The study will be conducted as a collaborative effort between the NMRC, UMB CVD, WRAIR and Sanaria, Inc. The study screening, immunizations, and follow-ups for Groups 1 \& 2 will take place at the UMB CVD. The study screening, immunizations, and follow-ups for Groups 3 \& 4 will take place at the NMRC CTC in Bethesda, MD. The controlled human malaria infections (CHMI) will be conducted at WRAIR Entomology, Silver Spring, MD for NMRC subjects, and at UMB CVD for UMB CVD subjects.
There will be 4 groups and a total of 92 subjects (60 immunized subjects and 32 infectivity controls). Group 1 (n = 15) subjects will receive PfSPZ Vaccine administered by direct venous inoculation (DVI), with 4 doses of 4.5 x 10\^5 PfSPZ given every two days, followed by a single, boosting dose of 4.5 x 10\^5 PfSPZ given 16 weeks later. For participants who were not protected after the first CHMI, an additional boosting dose of 4.5x10\^5 PfSPZ will be given 21 weeks later.
Group 2 (n = 15) subjects will receive PfSPZ Vaccine administered by DVI, with 3 doses of 9.0 x 10\^5 PfSPZ administered every 8 weeks. For participants who were not protected after the first CHMI, a boosting dose of 9.0 x 10\^5 PfSPZ will be given 21 weeks later.
Group 3 (n = 15) subjects will receive PfSPZ Vaccine administered by DVI, with 3 doses of 18 x 10\^5 PfSPZ administered every 8 weeks. Following CHMI at 40 weeks, protected subjects and one-half of unprotected subjects will receive a final, boosting dose of 18 x 10\^5 PfSPZ. The remaining half of unprotected subjects will receive a final, boosting dose of 4.5 x 10\^5 PfSPZ.
Group 4 (n = 15) subjects will receive PfSPZ Vaccine administered by DVI, with 27 x 10\^5 PfSPZ administered once as a priming dose, followed by 2 doses of 9.0 x 10\^5 PfSPZ administered every 8 weeks. Following CHMI at 40 weeks, protected subjects and one-half of unprotected subjects will receive a final, boosting dose of 9 x 10\^5 PfSPZ. The remaining half of unprotected subjects will receive a final, boosting dose of 2.25 x 10\^5 PfSPZ.
Protective efficacy will be assessed by CHMI, conducted by exposure to the bites of three to five mosquitoes infected with heterologous (7G8 or NF135.C10) Pf parasites, with the number of mosquitoes depending on the infection intensity in the mosquitoes). At UMB CVD, protective efficacy will be assessed at both 28 and 40 weeks after the first immunization, in Groups 1 and 2, along with 8 infectivity controls for each CHMI. At NMRC, protective efficacy will be assessed at 40 weeks (7G8 infected mosquitoes), and 66 weeks (NF135.C10 infected mosquitoes) after the first immunization, in Groups 3 and 4. Unprotected subjects in Groups 1 and 2, and all subjects in Groups 3 and 4, will be invited to receive a booster vaccination 21 days prior to the second CHMI at the respective sites, in order to assess the efficacy of a booster dose in previously vaccinated persons. These vaccine subjects may participate in the second CHMI whether or not they were protected in the first CHMI, and independent of their decision to receive the booster immunization, to serve as controls for the effect of the first CHMI on immunity. Subjects may proceed to CHMI provided they have received at least two of the three immunizations scheduled for Groups 2-4, or at least two of the four priming immunizations as well as the boost scheduled for Group 1. 7G8-infected mosquitoes may be substituted for NF135.C10 mosquitoes in case of difficulties with mosquito production.
Two subjects in each group will serve as "pilot subjects" in the event of first in human dosing, and will be immunized approximately 24 hours prior to the rest of the subjects in the respective group. If there are no safety concerns identified in the pilot subjects that trigger the stopping rules, then the remainder of subjects will be immunized the day after the pilot subjects are immunized. Subjects will be followed for 56 days beyond both the week 40 and week 66 CHMIs.
