Increase of dose associated with decrease in protection against controlled human malaria infection by PfSPZ vaccine in Tanzanian adults

BACKGROUND: A vaccine would be an ideal tool for reducing malaria's impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1,526 malaria-naive and experienced 6-month to 65-year-olds in the U.S., Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7x105 PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the U.S. and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%). METHODS: To increase VE in Tanzania, we increased PfSPZ/dose (9x105 or 1.8x106) and decreased numbers of doses to three at 8-week intervals in a double blind, placebo-controlled trial. RESULTS: All 22 CHMIs in controls resulted in parasitemia by qPCR. For the 9x105 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (p<0.000l, Barnard's test, 2-tailed). For 1.8x106 PfSPZ, VE was 33% (2/6) at 7.5 weeks (p=0.028). VE of dosage groups (100% vs 33%) was significantly different (p=0.022). Volunteers underwent repeat CHMI at 37 to 40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9x105 PfSPZ group (10.89 vs 7.80 days) (p=0.039), indicating a significant reduction in parasites in the liver. Antibody and T cell responses were higher in the 1.8x106 PfSPZ group. CONCLUSIONS: In Tanzania increasing the dose from 2.7x105 to 9x105 PfSPZ increased VE from 20% to 100%, but increasing to 1.8x106 PfSPZ significantly reduced VE. TRIAL REGISTRATION: Clinical Trials.gov (NCT02613520).