Malaria Challenge in Healthy Volunteers
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine if sterile, protective immunity to malaria can be
      induced by malaria parasite exposure limited to the early liver stage of the parasite
      lifecycle.
    

Detailed description: 
      This randomized, partial double-blind, placebo-controlled phase 1 study is designed to
      evaluate whether sterile protective immunity to P. falciparum can be induced by wild-type
      (non-attenuated) sporozoite immunizations when exposure is limited to sporozoite and early
      liver stage of the parasite life cycle and at a low dose sporozoite inoculum relative to
      other whole parasite vaccination models using live attenuated P. falciparum parasites (e.g.
      irradiated sporozoites). A secondary objective of the study is to evaluate newly identified
      antigens as potential targets of an immune response preferentially induced in individuals
      protected by whole sporozoite vaccination. Once identified as immune targets, these antigens
      can then be prioritized for subunit vaccine development. Subjects will be closely monitored
      for signs and symptoms of malaria and/or drug toxicity throughout the study.

      A total of 36 healthy, malaria-naive adult subjects will be enrolled in the study. Six
      subjects will be randomized to the Pilot Phase (Arm 1), 24 to the Main ITV Phase (Arms 2, 3,
      and 4), and six subjects will be randomized for challenge control (Arm 5) to start on the day
      of challenge of the Challenge Phase.

      Subjects in Arms 1-4 will receive three episodes of ITV immunization and a subsequent
      challenge with homologous P. falciparum sporozoites in the absence of chemoprophylaxis. The
      ITV immunization in this study consists of:

        1. Experimental infection with wild-type (non-attenuated) NF54 strain P. falciparum
           sporozoites delivered by the bites of 12 - 15 infected A. stephensi mosquitoes (ITV
           infection) administered in conjunction with

        2. Causal prophylaxis with PQ or placebo, timed to eliminate parasites early in the liver
           stage of development, after hepatocyte invasion but prior to maturation and release into
           the bloodstream, and

        3. Continuous suppressive prophylaxis with the blood-stage antimalarial drug CQ to prevent
           development of patent parasitemia and clinical malaria.

      The study includes a Pilot Phase because the timing of PQ dosing relative to parasite
      exposure is critical to the efficacy of PQ as causal prophylaxis yet still allowing for
      maximized antigenic exposure to liver-stage parasites. The Pilot Phase will compare the
      prevention of blood-stage parasitemia by PQ administered two days vs. three days after a
      single ITV infection. Based on protection data from the Pilot Phase, a dosing algorithm will
      be used to determine timing of the PQ dose for the Main ITV Phase.

      In the Challenge phase, which occurs after the three ITV events, sterile protective immunity
      will be assessed by challenge with homologous P. falciparum sporozoites in the absence of
      chemoprophylactic drugs. Five weeks after stopping chemoprophylaxis, subjects will undergo
      experimental P. falciparum infection by the bites of five infective mosquitoes and will be
      closely monitored for signs and symptoms of malaria in a hotel setting.

      Subjects who develop patent parasitemia will be immediately treated with a standard dose of
      Malarone and withdrawn from the study. Treated subjects will continue to be monitored with
      daily blood smears until three consecutive daily blood smears are negative and any residual
      symptoms of malaria are mild or resolved.

      Subjects are closely monitored throughout the study for solicited and unsolicited adverse
      events related to any part of the ITV immunization. The study is expected to last 4 to 9
      months depending on which the subject is assigned, and may have up to 64 scheduled study
      visits during the time period.

      Subjects will be followed in the clinic for 35 days after the challenge and a follow up phone
      call will be conducted at six months after the challenge. In an effort to evaluate the
      duration of an immune response to ITV, all subjects will be invited to return for optional
      evaluations at three and six months post challenge.
    

Intervention name(s): P. falciparum infection; Chloroquine; Primaquine; Primaquine
Intervention type(s): Biological; Drug; Drug; Drug
Intervention description(s): P. falciparum (NF54 strain) infection delivered by the bites of 12 - 15 infected A. stephensi mosquitos; Weekly chloroquine dosing (600 mg loading dose, 300 mg thereafter); Primaquine (45 mg) on day 2 or 3 post ITV infection; Primaquine (45 mg) on day 2 or 3 (pending results of pilot study) post ITV infection
Intervention MeSH terms: Chloroquine; Primaquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: malaria; challenge; P. falciparum; prevention