Testing Pfs25-EPA/Alhydrogel as a Potential Malaria Transmission Blocking Vaccine
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Malaria is a disease that is spread by mosquitoes. Researchers are looking for a vaccine
      that can prevent mosquitoes from transmitting malaria to people. They want to test a vaccine
      called Pfs25-EPA/Alhydrogel that may help stop malaria parasites from developing in
      mosquitoes. When a mosquito bites a vaccinated person, the vaccine should prevent parasites
      from developing in the mosquito. As a result, the mosquito will not spread malaria to the
      next person it bites. However, the vaccine will not directly prevent people vaccinated from
      getting sick with malaria. Researchers want to test this vaccine in people who live in rural
      Mali. To do so, the study will compare the symptoms and the blood tests of the participants
      who receive either the study vaccine or a regular hepatitis B/meningococcal vaccine.

      Objectives:

      - To see if Pfs25-EPA/Alhydrogel is a safe and effective malaria vaccine.

      Eligibility:

      - Healthy volunteers between 18 and 45 years of age who live in Bancoumana, Mali.

      Design:

        -  Participants will be screened with a medical history, physical exam, and blood tests.

        -  Participants will be separated into two groups. One group will have Pfs25-EPA/Alhydrogel
           to test the study vaccine. The other group will have the regular Hepatitis B vaccine
           series, meningococcal vaccine.

        -  In the study vaccine group, participants will have either a lower dose or a higher dose.
           For the lower dose, they will have two vaccine shots over 1 year. For the higher dose,
           they will have four vaccine shots over about 14 months.

        -  In the other vaccine group, participants will have the Hepatitis B vaccine series,
           meningococcal vaccine according to the standard dose schedule.

        -  All participants will provide regular blood samples for testing during the study.

        -  Participants who develop malaria during the study will participate in evaluation of
           transmission and parasite development of malaria parasite from the person to mosquito
           via transmission assays. They will allow mosquitoes (that have no diseases) to bite them
           in a controlled clinic setting. This will let researchers see if the vaccine can stop
           the mosquitoes from carrying malaria to other people.
    

Detailed description: 
      A vaccine to interrupt malaria transmission would be a valuable tool for local elimination or
      eradication of this disease. Pfs25, a surface antigen of ookinetes in the mosquito stage of
      P. falciparum, is a lead candidate for a malaria transmission blocking vaccine. Recombinant
      Pfs25 has been conjugated to Pseudomonas aeruginosa ExoProtein A (EPA), and adjuvanted with
      Alhydrogel . This dose escalating, double-blind, randomized controlled trial will determine
      safety and immunogenicity of the vaccine in malaria exposed adults. One hundred twenty (120)
      subjects will be enrolled and randomized to receive the low dose (16 g of conjugated Pfs25,
      n=10), the high dose (47 g of conjugated Pfs25, n=50), or the comparator vaccine (Euvax B for
      first 3 vaccinations, then Menactra vaccine for the fourth vaccination, n=10 for 2
      vaccinations, n=50 for 4 vaccinations). Enrollment within the high dose group will be
      staggered for additional safety. The low dose and the matching comparator cohort (Group 1)
      will receive 2 vaccine doses given at 0 and 2 months. For the rest of the subjects, 3 doses
      will be given at a 0, 2, 4 month dosing intervals, and a fourth (booster) dose will be given
      12 months following the third dose at the start of the subsequent transmission season.
      Subjects will be followed for 12 months following the last vaccination. Safety outcomes will
      be local and systemic adverse events (AEs) and serious adverse events (SAEs). Immunogenicity
      outcomes will be antibody responses as measured by ELISA against recombinant Pfs25 and EPA,
      and B cell responses. Functional activity of the induced antibody will be assessed by direct
      transmission blocking assays (direct skin feeds, direct membrane feeding assays) conducted at
      the Malaria Research and Training Center (MRTC) in Mali and in a standard membrane feeding
      assay conducted at the National Institute of Allergy and Infectious Diseases (NIAID) in the
      United States.
    

Intervention name(s): Pfs25-EPA/Alhydrogel; Euvax B; Menactra
Intervention type(s): Biological; Biological; Biological
Intervention description(s): The Pfs25-EPA conjugate was produced by reaction between thiolated PpPfs25 and maleimideactivated EcEPA, followed by purification using size-exclusion chromatography. The cGMP Pfs25-EPA conjugate Lot# WRAIR1634 was manufactured at Walter Reed Bioproduction facility in cGMP compliance in May 2010. Alhydrogel (Brenntag, Denmark) is an aluminum hydroxide gel and has been extensively used as an adjuvant in licensed human vaccines. Alhydrogel is supplied as a sterile product in water without preservatives. Pfs25- EPA/Alhydrogel WRAIR Lot #1668 was manufactured and filled as single-use vials at Walter Reed Bioproduction facility in cGMP compliance in October 2010. Each vial contains 78 g/mL conjugated Pfs25, 93 g/mL conjugated EPA and 1600 g/mL Alhydrogel in a volume of 0.8 mL. The vial label reads: 78 g/mL Conjugated Pfs25 on Alhydrogel .; Euvax B consists of highly purified, noninfectious particles of HBsAg absorbed onto aluminum salts as an adjuvant and preserved with thimerosal.; Menactra , Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine, is a sterile, intramuscularly administered vaccine that contains Neisseria meningitidis serogroup A, C, Y and W-135 capsular polysaccharide antigens individually conjugated to diphtheria toxoid protein. N meningitidis A, C, Y and W-135 strains are cultured on Mueller Hinton agar (3) and grown in Watson Scherp (4) media. The polysaccharides are extracted from the N meningitidis cells and purified by centrifugation, detergent precipitation, alcohol precipitation, solvent extraction and diafiltration.
Intervention MeSH terms: Aluminum Hydroxide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Antigen; Ookinetes; Mosquito; Membrane; Assay