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Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine Against Plasmodium Falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali

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ClinicalTrials.gov Identifier: NCT03917654
Recruitment Status : Recruiting
First Posted : April 17, 2019
Last Update Posted : May 24, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

Background:

Malaria affects many people in Mali and other parts of Africa. It is spread by mosquito bites. Malaria can make people sick or can lead to death. Scientists want to learn if a vaccine can stop it from spreading to other people.

Objective:

To test how well an experimental malaria vaccine works to decrease malaria infections.

Eligibility:

Healthy people ages 5 and older who live in Doneguebougou, Mali, and surrounding areas

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

EKG

Participants will be randomly assigned to get either the experimental vaccine or an approved vaccine. They will not know which they are getting.

Participants will have a visit about a week before their first vaccine. They will take a medicine that kills malaria. They will take it at the clinic the next 2 days. Participants ages 5-8 will take the drug again 2 weeks before their third vaccine.

Participants get the vaccine through a needle in the arm. They will have visits 1, 3, 7, and 14 days after. They will have blood tests or finger pricks.

Participants will get another vaccine 1 and 6 months later.

Participants will have blood tests once a month. At these visits they may also have urines tests or mosquito feeds. For the feeds a cup full of mosquitoes will be placed on arms or legs for 15-20 minutes.

Participants will have visits twice a month for 4 months after their last vaccine.


Condition or disease Intervention/treatment Phase
Malaria Biological: Pfs230D1M-EPA/AS01 Biological: HAVRIX Biological: 10.2.2TYPHIM Vi (Salmonelle typhi vaccine) Phase 2

Detailed Description:

A vaccine to interrupt malaria transmission (VIMT), targeting disruption of both human and mosquito transmission, would be a valuable tool for local elimination or eradication of this disease. One strategy to design a VIMT is using components that block transmission of malaria to mosquitoes, such as Pfs230. Pfs230, a surface antigen of intracellular gametocytes, as well as extracellular gametes and zygotes in the mosquito stage of Plasmodium falciparum, is currently the leading candidate in clinical trials for a malaria transmission-blocking vaccine (TBV). Recombinant Pfs230D1M has been conjugated to a recombinant Pseudomonas aeruginosa ExoProtein A (EPA) and adjuvanted with AS01. When formulated in AS01, results from a recent first-in-human trial demonstrated that Pfs230-EPA induces functional transmission-reducing, and in a significant proportion of vaccinees, transmission-blocking serum activity that can be measured for months, the vaccine is well-tolerated and safe in adults, and our recent natural history data clearly indicate that children play a disproportionate role in malaria transmission. The next step in the development of Pfs230D1M-EPA as a TBV is therefore to conduct an age de-escalation trial to ensure that the vaccine is safe to administer to children and then to conduct a community clinical trial to assess efficacy in family groups.

This Phase 2 study will first determine safety and tolerability of Pfs230D1M-EPA/AS01 in healthy Malian children of decreasing ages: 9-18 years old, followed by 5-8 years old. A total of 60 subjects will be enrolled in Doneguebougou, Mali, West Africa. Children will be recruited from compounds/family that have agreed to participate in the main phase of the study and will enroll in a staggered manner to receive either Pfs230D1M-EPA/AS01 vaccine or comparator as assigned by their compound block randomization. Prior to receipt of vaccination number 1, all subjects will receive a full treatment course of artemether/lumefantrine (AL). Safety and tolerability will be monitored and reported as local and systemic adverse events (AEs) and serious adverse events (SAEs) and reviewed by DSMB, Sponsor, medical monitors, and study team prior to proceeding with enrollment of the main phase.

If there are no safety concerns, in a staggered manner, the main phase will begin enrollment of at least 84 compounds (about 1500 vaccinees + about 400 under 5 years of age for parasite surveillance). Children enrolled during the pilot safety phase will join their main phase compounds/family for vaccination number 3. Prior to receipt of first vaccination, all subjects will receive a full treatment course of AL. All vaccinated subjects will be monitored for safety and tolerability. Immunogenicity outcomes will be antibody responses as measured by enzyme-linked immunosorbent assay (ELISA) against recombinant Pfs230D1M. Functional activity of the induced antibodies will be assessed by standard membrane feeding assays in select samples. Vaccine activity will be measured in children 9-18 years of age who will undergo direct skin feeds (DSF) starting 2 weeks post vaccination number 3 for a total of 8 DSFs.

