Trial to Evaluate the Safety, Immunogenicity and Protective Efficacy of Three or Five Administrations of GAP3KO Sporozoites
Condition: Plasmodium Falciparum Infection
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      This Phase 1 trial will include 16 subjects who will receive the Genetically-attenuated
      p52-/p36-/sap1- Plasmodium falciparum Parasites (GAP3KO) vaccine administered by the bite of
      approximately 200 infected Anopheles stephensi Mosquitoes in a controlled clinical
      environment and 12 Controlled Human Malaria Infection (CHMI) infectivity controls (six for
      each of the two CHMIs). Subjects will be observed for adverse events after each GAP3KO
      administration. Solicited local and systemic Adverse Events (AEs) will be recorded on a
      memory aid beginning of the day of first vaccine administration and continuing through 28
      days after the last administration. During the vaccination phase clinical laboratory
      evaluations for safety will be performed on venous blood. Unsolicited AEs will be collected
      from the day of first vaccination through 28 days after last vaccination and serious adverse
      events (SAEs) will be collected from the day of first GAP3KO administration through the end
      of study follow-up. Subjects will be monitored for possible breakthrough peripheral
      parasitemia with qRT-PCR testing. Four weeks after the last GAP3KO administration, all
      subjects who completed the immunization phase (up to 16) and a group of six malaria-naïve
      infectivity controls will be challenged on the same day with wild-type Plasmodium falciparum
      NF54 sporozoites. Approximately twenty-six weeks after that challenge, all of the protected
      subjects in Arms 1 and 2 (up to 16) and another six malaria-naïve infectivity controls will
      receive five infectious A. stephensi mosquito bites on the same day using standard CHMI
      procedures. For subjects in Study Arms 1 and 2 without documented parasitemia additional
      post-CHMI follow-ups will occur. For subjects in Study Arms 1 and 2 with documented
      parasitemia after the first CHMI or who are discontinued for other reasons after the first
      CHMI, and for the infectivity controls, additional follow ups will occur. Serious Adverse
      Events (SAEs) will be recorded from the day of CHMI through the end of study follow up and
      clinical laboratory evaluations for safety will be performed on Day 29 and as clinically
      indicated (all subjects) and, for subjects with documented parasitemia, on the day malaria
      treatment is initiated and three days after malaria treatment is initiated. The primary
      objectives are: 1) To assess the safety and reactogenicity of candidate GAP3KO malaria
      vaccine when administered by the bite of approximately 200 infected mosquitoes on a five dose
      schedule, with the first four vaccinations given four weeks apart and the fifth vaccination
      given eight weeks after the fourth vaccination, and on a three dose schedule, with the second
      vaccination given four weeks after the first vaccination and the third vaccination given
      eight weeks after the second vaccination, to healthy malaria-naïve adults aged 18 through 50
      years , 2) To confirm attenuation of GAP3KO parasites by assessing the occurrence of
      breakthrough peripheral parasitemia from the time of first GAP3KO administration through 28
      days after last GAP3KO administration.
    

Detailed description: 
      This Phase 1 trial will include 16 subjects in Study Arms 1 and 2 who will receive the
      Genetically-attenuated p52-/p36-/sap1- Plasmodium falciparum Parasites (GAP3KO) vaccine
      administered by the bite of approximately 200 infected Anopheles stephensi Mosquitoes in a
      controlled clinical environment and 12 Controlled Human Malaria Infection (CHMI) infectivity
      controls (six for each of the two CHMIs). Subjects will be observed for adverse events for at
      least 60 minutes after each GAP3KO administration. Solicited local and systemic Adverse
      Events (AEs) will be recorded on a memory aid beginning of the day of first vaccine
      administration and continuing through 28 days after the last administration. During the
      vaccination phase clinical laboratory evaluations for safety will be performed on venous
      blood. Unsolicited AEs will be collected from the day of first vaccination through 28 days
      after last vaccination and serious adverse events (SAEs) will be collected from the day of
      first GAP3KO administration through the end of study follow-up. Subjects will be monitored
      for possible breakthrough peripheral parasitemia with qRT-PCR testing. Four weeks after the
      last GAP3KO administration, all subjects who completed the immunization phase (up to 16) and
      a group of six malaria-naïve infectivity controls will be challenged on the same day with
      wild-type Plasmodium falciparum NF54 sporozoites. Approximately twenty-six weeks (six months)
      after that challenge, all of the protected subjects in Arms 1 and 2 (up to 16) and another
      six malaria-naïve infectivity controls will receive five infectious A. stephensi mosquito
      bites on the same day using standard CHMI procedures. For subjects in Study Arms 1 and 2
      without documented parasitemia additional post-CHMI follow-ups will occur. For subjects in
      Study Arms 1 and 2 with documented parasitemia after the first CHMI or who are discontinued
      for other reasons after the first CHMI, and for the infectivity controls, additional follow
      ups will occur. Serious Adverse Events (SAEs) will be recorded from the day of CHMI through
      the end of study follow up and clinical laboratory evaluations for safety will be performed
      on Day 29 and as clinically indicated (all subjects) and, for subjects with documented
      parasitemia, on the day malaria treatment is initiated and three days after malaria treatment
      is initiated. The primary objectives are: 1) To assess the safety and reactogenicity of
      candidate GAP3KO malaria vaccine when administered by the bite of approximately 200 infected
      mosquitoes on a five dose schedule, with the first four vaccinations given four weeks apart
      and the fifth vaccination given eight weeks after the fourth vaccination, and on a three dose
      schedule, with the second vaccination given four weeks after the first vaccination and the
      third vaccination given eight weeks after the second vaccination, to healthy malaria-naïve
      adults aged 18 through 50 years , 2) To confirm attenuation of GAP3KO parasites by assessing
      the occurrence of breakthrough peripheral parasitemia from the time of first GAP3KO
      administration through 28 days after last GAP3KO administration. The secondary objectives
      are: 1) To assess the efficacy of GAP3KO vaccine given on a five dose schedule and GAP3KO
      vaccine given on a three dose schedule against malaria challenge four weeks after last
      vaccination, and re-challenge 26 weeks (six months) after the first challenge, using standard
      controlled human malaria infection (CHMI) procedures, 2) To assess humoral and cell-mediated
      immune responses to malaria antigens induced by GAP3KO administration and by CHMI.
    

Intervention name(s): Genetically-attenuated p52-/p36-/sap1- Plasmodium falciparum parasite (GAP3KO) strain; Malaria challenge
Intervention type(s): Biological; Other
Intervention description(s): Genetically attenuated parasite created by triple deletion (GAP3KO) by deleting the P52, P36, and SAP1 genes in the NF54 wild-type (WT) strain of Plasmodium falciparum (Pf p52(-)/p36(-)/sap1(-) GAP).; Exposure to mosquitoes infected with P. falciparum.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Anopheles stephensi Mosquitoes; GAP3KO; Genetically-attenuated; Malaria-Naïve Adults; Phase 1; Plasmodium falciparum