A randomized controlled trial showing safety and efficacy of a whole sporozoite vaccine against endemic malaria

Abstract

A highly effective malaria vaccine remains elusive despite decades of research. Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), a metabolically active, nonreplicating, whole parasite vaccine demonstrated safety and vaccine efficacy (VE) against endemic P. falciparum for 6 months in Malian adults receiving a five-dose regimen. Safety, immunogenicity, and VE of a three-dose regimen were assessed in adults in Balonghin, Burkina Faso in a two-component study: an open-label dose escalation trial with 32 participants followed by a double-blind, randomized, placebo-controlled trial (RCT) with 80 participants randomized to receive three doses of 2.7 × 10⁶ PfSPZ (N = 39) or normal saline (N = 41) just before malaria season. To clear parasitemia, artesunate monotherapy was administered before first and last vaccinations. Thick blood smear microscopy was performed on samples collected during illness and every 4 weeks for 72 weeks after last vaccinations, including two 6-month malaria transmission seasons. Safety outcomes were assessed in all 80 participants who received at least one dose and VE for 79 participants who received three vaccinations. Myalgia was the only symptom that differed between groups. VE (1 - risk ratio; primary VE endpoint) was 38% at 6 months (P = 0.017) and 15% at 18 months (0.078). VE (1 - hazard ratio) was 48% and 46% at 6 and 18 months (P = 0.061 and 0.018). Two weeks after the last dose, antibodies to P. falciparum circumsporozoite protein and PfSPZ were higher in protected versus unprotected vaccinees. A three-dose regimen of PfSPZ Vaccine demonstrated safety and efficacy against malaria infection in malaria-experienced adults.

Fig. 1.. Trial profile.

Fig. 2.. Efficacy of PfSPZ Vaccine against naturally occurring infection.

Inverse survival curves for the time after the last vaccination to the first positive TBS (asymptomatic + symptomatic infection). Efficacy was analyzed as 1 – RR (“proportional analysis”) and 1 – HR for the primary follow-up period (0 to 24 weeks after the third vaccination) and the extended follow-up period (0 to 76 weeks after the third vaccination). The survival curves include 79 participants who received all three vaccinations and were evaluable for the VE endpoint. The Kaplan-Meier estimated RRs are the ratio of the height of the blue solid curve to the height of the red dashed curve at 24 and 76 weeks.

Fig. 3.. Antibody responses.

Antibody responses to PfCSP were measured before immunization and at 2 weeks after the last dose of PfSPZ Vaccine or placebo (second dose for cohorts 1 to 4 and third dose for cohort 5, randomized controlled trial). Horizontal bars show medians (all groups) and interquartile range (IQR) (cohort 5 only). Antibody responses to PfCSP by ELISA are reported as the difference in reciprocal serum dilution at which the optical density (OD) was 1.0 (OD 1.0) between postimmunization and preimmunization sera (net OD 1.0) for cohorts 1 to 4 (A) and cohort 5 (B). Results for the PfSPZ automated immunofluorescence assay (aIFA) are the difference in reciprocal serum dilution at which arbitrary fluorescence units (AFU) was 2 × 10⁵ between postimmunization and preimmunization sera (net AFU, 2 × 10⁵) for cohort 5 (C). Results for the PfSPZ automated inhibition of SPZ invasion (aISI) assay are the difference in reciprocal serum dilution at which the inhibition of PfSPZ invasion was 80% between postimmunization and preimmunization sera (net inhibition of SPZ invasion 80%) for cohort 5 (D). Infection status is based on results of TBS microscopy within 24 weeks after the third vaccination, with unfilled circles representing infected participants and filled (red) circles representing uninfected participants. Horizontal bars show median values and IQR. P values are from Brunner-Munzel tests comparing distributions of antibody responses between vaccinees and controls and between infected and uninfected vaccinees. One participant from cohort 2, one from cohort 3 (A), and one from cohort 5 (placebo group) (B to D) are not represented because they did not contribute to post-baseline antibody results, and one outlier in cohort 5 (placebo group) was excluded.