Clinical trial NCT02942277: 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
Official title: Phase 1 Dose Escalating, Double-Blind, Randomized Comparator Controlled Trial of the Safety andImmunogenicity of Pfs25M-EPA/AS01 and Pfs230D1M-EPA/AS01 Vaccines, Transmission Blocking Vaccines Against Plasmodium Falciparum at Full and Fractional Dosing in Adults in Mali
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malaria
Keywords: Malaria
Reactogenicity
Antibody
Direct Skin Feed
Mosquito
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2016-10-24
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Maximum age (years): 52
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

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.

Primary outcomes:
measure: Number of Participants With Local and Systemic Adverse Events in Year 1
timeFrame: Within 7 days after each vaccination
measure: Number of Participants With Local and Systemic Adverse Events in Year 2
timeFrame: Within 7 days after each vaccination
Secondary outcomes:
Other outcomes:
Locations:
city: Bamako
country: Mali
facility: Bancoumana Malaria Vaccine Center
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Patrick E Duffy, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wu Y, Przysiecki C, Flanagan E, Bello-Irizarry SN, Ionescu R, Muratova O, Dobrescu G, Lambert L, Keister D, Rippeon Y, Long CA, Shi L, Caulfield M, Shaw A, Saul A, Shiver J, Miller LH. Sustained high-titer antibody responses induced by conjugating a malarial vaccine candidate to outer-membrane protein complex. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18243-8. doi: 10.1073/pnas.0608545103. Epub 2006 Nov 16.
citation: Tachibana M, Wu Y, Iriko H, Muratova O, MacDonald NJ, Sattabongkot J, Takeo S, Otsuki H, Torii M, Tsuboi T. N-terminal prodomain of Pfs230 synthesized using a cell-free system is sufficient to induce complement-dependent malaria transmission-blocking activity. Clin Vaccine Immunol. 2011 Aug;18(8):1343-50. doi: 10.1128/CVI.05104-11. Epub 2011 Jun 29.
citation: Diallo M, Toure AM, Traore SF, Niare O, Kassambara L, Konare A, Coulibaly M, Bagayogo M, Beier JC, Sakai RK, Toure YT, Doumbo OK. Evaluation and optimization of membrane feeding compared to direct feeding as an assay for infectivity. Malar J. 2008 Dec 2;7:248. doi: 10.1186/1475-2875-7-248.