Radar de Estudos Clínicos

This is a first-in-humans randomized, double-blind, placebo-controlled, age de-escalation Phase 1 trial of Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) malaria vaccine (Sanaria® PfSPZ-LARC2 Vaccine) administered to healthy, malaria-exposed adults and children by direct venous inoculation (DVI) to determine safety, tolerability, and immunogenicity. The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double gene deletion, of the Mei2 and LINUP genes. As a result, they 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). 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). Because the parasites are intrinsically attenuated, they are also expected to be safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine and to the single-gene(Mei2)-deleted GA2 parasites (also LARC phenotype) tested at the Leiden University Medical Center (LUMC), which, like PfSPZ-LARC2 Vaccine, disintegrate after replicating in the liver. PfSPZ-LARC2 Vaccine thus avoids the safety concerns associated with PfSPZ-CVac, which uses fully infectious, non-attenuated parasites to achieve replication and depends on co-administered chloroquine for attenuation. In summary, the genetically attenuated PfSPZ-LARC2 Vaccine should combine the best-in-class immunogenic potency and protective efficacy of PfSPZ-CVac (chloroquine) with the excellent safety and tolerability of intrinsically attenuated PfSPZ Vaccine and GA2 vaccine.

This trial is designed to test the hypotheses that:

1. The vaccine is safe and well tolerated in each age group.
2. The true rate of breakthrough blood stage infection (or other concerning adverse events) is less than about 5%, with an 95% confidence level (this will be the level of confidence that there are no breakthroughs if no breakthroughs occur in the 50 participants receiving PfSPZ-LARC2 Vaccine).

This is a randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial. The dose of PfSPZ to be tested in all age groups is 2.0x10e5, the same as the dose used in an NIH study of PfSPZ-CVac (chloroquine) which resulted in 100% vaccine efficacy against a heterologous controlled human malaria infection (CHMI) conducted 12 weeks after immunization]. 100% heterologous protection at 12 weeks represents the best protection ever recorded for a malaria vaccine. The selected dose, 2.0x10e5 PfSPZ, is roughly similar to the dose used in the GA2 study at LUMC. In one of the two adult groups, however, the 10 participants receiving vaccine will be administered a two-fold higher dose - 4.0x10e5 PfSPZ - to assess the risk of breakthrough more stringently in a malaria-experienced adult population at low risk for serious complications of malaria infection. If this high dose of PfSPZ does not lead to breakthrough in adults, it is unlikely that a 2-fold lower dose will lead to breakthrough in children.

There will be three cohorts of participants initiated in staggered fashion. These consist of 2 groups of adults in cohort 1 (receiving, respectively, 2.0x10e5 PfSPZ and 4.0x10e5 PfSPZ), followed by 2 groups of adolescents/older children in cohort 2 (each receiving 2.0x10e5 PfSPZ), followed by 1 group of younger children in cohort 3 (receiving 2.0x10e5 PfSPZ). Each group will be composed of 15 participants, 10 to receive PfSPZ-LARC2 Vaccine, and 5 to receive normal saline (NS) placebo, with randomized, blinded, 2:1 allocation to vaccine and placebo in each group. Each group will begin with a pilot group of 2 vaccinees and 1 placebo recipient three or more days before the rest of the cohort initiates, as a safety precaution. In the two cohorts with two groups, the pilot group for the second group will be initiated at least 3 days after the pilot group for the first group. A Safety Monitoring Committee (SMC) will review safety and tolerability data before proceeding to the next cohort.

Each group except group 1 (2.0x10e5 PfSPZ adult group) will receive only a single dose. This is because the risk of breakthrough is thought to be greatest after a first exposure; thereafter, the vaccine-induced immunity from the first dose reduces the risk of breakthrough after subsequent doses . Administering a single "highest-risk-of-breakthrough" first dose in all four age groups allows follow-up without the complexity of intervening second and third immunizations. However, it is theoretically possible (without any supporting evidence) that the biology associated with repeated dosing of LARC2 parasites could be different from this expectation. For this reason, group 1 will be administered second and third doses of 2.0x10e5 PfSPZ, each dose with 28 days of follow-up. It is noted that in the first GA2 trial in Leiden, 9 participants were immunized by mosquito bite three times at monthly intervals and there was no breakthrough after any of the doses. Including 3 doses in group 1 will additionally allow measurement of the immunogenicity of a standard 3-dose regimen for this vaccine (doses on Days 1, 29 and 57) in a malaria-exposed population, allowing comparison with a planned trial in Seattle, where malaria-naive adults will receive the same 3-dose regimen.

