Phase 2 Field Trial of PfSPZ-LARC2 Vaccine in Burkinabe Adults

This is a randomized, double-blind, placebo-controlled, single-center Phase 2 clinical trial. Healthy nonpregnant, non-lactating adults will be enrolled. Women of child-bearing potential must agree to high efficacy birth control during the period of immunization. Screening tests will include an ECG, hepatitis B and C serology, HIV testing, sickle cell testing, a thick blood smear (TBS), white blood count, neutrophil count, lymphocyte count, hemoglobin, platelets, creatinine, alanine aminotransferase (ALT), bilirubin, gamma-glutamyl transferase (GGT) and a fasting blood glucose for all screenees to assure overall good health, and a pregnancy test for women. The trial will compare a single dose regimen (6x10\^5 PfSPZ administered once) to a two dose regimen (4x10\^5 PfSPZ administered twice). There are three groups: Group 1: two doses of PfSPZ-LARC2 Vaccine (4x10\^5 PfSPZ) four weeks apart. Group 2: one dose of normal saline placebo and one dose of PfSPZ-LARC2 Vaccine (6x10\^5 PfSPZ) four weeks apart. Group 3: two doses of normal saline placebo four weeks apart. All participants will be cleared of any existing parasitemia by (minimally) a three day treatment course of artemether /lumefantrine. This will be done 5-6 weeks prior to the first dose of investigational product, to prevent the known immunosuppressive effects of parasitemia on the induction of protective immunity and to prevent such infections from recrudescing later in the trial. If, at a pre-immunization visit 2 weeks before the first dose, any participant is positive by TBS, they will be retreated with the same regimen of artemether/lumefantrine. Clearance will be repeated 2 weeks before the second dose in all participants. The justification for assuring TBS negative status prior to each immunization is based on data from two trials of PfSPZ vaccines in Africa where protection was markedly diminished in participants with parasitemia prior to clearance two weeks before immunization. We plan to extend the interval between pre-treatment and immunization from 2 to 5-6 weeks before the first immunization, to provide more time for the immune system to recover from the effects of parasitemia. Because immunization will be done during the dry season when malaria is rarely transmitted, only a few retreatments (if any) may be required, despite the 5- to 6-week gap, prior to the first vaccination. For the first immunization (V1), group 1 will receive one dose of vaccine (4x10\^5PfSPZ) and groups 2 and 3 will receive one dose of normal saline (normal saline placebo). Four weeks later, group 1 will receive a second dose of vaccine (4x10\^5 PfSPZ), group 2 will receive a first dose of vaccine (6x10\^5 PfSPZ) and group 3 will receive a second dose of normal saline. A syringe of vaccine and a syringe of normal saline are indistinguishable, facilitating the double-blind design. All administrations will be by DVI, a nearly painless procedure in which a narrow gauge needle is inserted into a superficial vein, blood flashback is demonstrated, and the contents of the syringe rapidly injected. Safety monitoring: Monitoring for adverse events (AEs) will take place during the 28-day interval between immunizations and for 28 days after the second immunization (56 days in total). Local (site of injection) AEs will be solicited for two days, systemic AEs will be solicited for 14 days and unsolicited AEs will be collected for 28 days after each immunization. In addition, participants will be instructed to notify the clinical team day or night should symptoms suggestive of malaria develop. Any symptoms consistent with malaria will be immediately investigated by TBS, which will be repeated if symptoms are ongoing - daily if the initial TBS is negative and symptoms are grade 1 or 2 in severity, or every 8 to 12 hours if initial TBS is negative and symptoms are grade 3 in severity. Malaria signs and symptoms include fever (axillary temperature in \> 37.5°C \[\>99.5°F\]), subjective fever, headache, dizziness, malaise, fatigue, chills, rigors, sweats, myalgia, arthralgia, nausea, vomiting, diarrhea, abdominal pain, cough and chest pain. Finally, medically-attended adverse events (MAAEs) and serious adverse events (SAEs) will be monitored throughout the trial. Laboratory tests (white blood count, neutrophil count, lymphocyte count, hemoglobin, platelets, creatinine, alanine aminotransferase) will be done on the day of each immunization and 7 days after each immunization. Surveillance for malaria: Two weeks following immunization, active and passive surveillance for clinical malaria and malaria infection will begin. Passive detection will be achieved by encouraging all participants to immediately report any signs or symptoms consistent with malaria to the clinical team, which will be available 24/7. A TBS will be obtained as quickly as possible and read. A positive result will mark a clinical malaria endpoint, assuming that the case definition is met. It will also signify a malaria infection endpoint. Active surveillance will consist of obtaining a TBS every two weeks from the entire study cohort starting two weeks after the second immunization, regardless of symptoms. These will be read in real-time only if there are malaria signs and symptoms. At each two week visit, participants will be reminded of the importance of contacting the clinical team if they develop malaria symptoms. The primary efficacy endpoint will be after 24 weeks of surveillance (26 weeks after immunization). Efficacy will also be calculated after the full 40 weeks of follow-up. A complete blood count will also be obtained at 24 weeks to see if vaccination with PfSPZ-LARC2 Vaccine had any effect on hemoglobin concentrations at the end of the rainy season. TBS collected actively from asymptomatic individuals will be read retrospectively, and any new onset asymptomatic infections will be added as malaria infection endpoints as long as there was no clinical malaria endpoint reached in the same participant within two weeks of the asymptomatic parasitemia identified by active case detection. Surveillance will continue past the 24 week primary endpoint until at least 40 weeks, with an option to continue for a second season of surveillance if merited by efficacy demonstrated during the first rainy season and identification of funding for additional follow-up. If there is no continuation, the last study visit will be at 40 weeks of surveillance (42 weeks after second immunization). At each two week visit when blood is sampled for TBS and at any time that TBS is made for the purpose of diagnosing clinical malaria, dried blood spots will be collected for possible later analysis by qPCR as an exploratory objective. Prior to treating any malaria infection, blood samples will be obtained to allow for conducting genetic analyses of parasites, which could include sieve analysis to determine if lack of protection by vaccination is associated with particular genetic variants. After treatment for malaria, 28 days of person-time at risk will be discounted (because of protection afforded by piperaquine), and then surveillance will continue to collect data on any additional parasitemias or clinical cases.