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.