Cohort 1:

Group 1 (20-50-year-olds): 15 participants receive 3 injections of 2.0x10e5 PfSPZ or NS (days 1, 29 and 57).

Group 2 (20-50-year-olds): 15 participants receive 1 injection of 4.0x10e5 PfSPZ or NS .

Cohort 2 Group 3 (11-19-year-olds): 15 participants receive 1 injection of 2.0x10e5 PfSPZ or NS.

Group 4 (6-10-year-olds): 15 participants receive 1 injection of 2.0x10e5 PfSPZ or NS.

Cohort 3 Group 5 (1-5-year-olds): 15 participants receive 1 injection of 2.0x10e5 PfSPZ or NS.

Total sample size: 15 x 5 groups = 75 participants, 50 receiving vaccine and 15 placebo.

Two SMC meetings will be scheduled to review safety and tolerability data collected over 28 days in cohorts 1 and 2, respectively. If there are no vaccine strain breakthrough infections in the two cohort 1 groups during 28 days of follow-up after the first dose, and if the vaccine is safe and well-tolerated as revealed by solicited adverse events, unsolicited adverse events, and laboratory abnormalities, the SMC will be asked to recommend proceeding to the next cohort (cohort 2). If there are vaccine strain breakthroughs, the trial will be halted pending review by the SMC, IRBs and regulatory agencies. In like fashion, the SMC will meet a 2nd time to review 28 days of follow-up from cohort 2 and will provide a recommendation regarding the initiation of cohort 3.

To monitor for breakthrough infections following immunization, participants will be followed for 28 days after each immunization for signs and symptoms of malaria by daily recording of solicited and unsolicited adverse events. The likelihood that a given density of parasitemia will be symptomatic is affected by naturally acquired immunity (NAI), which develops gradually during childhood in endemic areas following repeated Pf infection. NAI includes both anti-parasite immunity, which results in lower parasite densities in the blood, and anti-clinical manifestations immunity, which results in reduced signs and symptoms of malaria for a given density of parasitemia. Pre-school malaria-exposed children have minimal NAI and experience the signs and symptoms of malaria at lower parasite densities (e.g., <100 parasites/uL) compared to malaria-exposed adults, who generally limit the density of parasitemia through NAI and may not experience clinical illness unless parasite density exceeds 100-200 parasites/uL. Older children are intermediate in their level of NAI.

Monitoring will also be done by scheduled thick blood smears (TBS), with a frequency based on the following principles: (1) follow-up should be more frequent for cohort 1 (groups 1 and 2), which is planned as first-in-humans; once it is demonstrated that there are no breakthroughs in the first cohort, which includes 10 adults receiving 2.0x10e5 PfSPZ and 10 adults 4.0x10e5 PfSPZ (to augment the risk of breakthrough), the frequency of TBS sampling can be reduced in subsequent cohorts ; (2) blood drawing should be minimized in children to reduce pain and improve compliance, following both Burkinabe and international standards , noting that this diminished TBS frequency is compensated by the fact that parasitemia will clinically manifest at lower parasite densities in children with less NAI than adults, and any symptoms referable to malaria will result in an immediate performance of TBS; (3) to assure safety, it is important that we achieve follow-up in all children; based on Burkinabe experience, parents may withdraw their children from the trial if there are daily needle sticks as planned for the adult cohort, and it is recommended that frequency not exceed every other day to assure compliance.

Based on these considerations, there are different follow-up TBS schedules for adult and pediatric groups. In the adults (groups 1 and 2, first-in-humans), TBS to monitor for Pf blood stage infections will be performed daily from day +6 to day +20 and then every two days until day +28, at which time terminal antimalarial treatment will be administered as a safety measure to group 2 , with a follow-up TBS on day +30 to confirm negativity after 48 hours of treatment (group 1 will receive terminal treatment day +28 after the third dose - see below). Assuming that there are no breakthrough infections in groups 1 and 2 during the first 28 days of follow-up, meaning that the "pre-test probability" of breakthrough infections in the pediatric groups is reduced, and in conformity with research guidelines to minimize the frequency of blood draws in children and to strengthen compliance, the frequency of TBS to detect parasitemia will be reduced in the pediatric age groups to every other day from day +6 to +18, then on days +21, +24 and +28, with terminal treatment initiated on day +28 and a follow-up TBS on day +30 to confirm negativity after 48 hours of treatment. This reduces the number of needle sticks (venipuncture or finger stick) for TBS during the first 30 days from 20 in adults to 11 in children. This is felt to be the maximum number of blood draws with which the pediatric population and their parents/guardians will comply.

As stated earlier, first immunizations induce substantial immunity to Pf malaria. Therefore, TBS follow-up f...

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