BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) 
malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against 
homologous Pf (same strain as in the vaccine) controlled human malaria infection 
(CHMI) 3 weeks after 5 doses administered intravenously. The next step was to 
assess protective efficacy against heterologous Pf (different from Pf in the 
vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed 
tolerability, safety, immunogenicity, and protective efficacy of direct venous 
inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects. 
RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 105 PfSPZ 
protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous 
CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 × 
105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. 
Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10 
(70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6]) 
against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 
76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ 
Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell 
responses correlated with protection. CONCLUSIONS: We have demonstrated for the 
first time to our knowledge that PfSPZ Vaccine can protect against a 3-week 
heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose 
regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, 
respectively) in this population. These results provide a foundation for 
developing an optimized immunization regimen for preventing malaria. TRIAL 
REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided 
through the US Army Medical Research and Development Command, Military 
Infectious Diseases Research Program, and the Naval Medical Research Center's 
Advanced Medical Development Program.