Safety, Tolerability, and Immunogenicity of Plasmodium falciparum Sporozoite Vaccine Administered by Direct Venous Inoculation to Infants and Young Children: Findings From an Age De-escalation, Dose-Escalation, Double-blind, Randomized Controlled Study in Western Kenya

Abstract

Background: The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited.

Methods: We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay.

Results: Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001).

Conclusions: PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic.

Clinical trials registration: NCT02687373.

Keywords: infants; malaria; safety; sporozoite; vaccine.

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram of participant enrollment. Abbreviations: IV, intravenous; PfSPZ, Plasmodium falciparum sporozoite; PI, principal investigator.

Figure 2.

Solicited symptoms, including systemic and local, by dose group and maximum severity, all ages combined.

Figure 3.

Number of injection attempts and use of indwelling catheter, by age group, among all enrolled participants. Partial injection means that less than the full 0.5 mL of study product or normal saline placebo was injected intravenously; failed venous access means that no study product or normal saline placebo was injected intravenously. The order of the bar charts from left to right generally indicates the chronological order of study group enrollment (although the lowest dose group of the 13- to 59-month-olds were vaccinated at the same time as the highest dose group of the 5- to 9-year-olds, and the lowest dose group of the 5- to 12-month-olds was vaccinated at the same time as the 4.5 × 10⁵ dose group of the 13- to 59-month-olds). Each dose group contains placebo and vaccine recipients. Abbreviations: DVI, direct venous inoculation; DVIc, direct venous inoculation using an intravenous cannula; 2+ DVI, 2 or more direct venous inoculations required; Vac 1, vaccine dose 1; Vac 2, vaccine dose 2.

Figure 4.

Antibodies to Plasmodium falciparum circumsporozoite protein (PfCSP) measured 8 days after the second dose of P. falciparum sporozoite (PfSPZ) vaccine in vaccinees and normal saline controls in the 9.0 × 10⁵ and 1.8 × 10⁶ PfSPZ groups. Statistical analysis was done with Wilcoxon rank-sum test. Only P values <.05 are shown. Optical density (OD) 1.0 is the serum dilution at which the optical density was 1.0. Net OD 1.0 is the difference between the OD 1.0 eight days after the second immunization and the OD 1.0 prior to the first immunization. Abbreviation: ELISA, enzyme-linked immunosorbent assay.