Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial

Abstract

Background: Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali.

Methods: After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Donéguébougou and surrounding villages in Mali. We recruited 18-35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov, number NCT01988636.

Findings: Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three [7%] people in the vaccine group vs four [9%] in the placebo group) followed by fatigue (one [2%] person in the placebo group), fever (one [2%] person in the placebo group), and myalgia (one [2%] person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313-0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528-0·918) by proportional analysis (p=0·006).

Interpretation: PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season.

Funding: US National Institutes of Health Intramural Research Program, Sanaria.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

Study completion was defined as staying in the study until the end of malaria transmission season (study day 308). PfSPZ=Plamodium falciparum sporozite.

Figure 2:. Protective efficacy of PfSPZ Vaccine against naturally occurring infection

Protective efficacy was analysed by time to first positive blood smear, with day 0 at 28 days after the fifth vaccination. The inverse survival curves include participants who received all five vaccinations and were evaluable for the primary exploratory efficacy endpoint. Five participants (one in the PfSPZ Vaccine group and four in the placebo group) were censored from the primary efficacy analysis because they had a positive blood smear before 28 days after the fifth vaccination. PfSPZ=Plamodium falciparum sporozite.

Figure 3:. Antibody responses

Antibody responses to PfSPZ and PfCSP were measured before immunisation and at 2 weeks after the fifth dose of PfSPZ Vaccine. For all assays, uninfected individuals are shown as filled (red) circles and infected individuals are unfilled circles. For each of the defined groups, the median response values are shown with bars representing the IQR. (A) Antibodies to PfSPZ by automated immunofluorescence assay are reported as net AFU 2 × 105; the reciprocal serum dilution at which the fluorescent units were 2 × 105 in post-immunisation minus pre-immunisation sera. (B) Percentage inhibition of PfSPZ invasion is reported as the percentage reduction in the numbers of PfSPZ that invaded a human hepatocyte line (HC-04) in the presence of post immunisation vs pre-immunisation sera from the same subject, both at a dilution of 1:5. (C) Antibodies to PfCSP by ELISA reported as the difference in OD 1–0 between post-immunisation and pre-immunisation sera (net OD 1·0). (D) Antibodies to PfCSP by ELISA reported as the ratio of post-immunisation OD 1·0 to the pre-immunisation OD 1·0. Ratio of post-immunisation OD 1·0 to pre-immunisation OD 1·0 in the (E) placebo group and (F) PfSPZ Vaccine group, by time to first infection or not having an infection. In each part of the figure, two participants from the vaccine group are not represented because of early withdrawal, and one participant from the placebo group is not represented because of missing samples. PfSPZ=Plasmodium falciparum sporozite. PfCSP=Plasmodium falciparum circumsporozoite protein. AFU=arbitrary fluorescence units. OD=optical density.