Prior to scheduled last vaccination in members of the compound/family, children 1-4 years of age and vaccinated children 5-8 years of age will receive a full treatment course of AL prior to the expected start of the transmission season and will then be followed every 2 weeks by blood smear (BS) along with all vaccinated children. Children 9-18 years of age will also be assessed for vaccine efficacy, but as a separate analysis from those 1-8 years of age.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Safety, Immunogenicity and Efficacy of Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine Against Plasmodium Falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali
Estimated Study Start Date : May 29, 2019
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: Arm 1a/3c
Arm 1a (pilot) + Arm 3c (main) to receive 40 microg of Pfs230D1M-EPA/AS01 on days 0, 28, 168; receipt of artemether/lumefantrine (AL) on day -7
Biological: Pfs230D1M-EPA/AS01
Pfs230D1M-EPA was formulated as conjugated Pfs230D1M in 4 mM phosphate-buffered saline (PBS) to a 2x dilution of the high dose (160 micrograms/mL in cGMP compliance at Walter Reed Bioproduction facility in April 2016 and will be provided as a single use vial. AS01B adjuvant was manufactured for use in the SHINGRIX vaccine by G

Active Comparator: Arm 1b/3d
Arm 1b (pilot) + Arm 3d (main) to receive HAVRIX (day 0), TYPHIM Vi (day 28), HAVRIX (day 168); receipt of AL on day -7
Biological: HAVRIX
HAVRIX (Hepatitis A Vaccine; HAV) is produced by GSK and is a sterile suspension of inactivated virus for IM administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. HAVRIX is FDA approved for active immunization against disease caused by HAV for persons 12 months of age and older.

Biological: 10.2.2TYPHIM Vi (Salmonelle typhi vaccine)
TYPHIM Vi (Typhoid Vi Polysaccharide Vaccine), produced by Sanofi Pasteur SA, for IM use, is a sterile solution containing the cell surface Vi polysaccharide extracted from serovar Typhi, S typhi Ty2 strain (inactivated, subunit vaccine). TYPHIM Vi vaccine is indicated for active immunization for the prevention of typhoid fever caused by S typhi and is FDA approved for use in persons 2 years of age or older

Experimental: Arm 2a/3a
Arm 2a (pilot) + Arm 3a (main) to receive 40 microg of Pfs230D1M-EPA/AS01 on days 0, 28, 168; receipt of AL on day -7 and 154
Biological: Pfs230D1M-EPA/AS01
Pfs230D1M-EPA was formulated as conjugated Pfs230D1M in 4 mM phosphate-buffered saline (PBS) to a 2x dilution of the high dose (160 micrograms/mL in cGMP compliance at Walter Reed Bioproduction facility in April 2016 and will be provided as a single use vial. AS01B adjuvant was manufactured for use in the SHINGRIX vaccine by G

Active Comparator: Arm 2b/3b
Arm 2b (pilot) + Arm 3b (main) to receive HAVRIX (day 0), TYPHIM Vi (day 28), HAVRIX (day 168); receipt of AL on day -7 and 154
Biological: HAVRIX
HAVRIX (Hepatitis A Vaccine; HAV) is produced by GSK and is a sterile suspension of inactivated virus for IM administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. HAVRIX is FDA approved for active immunization against disease caused by HAV for persons 12 months of age and older.

