Collaborations with Sanaria Inc and the Malaria Research and Training Center at the University of Bamako, Mali to conduct these PfSPZ related studies was initiated in 2012. PfSPZ Vaccine in Mali (NIAID Protocol 14-I-N010) Manuscript summarizing the clinical trial results was published in Lancet Infectious Diseases in Jan 2017. PfSPZ Vaccine in Mali, Africa Dose Escalation (16-I-N004) The phase 1 dose escalating and randomized, placebo-controlled, double-blind study to assess the safety, immunogenicity, and protective efficacy of PfSPZ Vaccine in Mali started in Dec 2015. Pilot Phase Overall, PfSPZ Vaccinations were very well tolerated in those receiving 4.5x105 (n=5) and 9x105 (n=5) One subject (randomized to ASAQ treatment prior to vaccination) who experienced an asymptomatic Grade 3 elevated ALT following Vaccination #1 which is summarized below in the Main Phase summary. Approximately 7 weeks prior to homologous CHMI with 3.2x103 PfSPZ Challenge, 29 (96.7%) Pilot Phase 1.8x106 PfSPZ vaccinees and 15 infectivity controls received a full treatment course ASAQ. All 44 subjects completed CHMI follow-up. Of the 29 PfSPZ vaccinees, 0/29 vaccinees and 1/15 infectivity controls became BS positive. By qPCR 0/29 vaccinees and 8/15 (53.3%) infectivity controls became positive. Most qPCR positive infectivity controls were qPCR positive only for a single timepoint (5/8; 62.5%). By qPCR vaccine efficacy was significant by interval-censored log rank p<0.001 for time-to-infection, and vaccine efficacy was 100% (p=<0.001, CI 73-100%) by proportional analysis. Main Phase 60 subjects received at least 1 dose of PfSPZ Vaccine and 60 subjects received placebo. 57 (95%) received all 3 doses of PfSPZ Vaccine and 55 (91.7%) subjects received normal saline placebo. Scheduled unblinding of the trial was completed in January 2017. PfSPZ vaccinations were safe and well tolerated except as noted prior there were 3 additional unanticipated significantly elevated transaminases (Grade 3 to 4) in 3 Main Phase participants (1 PfSPZ Vaccine, 2 placebo) at varying stages post vaccination and ASAQ (14 to 65 days post ASAQ). All 4 subjects were asymptomatic with no associated agranulocytosis, and abnormalities resolved without sequelae (duration 169 to 214 days). Overall, there was no significant differences in local or systemic AEs or laboratory abnormalities between PfSPZ Vaccine and placebo groups. 55 subjects in the PfSPZ Vaccine group and 54 subjects from the placebo group were evaluable for per protocol analysis. Of these participants, 42 (77.8%) from the placebo group and 32 (58.1%) from the vaccine group developed Pf infection. Per protocol, the vaccine efficacy was 51% (p=0.004, 95% CI 20-70) by time-to-infection analysis (ITT 39%, p=0.033) and 24% (p=0.031, 95% CI 2-41) by proportional analysis (ITT 22%, p= 0.041). Summary: Collaborations with Sanaria Inc to conduct these PfSPZ CVac related studies was initiated in 2013. PfSPZ CVac-PYR (NIAID Protocol 15-I-0169) The phase 1 open label experimental medicine study to investigate the safety, tolerability, immunogenicity, and protective efficacy against homologous CHMI of 3-doses of 51,200 aseptic, purified, cryopreserved NF54 Pf SPZ (Sanaria PfSPZ Challenge) given via DVI every 28 days while under chloroquine (CQ) cover and pyrimethamine (PYR) (PfSPZ PYR/CQ CVac) started in Nov 2015. The initial Pilot PYR/CQ Arm (n=2; 50mg of PYR on days 2, 3 post PfSPZ Challenge) was enrolled 1st to explore safety and tolerability of the proposed PYR/CQ CVac regimen and prevention of asexual parasite exposure. Both subjects were confirmed negative by patent (blood smearBS) and subpatent (qPCR) evaluations, thus no further pilot regimens were explored. In Jan 2016, the Main Phase of the study started with the PYR/CQ Arm (n=12) and CQ Arm (n=6); all subjects underwent 3 iterations separated by 28 days of PfSPZ Challenge with 51,200 PfSPZ while under CQ coverage (10 doses in total), with the PYR/CQ Arm receiving 50mg PYR on days 2, 3 post PfSPZ Challenge. 