Field Trial of PfSPZ-LARC2 Vaccine in Burkinabe Adults

This is a phase 2 clinical trial of a Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) vaccine (Sanaria® PfSPZ-LARC2 Vaccine) that will assess field efficacy in Africa.

The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double deletion of the genes encoding the Mei2 and LINUP proteins, both of which are required for transition from liver to blood stage malaria. As a result, mei2-/linup- parasites undergo developmental arrest in the late liver stages without releasing merozoites into the blood stream. No blood stage parasites are produced, either asexual or sexual, and the parasite life cycle does not progress. Because Pf parasites with the LARC phenotype replicate in the liver before disintegrating, they amplify and diversify parasite protein expression and are expected to be a potent immunogen to induce anti-malarial immunity, equaling or exceeding the potency and efficacy of the replication-competent chemo-attenuated Sanaria® PfSPZ-CVac (chloroquine) vaccine approach. Because the parasites are intrinsically attenuated, they are expected to be safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine, to the replication deficient, early arresting PfSPZ-GA1 Vaccine, and to the single-gene(mei2)-deleted GA2 (LARC1) parasites tested at the Leiden University Medical Center that provided 90% protection against CHMI after a single dose.

The active treatments to be assessed for efficacy are one immunization of 6.0x10⁵ PfSPZ or two immunizations with 4.0x10⁵ PfSPZ of PfSPZ-LARC2 Vaccine four weeks apart, timed so that the immunization of the one dose regimen coincides with the second immunization of the two dose regimen.

The alternative treatment is immunization with normal saline (placebo group), which is indistinguishable from the test article.

The primary variable of interest is whether and when trial participants develop Pf malaria parasitemia during surveillance. Malaria parasitemia will be detected by thick blood smear (TBS), which will be performed every two weeks starting two weeks after the second vaccination (to allow time for the vaccine to work) and extending to week 26 after the second vaccination (24-week surveillance period). Surveillance will continue for 40 weeks but the primary outcome will be determined at 24 weeks of surveillance so the data are comparable to other studies of PfSPZ vaccines.

This is a randomized, double-blind, placebo-controlled, single-center phase 2 clinical trial in healthy adults.

The trial will compare a single dose regimen (6x10⁵ PfSPZ administered once) to a two dose regimen (4x10⁵ PfSPZ administered twice). There are three groups:

Group 1: two doses of PfSPZ-LARC2 Vaccine (4x10⁵ PfSPZ) four weeks apart.

Group 2: one dose of normal saline placebo and one dose of PfSPZ-LARC2 Vaccine (6x10⁵ 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.

For the first immunization (V1), group 1 will receive one dose of vaccine (4x10⁵ PfSPZ) and groups 2 and 3 will receive one dose of normal saline (NS placebo). Four weeks later, group 1 will receive a second dose of vaccine (4x10⁵ PfSPZ), group 2 will receive a first dose of vaccine (6x10⁵ 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 direct venous inoculation (DVI).

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.

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.

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.

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. 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.