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
Intervention: Pfs25M-EPA; Pfs230D1M-EPA; AS01; Engerix-B; Menactra; Normal Saline; Coartem
Intervention description: 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
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 301.0
Sex: All
Minimum age: 18 Years
Maximum age: 52 Years
Healthy volunteers: No
Keywords: Malaria; Reactogenicity; Antibody; Direct Skin Feed; Mosquito

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.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Age greater than or equal to 18 and less than or equal to 50 years.

          2. Available for the duration of the trial.

          3. Able to provide proof of identity to the satisfaction of the study clinician
             completing the enrollment process.

          4. In good general health and without clinically significant medical history in the
             opinion of the investigator.

          5. Females of childbearing potential must be willing to use reliable contraception (as
             defined below) from 21 days prior to Study Day 0 (Study Day 476 for re-enrollment) and
             then until 3 months after last vaccination.

               -  Reliable methods of birth control include one of the following: confirmed
                  pharmacologic contraceptives (parenteral) delivery; intrauterine or implantable
                  device.

               -  Reliable methods of birth control include concurrent use of a pharmacologic and a
                  barrier method, i.e. two of the following: confirmed pharmacologic contraceptives
                  (oral, transdermal) delivery or vaginal ring AND condoms with spermicide or
                  diaphragm with spermicide.

               -  Non-childbearing women will also be required to report date of last menstrual
                  period, history of surgical sterility (i.e. tubal ligation, hysterectomy) or
                  premature ovarian insufficiency (POI), and will have a baseline urine or serum
                  pregnancy test performed.

          6. Willingness to have blood samples stored for future research.

          7. Willingness to undergo DSFs (Arms 3c, 3d, 4c only).

          8. Known resident of Bancoumana or Doneguebougou or surrounding area or known student or
             long term resident (more than 1 year) of Bamako/Sotuba, Mali

        EXCLUSION CRITERIA:

          1. Pregnancy as determined by a positive urine or serum human choriogonadotropin
             (beta-hCG) test (if female).

             NOTE: Pregnancy is also a criteria for discontinuation of any further dosing or
             non-safety related interventions for that subject.

          2. Currently breast-feeding (if female).

          3. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator
             affects the ability of the participant to understand and comply with the study
             protocol.

          4. Hemoglobin, WBC, absolute neutrophils, and platelets outside the local
             laboratory-defined limits of normal (subjects may be included at the investigator s
             discretion for not clinically significant values outside of normal range and less than
             or equal to Grade 1).

          5. Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined
             upper limit of normal (subjects may be included at the investigator s discretion for
             not clinically significant values outside of normal range and less than or equal to
             Grade 1).

          6. Infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
             hepatitis B (HBV).

          7. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine,
             rheumatologic, autoimmune, hematological, oncologic, or renal disease by history,
             physical examination, and/or laboratory studies including urinalysis.

          8. History of receiving any investigational product within the past 30 days.

          9. Participation or planned participation in a clinical trial with an investigational
             product prior to completion of the follow up visit 28 days following last vaccination
             OR planned participation in an investigational vaccine study until the last required
             protocol visit

         10. Subject has had medical, occupational, or family problems as a result of alcohol or
             illicit drug use during the past 12 months.

         11. History of a severe allergic reaction or anaphylaxis.

         12. Severe asthma, defined as asthma that is unstable or required emergent care, urgent
             care, hospitalization, or intubation during the past 2 years, or that has required the
             use of oral or parenteral corticosteroids at any time during the past 2 years.

         13. Pre-existing autoimmune or antibody-mediated diseases including but not limited to:
             systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis,
             Sj(SqrRoot)(Delta)gren s syndrome, or autoimmune thrombocytopenia.

         14. Known immunodeficiency syndrome.

         15. Known asplenia or functional asplenia.

         16. Use of chronic (greater than or equal to 14 days) oral or intravenous corticosteroids
             (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day)
             or immunosuppressive drugs within 30 days of Study Day 0.

         17. Prior to Study Day 0 and every subsequent vaccination day, receipt of a live vaccine
             within the past 4 weeks or a killed vaccine within the past 2 weeks.

         18. Receipt of immunoglobulins and/or blood products within the past 6 months.

         19. Previous receipt of an investigational malaria vaccine in the last 5 years.

         20. History of severe reaction to mosquito bites (Arms 3c, 3d, 4c only)

         21. History of allergy to the comparator vaccine (such as latex, yeast, or previous
             Hepatitis B vaccine)

         22. Known allergies or contraindications (such as significant cardiac disease; prolonged
             QTc >450 ms; currently taking medications that may prolong your QTc; serious side
             effects from Coartem in the past) to study treatment (Coartem
             [artemether/lumefantrine]) (Arms 3c, 3d, 4c only)

         23. Other condition that in the opinion of the investigator would jeopardize the safety or
             rights of a participant participating in the trial, interfere with the evaluation of
             the study objectives, or would render the subject unable to comply with the protocol.