Age De-escalation Clinical Trial to Evaluate the Safety, Tolerability and Immunogenicity of a Late Liver Stage-arresting, Replication-competent Plasmodium Falciparum Sporozoite Vaccine (Sanaria® PfSPZ-LARC2 Vaccine) Administered by Direct Venous Inoculation to Malaria-exposed Adults and Children in Burkina Faso
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).
• Healthy males and females, based on clinical and laboratory findings
• From the age 1 to 50 years
• Adults with a Body Mass Index (BMI) 18 to 30 Kg/m2; or adolescents, and children with Z-score of the selected indicator (\[weight-for-height\], \[(height and BMI) for age\]) category within ±2SD.
• Residence in the study area for the duration of the study.
• Agreement to release medical information and to inform the study doctor concerning contraindications for participation in the study
• Willingness to be attended to by a study clinician and take all necessary medications prescribed during study period
• Agreement to provide contact information of a third party household member or close friend to study team
• Agreement not to participate in another clinical trial during the study period
• Agreement not to donate blood during the study period (until final clearance is completed)
⁃ Able and willing to complete the study visit schedule over the study follow up period.
⁃ Willingness to undergo HIV, hepatitis B (HBV), hepatitis C (HCV), and sickle cell anemia tests
⁃ Volunteer participant (subjects 21 years of age and older) or the parent / guardian signing the informed consent (for subjects \<21 years of age) is able to demonstrate their understanding of the study by responding correctly to 9 out of 10 true/false statements (in a maximum of two attempts for those who failed to respond correctly to all true/false statements in the first attempt)
⁃ Signed written informed consent, in accordance with local practice, provided by adult volunteers, parents or legal representatives and relevant assent for children participants as applicable
⁃ Has not been treated with any antimalarial medication for at least two weeks prior to the initial clearance treatment.
⁃ Female volunteers aged 12 years and above must be non-pregnant (as demonstrated by a negative urine pregnancy test), and provide consent / assent of their willingness to take protocol-defined measures not to become pregnant during the study and safety follow-up period. Acceptable measures to not become pregnant include oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner during the entire study. Women with a history of surgical or chemical sterilization (e.g., tubal ligation, hysterectomy, other) must provide written documentation of the procedure from a health care provider.
⁃ One additional inclusion criterion is demonstration of the ability to complete pre-vaccination drug clearance without significant untoward effects.