21 subjects underwent 3,200 NF54 PfSPZ Challenge via DVI administered over 3 days (Jun 2016). All subjects who underwent CHMI completed their end of study visits. One subject was withdrawn from the study after CVac #3 due to development of a SAE. The CQ-related SAE event was encephalopathy NOS and was reported to the Sponsor, NIAID IRB, SMC and FDA in April 2016. This subject recovered with no sequalae. PfSPZ CVac Phase Overall PfSPZ CVac-PYR and CVac-CQ were well tolerated. There were 3 reported Grade 3 AEs: sleep disorder and acute gastroenteritis (unlikely related to any of the study products; both occurred in the same subject) and encephalopathy NOS (also reported as a SAE) that was determined to be possibly related to CQ. All AEs reported during the CVac Phase resolved without complication. For all subjects receiving PfSPZ CVac-PYR, detection of BS parasites by qPCR was negative at all timepoints during the PfSPZ CVac Phase. PfSPZ CHMI Phase 2/11 PYR/CQ individuals who received the CVac-PYR regimen had sterile protection against homologous CHMI while 4/5 CVac-CQ were protected. The protective efficacy seen with PfSPZ CVac-CQ was similar to previously reported with this regimen. PfSPZ CVac-PYR2 (NIAID Protocol 17-I-0067) This is a phase 1 dose escalation study to investigate the safety and tolerability of Sanaria PfSPZ Challenge (NF54) administered by DVI , combined with CQ or PYR treatment. The study is also designed to explore the immunogenicity and protective efficacy of this regimen, given as 3-dose series, against homologous (NF54) and heterologous (7G8) CHMI. The study is divided into a pilot and main phase. The pilot phase started with small cohorts (n=2 per group) to study whether the sequential increase of the dose of Sanaria PfSPZ Challenge (NF54) from 50,000 to a target dose of 200,000 sporozoites while on either CQ or PYR is safe and well tolerated. For the PYR pilot (Arm 1), participants receive 2 doses of PYR (50 mg or 75 mg), administered on 2 and 3 days post Sanaria PfSPZ Challenge DVI. For the CQ pilot (Arm 5), participants receive 2 doses of CQ, a loading dose (1000 mg) on 2 days before DVI and a second dose (500 mg) 5 days later. The pilot phase participants will only receive one PfSPZ Challenge injection. The main phase will enroll a larger group of volunteers who will first undergo a total of three injections, given 4 weeks apart, while on either PYR or CQ with subsequent homologous or heterologous CHMI. The pilot phase of the PfSPZ CVac-PYR arms (Arm 1) began in June 2017. The Arm 1a pilot (50,000 PfSPZ + 50 mg of PYR on d2, 3), Arm 1b pilot (100,000 PfSPZ + 50 mg of PYR on d2, 3), and Arm 1d pilot (200,000 PfSPZ + 50 mg of PYR on d2, 3) all have successfully prevented patent and subpatent parasitemia from 6 days through 14 days post PfSPZ Challenge. In addition, the PfSPZ CVac-PYR regimen has been safe and well tolerated by subjects. The pilot phase of the PfSPZ CVac-CQ arms (Arm 5) began in July 2017. The Arm 5a pilot (100,000 PfSPZ + CQ x 2) were safe and well tolerated by subjects. Neither subject was BS positive nor met halting criteria for additional treatment due to symptoms related to blood stage exposure. Both subjects were qPCR positive as expected on days 7 and 8 post PfSPZ Challenge exposure. The next pilot groups (Arm 1dR; n=2; and Arm 5b; n=2) are in process now. If the remaining pilot groups continue to meet per protocol objectives and the regimen remains safe, the plan is to start the main phase of the study in October 2017 with Arm 2 (200,000 PfSPZ + 50 mg of PYR on d2, 3) and Arm 3 (200,000 PfSPZ + CQ x 2.
