Safety and Immunogenicity of Pfs25M-EPA/AS01 and Pfs230D1M-EPA/AS01 Vaccines, Transmission Blocking Vaccines Against Plasmodium Falciparum, at Full and Fractional Dosing in Adults in Mali
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Researchers are looking for new ways to control and eradicate malaria. They want to test
      vaccines to block malaria transmission in adults in Mali. These vaccines work by inducing
      antibodies in a person. The antibody is then taken up with blood by a mosquito that bites the
      person. This blocks parasite development in the mosquito. This stops malaria transmission to
      another person.

      Objective:

      To test the safety, reactogenicity, immunogenicity, and transmission-blocking activity of the
      vaccines Pfs25M-EPA and Pfs230D1M-EPA with AS01 in Malian adults.

      Eligibility:

      Healthy Malians ages 18-50 living in certain areas in Mali who:

      Are not pregnant or breastfeeding

      Are not infected with HIV, Hepatitis B and Hepatitis C

      Do not have evidence of immunodeficiency

      Do not have history of severe allergic reaction or anaphylaxis

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Malaria Comprehension Exam

      Blood and urine tests

      Electrocardiogram (for participants in certain study groups)

      Participants will be randomly assigned to a study group.

      Participants will be monitored for 12-16 months. For the first 7 months, they will have
      between 1 and nine visits a month. The number depends on the month and on what group they are
      in. For the rest of the months, they will have 1 monthly visit.

      Each visit includes a physical exam. Most include blood tests.

      Participants will get 3 doses of a study or comparator vaccine. They get the vaccine through
      an injection in the upper arm. This occurs at their first visit, then 1 month later, and then
      5 months later.

      Participants will be followed for at least 6 months after the last vaccine.

      If participants develop an injection site rash or reaction, photographs may be taken of the
      site.
    

Detailed description: 
      A vaccine to interrupt malaria transmission (VIMT) would be a valuable tool for local
      elimination or eradication of this disease, and may contain components that block
      transmission to mosquitoes (such as Pfs25 or Pfs230) or that prevent human infection (such as
      the vaccine RTS,S). Pfs25 and Pfs230, surface antigens of zygotes and ookinetes (and
      gametocytes for Pfs230) in the mosquito stage of P. falciparum, are the lead candidates for a
      malaria transmission blocking vaccine (TBV). Recombinant Pfs25M and recombinant Pfs230D1M
      have each been conjugated to P. aeruginosa ExoProtein A (EPA) and adjuvanted with AS01. Our
      ongoing experience with Pfs25M-EPA and Pfs230D1M-EPA in Malian adult trial participants, and
      the extensive experience with the AS01 adjuvants in African children and adults, justify
      conducting the first-in-human trial of Pfs25M-EPA and Pfs230D1M-EPA with AS01 in Malian
      adults. This dose-escalating phase 1 study will determine safety, immunogenicity, and
      functional activity of these vaccines in Malian adults. Pfs25M-EPA + Pfs230D1M-EPA in AS01
      will be assessed by mosquito feeding assays in Malian adults for evidence that they may
      reduce the number of malaria transmission events in study subjects.

      A total of 305 subjects will be enrolled at multiple sites in Mali, West Africa to receive
      escalating doses of a malaria transmission blocking vaccine (s): Pfs25M-EPA/AS01,
      Pfs230D1M-EPA/AS01, or simultaneous administration of Pfs25M-EPA/AS01 and Pfs230D1M-EPA/AS01;
      or a comparator vaccine (ENERGIX-B). Enrollment within each group will be staggered for
      additional safety and subjects will only be enrolled into the co-administration group once
      each individual dose has been administered. Subjects will be followed for at least 6 months
      after the last vaccination. Safety outcomes will be local and systemic adverse events and
      serious adverse events. Immunogenicity outcomes will be antibody responses as measured by
      ELISA against recombinant Pfs25, Pfs230, EPA, CSP, and B cell and T cell responses.
      Functional activity of the induced antibodies will be assessed in TBV arms by standard
      membrane feeding assays conducted at the National Institute of Allergy and Infectious
      Diseases, and activity that interrupts malaria transmission will be measured in all arms by
      direct skin feeding assays in Mali.