Biological: 10.2.2TYPHIM Vi (Salmonelle typhi vaccine)
TYPHIM Vi (Typhoid Vi Polysaccharide Vaccine), produced by Sanofi Pasteur SA, for IM use, is a sterile solution containing the cell surface Vi polysaccharide extracted from serovar Typhi, S typhi Ty2 strain (inactivated, subunit vaccine). TYPHIM Vi vaccine is indicated for active immunization for the prevention of typhoid fever caused by S typhi and is FDA approved for use in persons 2 years of age or older

Experimental: Arm 3e
Arm 3e (main) to receive 40 microg of Pfs230D1M-EPA/AS01 on days 0, 28, 168; receipt of AL on day -7
Biological: Pfs230D1M-EPA/AS01
Pfs230D1M-EPA was formulated as conjugated Pfs230D1M in 4 mM phosphate-buffered saline (PBS) to a 2x dilution of the high dose (160 micrograms/mL in cGMP compliance at Walter Reed Bioproduction facility in April 2016 and will be provided as a single use vial. AS01B adjuvant was manufactured for use in the SHINGRIX vaccine by G

Active Comparator: Arm 3f
Arm 3f (main) to receive HAVRIX (day 0), TYPHIM Vi (day 28), HAVRIX (day 168); receipt of AL on day -7
Biological: HAVRIX
HAVRIX (Hepatitis A Vaccine; HAV) is produced by GSK and is a sterile suspension of inactivated virus for IM administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. HAVRIX is FDA approved for active immunization against disease caused by HAV for persons 12 months of age and older.

Biological: 10.2.2TYPHIM Vi (Salmonelle typhi vaccine)
TYPHIM Vi (Typhoid Vi Polysaccharide Vaccine), produced by Sanofi Pasteur SA, for IM use, is a sterile solution containing the cell surface Vi polysaccharide extracted from serovar Typhi, S typhi Ty2 strain (inactivated, subunit vaccine). TYPHIM Vi vaccine is indicated for active immunization for the prevention of typhoid fever caused by S typhi and is FDA approved for use in persons 2 years of age or older




Primary Outcome Measures :
  1. Safety and Reactogenenicity (Pilot) [ Time Frame: 6 months post vaccination ]
    Safety and reactogenicity of administration of Pfs230D1M-EPA/AS01-To assess vaccine activity of Pfs230D1M-EPA/AS01 against P.falciparum transmission by direct skin feeding assay (DSF)(Arms 1a/ab only) after receipt of 3rd vaccination and analyzed with the main group

  2. Vaccine Activity (Main) [ Time Frame: 6 months post vaccination ]
    Vaccine activity of Pfs239D1M-EPA/AS01 against P.falciparum transmission by direct skin feeding assay (DSF)(Arms 3c/3d only)


Secondary Outcome Measures :
  1. Vaccine Efficacy, Immunogenicity, Functional Antibody (Main [ Time Frame: 6 months post vaccination ]
    Vaccine efficacy of Pfs230D1M-EPA/ASO1 against P.falciparum infection measured 3rd vaccination and analyzed with the main group-To assess immunogenicity as measured by enzyme-linked immunosorbent assay (ELISA) titer response to Pfs230D1M-To assess functional antibody response by standard membrane feeding assay (SMFA) to Pfs230D1M



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA FOR GROUPS 1,2,3:

All of the following criteria must be fulfilled for a volunteer to participate in this trial:

  1. Meets age requirements for Arm currently being enrolled.
  2. Available for the duration of the trial.
  3. Family compound known resident or long-term resident (more than 1 year) of Doneguebougou, Mali or surrounding villages.
  4. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
  5. In good general health and without clinically significant medical history in the opinion of the investigator.
  6. Females of childbearing potential must be willing to use reliable contraception from 21 days prior to Study Day 0 and until 1 month after the last vaccination.

    • A reliable method of birth control includes one of the following:
  1. Confirmed pharmacologic contraceptives (parenteral) delivery;
  2. Intrauterine or implantable device

EXCEPTIONS to required pregnancy prevention includes the following:

1. Postmenopausal state: defined as no menses for 12 months without an alternative medical cause

2. Surgical sterilization

3. Unmarried AND not sexually active AND menstruating OR not menstruating females 12-17 years of age

4. NOTE: if a female of childbearing potential s status changes during the course of vaccination through 1 month post vaccination (e.g. they become >=18 years of age, married, or sexually active), the female will be required to start reliable contraception

7. Willing to have blood samples stored for future research.

INCLUSION CRITERIA FOR GROUP 4:

All of the following criteria must be fulfilled for a volunteer to participate in this trial:

  1. Meets age requirements for Arm currently being enrolled.
  2. Available for the duration of the trial.
  3. Family compound known resident or long-term resident (more than 1 year) of Doneguebougou, Mali or surrounding villages.
  4. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
  5. In good general health and without clinically significant medical history in the opinion of the investigator.
  6. Willing to have blood samples stored for future research.

