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× 10 5 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× 10 5 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.