      Subjects in the open label safety cohorts (Arms 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b) will be
      offered reenrollment for follow-up laboratory assessment to explore the duration of
      immunogenicity and functional activity at approximately 9, 12 months post vaccination.
      Following scheduled, intentional unblinding, subjects enrolled in Arms 2c, 2d, and 4c will be
      provided the opportunity to re-enroll for a fourth vaccination (Arm 2c and 2d with 40
      microgram dose of Pfs230D1M-EPA/AS01; Arm 4c with Menatctra) approximately 1 year post
      vaccination #3. Subjects in these arms will also be eligible to re-enroll for follow up of
      duration of immunogenicity and functional activity at approximately 9, 12 months post
      vaccination if they choose not to enroll to recive the booster vaccination. Subjects will be
      followed similarly to the previous year for safety, immunogenicity, and functional activity.
    

Intervention name(s): Pfs25M-EPA; Pfs230D1M-EPA; AS01; Engerix-B; Menactra; Normal Saline; Coartem
Intervention type(s): Biological; Biological; Other; Biological; Biological; Other; Drug
Intervention description(s): The PpPfs25M and EcEPA lots, both manufactured at Walter Reed Bioproduction facility (Silver Spring, Maryland) in cGMP compliance, were used to manufacture the conjugate. PpPfs25M is a Pichia- expressed recombinant Pfs25 with a molecular mass of 18,713 Daltons.The Pfs25M- EPA was formulated as conjugated Pfs25M in 4 mM PBS to a 2X dilution of the high dose (188 (Micro)g/ml in 0.5 ml volume) in cGMP compliance at Walter Reed Bio-production facility in April 2016 and will be provided as a single use vial.; The Pfs230D1M-EPA was formulated as conjugated Pfs230D1M in 4 mM PBS to a 2X dilution of the high dose (160 (Micro)g/ml in 0.5 ml volume) in cGMP compliance at Walter Reed Bio-production facility in April 2016 and will be provided as a single use vial.; AS01B adjuvant will also be provided as a single use vial by GSK, 100 microgram/mL MPL and 100microgram/mL QS21 in a liposomal formulation in a volume of 0.625 mL. One dose injected of AS01B corresponds to 50 μg QS21 and 50 μg MPL.; ENGERIX-B (hepatitis B vaccine; recombinant): is a sterile suspension of noninfectious hepatitis B virus surface antigen (HBsAg) for intramuscular administration. It contains purified HBsAg obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus. Each 1-mL adult dose contains 20 g of HBsAg adsorbed on 0.5 mg aluminum as aluminum hydroxide. FDA approved for persons 20 years of age and older for a series of 3 doses on a 0-, 1-, 6-month schedule.; Menactra is FDA approved for active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135 (but does not protect against serotype B) for use in individuals 9 months through 55 years of age; Sterile isotonic (0.9%) normal saline will be commercially procured in the US and shipped to Mali at ambient temperature. Normal saline will be administered in a 0.5 mL dose as an intramuscular injection. Normal saline will also be used for diluting Pfs25M-EPA and Pfs230D1M-EPA prior to formulation with AS01B for the lower dose groups in Bamako, Mali.; Artemether/lumefantrine (Coartem(R)) is a licensed antimalarial in the US and Mali for treatment of uncomplicated malaria. It has an excellent safety profile and is widely used to treat malaria. Subjects who may have any contraindications to the use of these drugs will be excluded at screening. Coartem will be dosed with food and administered over 3 days for a total of 6 doses, as per package insert and standard adult dosing
Intervention MeSH terms: Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Malaria; Reactogenicity; Antibody; Direct Skin Feed; Mosquito