EXCLUSION CRITERIA FOR GROUPS 1, 2, 3:

An individual will be excluded from participating in this trial if any one of the following criteria is fulfilled:

  1. Pregnant, as determined by a positive urine or serum beta human choriogonadotropin (beta-hCG) test (if female).

    NOTE: Pregnancy is also a criterion for discontinuation of any further vaccine dosing

  2. Menstruating females 11 years of age and younger. (In order to avoid cultural implications of further assessing pregnancy potential i.e. sexual activity in this age group.)
  3. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and comply with the study protocol at a level appropriate for the subject s age.
  4. Hemoglobin, white blood cell (WBC), absolute neutrophil count, or platelet levels 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 <= Grade 2.)
  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 <= Grade 2.)
  6. Infected with HIV
  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. Clinically significant prolonged QTc (by sex/age) on screening EKG
  9. History of receiving any investigational product within the past 30 days.
  10. Current or planned participation in an investigational vaccine study until the last required protocol visit.
  11. Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.
  12. History of a severe allergic reaction or anaphylaxis.
  13. Known:

    • 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.
    • Autoimmune or antibody-mediated disease including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj(SqrRoot)(Delta)gren s syndrome, or autoimmune thrombocytopenia.
    • Immunodeficiency syndrome.
    • Seizure disorder (exception: history of simple febrile seizures)
    • Asplenia or functional asplenia.
    • Use of chronic (>=14 days) oral or intravenous (IV) corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of Study Day 0.
    • Allergy to latex or neomycin
    • Adverse reaction to hepatitis A and/or typhoid vaccine in the past
    • Adverse reaction to artemether/lumefantrine in the past
  14. Receipt of:

    • Live vaccine within the past 4 weeks or a killed vaccine within the past 2 weeks to enrollment.
    • Immunoglobulins and/or blood products within the past 6 months.
    • Investigational malaria vaccine in the last 2 years.
  15. Any other condition that in the opinion of the investigator would jeopardize the safety or rights of a subject participating in the trial, interfere with the evaluation of the study objectives, or would render the subject unable to comply with the protocol.

Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than enrollment on observational studies. Consideration for co-enrollment in trials evaluating the use of a licensed medication will require the approval of the PI. Study staff should be notified of co-enrollment on any other protocol as it may require the approval of the investigator.

Exclusion Criteria for Group 4:

An individual will be excluded from participating in this trial if any one of the following criteria is fulfilled:

1. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and comply with the study protocol at a level appropriate for the subject s age.

2. 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.

3. Clinically significant prolonged QTc (by sex/age) on screening EKG

4. History of adverse reactions to artemether/lumefantrine in the past

5. History of receiving any investigational product within the past 30 days.

6. Current or planned participation in an investigational vaccine study until the last required protocol visit.

7. Receipt of:

  • Investigational malaria vaccine in the last 2 years.

    8. Any other condition that in the opinion of the investigator would jeopardize the safety or rights of a subject participating in the trial, interfere with the evaluation of the study objectives, or would render the subject unable to comply with the protocol.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03917654


Contacts
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Contact: Patrick E Duffy, M.D. (301) 761-5089 duffype@niaid.nih.gov

Locations
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Mali
Mrtc/Usttb Recruiting
Bamako, Mali
Contact: Issaka Sagara, M.D.    Not Listed    isagara@mrtcbko.org   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Patrick E Duffy, M.D. National Institute of Allergy and Infectious Diseases (NIAID)

Publications:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03917654     History of Changes
Other Study ID Numbers: 999919086
19-I-N086
First Posted: April 17, 2019    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: April 30, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Randomized
Assays
Blood Smear
Antibody
Parasites

Additional relevant MeSH terms:
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Vaccines
Immunologic Factors
Physiological Effects of Drugs