weeks after the last vaccination. Responses in all vaccinees and controls who received three doses of PfSPZ Vaccine or normal saline were measured by (A) Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) enzyme-linked immunosorbent assay (ELISA), (B) Automated immunofluorescence assay (aIFA), and (C) Inhibition of sporozoite invasion assay (ISI) assay. In the ELISA, antibody responses are reported as the net OD 1.0. OD 1.0 is the serum dilution at which the optical density is 1.0, and net OD 1.0 is the difference between the post- and pre-immunization OD 1.0. In the aIFA assay, antibody responses are reported as the reciprocal serum dilution at which the arbitrary fluorescence units (AFU) were 2 × 105. In the ISI assay, antibody responses are reported as the reciprocal serum dilution that gave 80% inhibition of PfSPZ invasion. Medians with interquartile ranges are shown.

Figure 4.

Comparison of anti-Plasmodium falciparum circumsporozoite protein (PfCSP) antibody responses in four different clinical trials in which the same dose of PfSPZ Vaccine was administered. Antibody responses measured by enzyme-linked immunosorbent assay (ELISA) are reported as the net OD 1.0. The OD 1.0 is the serum dilution at which the optical density is 1.0, and net OD 1.0 is the difference between the post- and pre-immunization OD 1.0. In the USA (VRC314/WRAIR 2080) (most subjects), Mali and Tanzania vaccinations were at 0, 4, and 8 weeks. In Equatorial Guinea (EG), vaccinations were at 0, 8, and 16 weeks. In the United States, Mali, and EG, sera were drawn at 2 weeks after the last vaccination. In Tanzania, sera were drawn at 4 weeks after the last vaccination. Bars with asterisks indicate the statistical significance, as determined by a Kruskal–Wallis test followed by a Dunn’s multiple comparisons test (P = * < 0.0001; ** < 0.0001; *** 0.0008).