Experimental PfSPZ Vaccine in Adults Without Malaria
Condition: Malaria; Prevention and Control; Acquired Immunity
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Malaria parasites are carried by mosquitoes, which spread the infection by biting
           people. Currently, there is no effective malaria vaccine. However, studies show that
           volunteers bitten many times by mosquitoes that carry weakened malaria parasites could
           fight off getting sick with malaria when later exposed to normal malaria parasites.
           Malaria parasites are weakened by exposing them to radiation when they are in the stage
           of development called sporozoites . Only the mosquitoes are irradiated and study
           volunteers are not exposed to radiation. The radiation stops the parasites from being
           able to cause disease but still promote protection. For many years, it was not possible
           to give these sporozoites to people as a vaccine since they could not be adequately
           purified from the mosquito. Scientists have recently figured out how to produce and
           isolate the weakened sporozoites so that they can be given in an injected vaccine. This
           vaccine is known as the "PfSPZ vaccine".

        -  A malaria challenge will be used to test whether the vaccine will prevent infection. In
           a malaria challenge, mosquitoes that have the malaria parasite will be allowed to bite a
           participant's arm. In the event that the vaccine does not work, the malaria parasite
           used for the challenge can be treated completely with common anti-malaria medications.
           Participants will be treated immediately if they develop malaria symptoms.

      Objectives:

      - To test the safety and effectiveness of the PfSPZ vaccine.

      Eligibility:

      - Healthy volunteers between 18 to 45 years of age.

      Design:

        -  Participants will be screened with a physical exam, medical history, and blood tests.
           There will be five different groups of study participants, all of whom will be monitored
           with frequent blood tests.

        -  Group 1 will have two vaccines with the lowest amount of the vaccine given 4 weeks
           apart, with regular clinic visits up to 24 weeks after the second vaccine. This group
           will not have a malaria challenge.

        -  Group 2 will have four or six vaccines given 4 weeks apart at a higher dose than group
           1. A malaria challenge will be given about 3 weeks after the last vaccine. Follow-up
           visits will continue through 24 weeks after the last vaccine.

        -  Group 3 will have four or six vaccines given 4 weeks apart at a higher dose than group
           2. A malaria challenge will be given about 3 weeks after the last vaccination, as for
           Group 2. Follow-up visits will continue through 24 weeks after last vaccine.

        -  Group 4 will have four or six vaccines given 4 weeks apart at a higher dose than group
           3. A malaria challenge will be given about 3 weeks after the last vaccination. Follow up
           visits will continue through 24 weeks after last vaccine.

        -  Group 5 will serve as a control group and will not receive the vaccine, but will have
           the malaria challenge. Follow-up visits will continue through 8 weeks after the
           challenge.

      All participants from any group who receive a malaria challenge will be treated promptly for
      malaria when it develops.
    

Detailed description: 
      Study Design: VRC 312 is the second study of the PfSPZ Vaccine and the first study to
      evaluate intravenous (IV) administration of this vaccine. The study is designed as an
      openlabel evaluation of the safety, tolerability, immunogenicity and protective efficacy of
      the vaccine at successively higher dosages (2000; 7500; 30,000 and 135,000 SPZ per injection)
      administered by the IV route. The 3 higher dosages will be evaluated for protection against a
      malaria challenge after 4 to 6 vaccinations. Control subjects are included in the malaria
      challenge. The primary objectives of the study are related to the safety and tolerability of
      the vaccine at the 4 dosage levels when administered IV; the secondary objectives are related
      to PfSPZ vaccine-mediated protection against Plasmodium falciparum (Pf) challenge at the 3
      higher dosage levels; and the exploratory objectives are related to the immunogenicity of the
      PfSPZ Vaccine and defining an immune correlate of protection.

      Product Description: The investigational PfSPZ Vaccine is manufactured by Sanaria, Inc
      (Rockville, MD) under current Good Manufacturing Practices (cGMP). The vaccine consists of a
      suspension of purified, metabolically-active, radiation-attenuated cryopreserved Pf
      sporozoites formulated in cryoprotectant and dispensed in a 0.5 mL screw-cap vial containing
      a 20 mcL aliquot at a concentration of 150,000 sporozoites (+/-50,000 sporozoites) per 20
      mcL. The vaccine is stored in the vapor-phase of liquid nitrogen (LNVP) at -140 to -196
      degrees C. The PfSPZ Vaccine is delivered by Sanaria, Inc. to the clinical investigators and
      diluted in phosphate buffered saline (PBS) with 1% human serum albumin (HSA) to achieve the
      correct dosage.

      Subjects: Healthy subjects, 18-45 years old, who are malaria-naive. The fewest number of
      subjects needed to complete the study as originally designed was 51; however, with inclusion
      of study provisions for back-up challenge subjects enrollment of additional vaccinees and
      options for rechallenge, as added by protocol amendments, the amended accrual allowance is 68
      subjects.

      Study Plan: Subjects will be enrolled in a step-wise, dose-escalation manner with stringent
      stopping rules designed for subject safety. The first 12 subjects will be allocated as the
      pilot subjects that comprise Groups 1, 2a, 3a, 4a; each of which includes 3 pilot subjects.
      For the pilot subjects, the 1st vaccination (V1) and 2nd vaccination (V2) will be
      administered no faster than one per pilot subject every 2 hours.

      Before administration of the first dose to the subsequent pilot Group (dose escalation), at
      least 5 weeks of cumulative safety data for the pilot subjects in a dosage group (i.e., 1
      week past 2nd vaccination) must be submitted to the Safety Monitoring Committee (SMC) and the
      FDA, and protocol-specified approval received for the dose escalation.

      Subjects in vaccine Groups 2, 3, 4 and the Group 5 controls will be challenged by exposure to
      Anopheles stephensi mosquitoes infected with Pf sporozoites in a controlled setting, followed
      by testing for parasitemia at specified intervals through up to 28 days post-challenge. To
      facilitate intensive daily close monitoring of clinical status and blood smears, 11 overnight
      stays are required from days 7-18 post-challenge. Subjects who develop blood stage P.
      falciparum infection will be treated as soon as a case is identified by the protocol
      criteria. Following treatment, a subject will be considered cured when 2 consecutive daily
      blood smears are negative. After establishing cure, blood smear checks may end and the
      subject may discontinue overnight stays.

      Challenges occur at specified timepoints in which each challenge includes vaccine recipients
      and control subjects. Rechallenge options to assess for durability of protective responses
      and further evaluation of immune correlates of protection are included in the protocol.

      Study Duration: The study will take approximately 18 months to complete. The period of
      follow-up for each vaccinated subject is through at least 24 weeks after the last
      vaccination. The total duration on study will vary depending upon the schedule assignment and
      whether or not the subject participates in a rechallenge. The Group 5 (challenge only)
      subjects and rechallenged subjects will be followed through 8 weeks after last challenge.
    

Intervention name(s): PfSPZ
Intervention type(s): Biological
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Healthy Subjects; Immunogenicity; Vaccine-Mediated Protection; Sporozoites; Parasitemia; Healthy Volunteer; HV