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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

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ClinicalTrials.gov Identifier: NCT02942277
Recruitment Status : Enrolling by invitation
First Posted : October 24, 2016
Last Update Posted : August 22, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

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.


Condition or disease Intervention/treatment Phase
Malaria Biological: Pfs25M-EPA/AS01 Biological: Pfs230D1M-EPA/AS01 Other: AS01 Biological: Bexsero (Comparator Vaccine) Biological: Fluarix Other: Normal Saline Drug: Coartem Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 591 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
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 Start Date : October 21, 2016
Estimated Primary Completion Date : July 31, 2019
Estimated Study Completion Date : January 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: 1a
(n=5), to receive 16 microgram Pfs25M-EPA/AS01 on D0, D28, D168 (Bamako)
Biological: Pfs25M-EPA/AS01
Pfs25, a surface antigen of zygotes and ookinetes in the mosquito stages of P.falciparum, is a lead candidate for developing a malaria transmission blocking vaccine. Recombinant Pfs25M was expressed in Pichia pastoris (P.pastoris). Recombinant ExoProtein A (EPA), a mutant, non-toxic protein corresponding to sequence of EPA of Pseudomonas aeruginosa (P.aeruginosa), was expressed in E.coli. Pfs25M and EPA were chemically crosslinked to form Pfs25M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs25M for a final formulation of either 16mcg conjugated Pfs25M, 15mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 1a, 3a or 47mcg conjugated Pfs25M, 45mcg conjugated EPA in AS01 for Arms 1b, 3b, 3c, 3d. The fractional dose (Dose3) in Arm 3d will be 1/5th of the 47mcg conjugated Pfs25M dose in AS01 (final formulation of 9.4mcg conjugated Pfs25M, 3mcg conjugated EPA in AS01 [5mcg MPL+5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Experimental: 1b
(n=10), to receive 47 microgram Pfs25M-EPA/AS01 on D0, D28, D168 (Bamako)
Biological: Pfs25M-EPA/AS01
Pfs25, a surface antigen of zygotes and ookinetes in the mosquito stages of P.falciparum, is a lead candidate for developing a malaria transmission blocking vaccine. Recombinant Pfs25M was expressed in Pichia pastoris (P.pastoris). Recombinant ExoProtein A (EPA), a mutant, non-toxic protein corresponding to sequence of EPA of Pseudomonas aeruginosa (P.aeruginosa), was expressed in E.coli. Pfs25M and EPA were chemically crosslinked to form Pfs25M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs25M for a final formulation of either 16mcg conjugated Pfs25M, 15mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 1a, 3a or 47mcg conjugated Pfs25M, 45mcg conjugated EPA in AS01 for Arms 1b, 3b, 3c, 3d. The fractional dose (Dose3) in Arm 3d will be 1/5th of the 47mcg conjugated Pfs25M dose in AS01 (final formulation of 9.4mcg conjugated Pfs25M, 3mcg conjugated EPA in AS01 [5mcg MPL+5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Experimental: 2a
(n=5), to receive 13 microgram Pfs230D1M-EPA/AS01 on D0, D28, D168 (Bamako
Biological: Pfs230D1M-EPA/AS01
Pfs230 is a malaria parasite antigen expressed in gametocytes and on the surface of emerging gametes in the mosquito host and is also a TBV target. Recombinant Pfs230D1M was expressed in P. pastoris. Recombinant EPA was expressed in E. coli. Pfs230D1M and EPA were chemically crosslinked to form Pfs230D1M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs230D1M for a final formulation of either 13mcg conjugated Pfs230D1M, 10mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 2a, 3a or 40mcg conjugated Pfs230D1M, 31mcg conjugated EPA in AS01 for Arms 2b, 3b, 3c, 3d. The fractional dose (Dose #3) in Arm 3d will be 1/5th of the Pfs230D1M dose in AS01 (final formulation of 8mcg conjugated Pfs25M, 2mcg conjugated EPA in AS01 [5mcg MPL+ 5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Experimental: 2b
(n=10), to receive 40 microgram Pfs230D1M-EPA/AS01 on D0, D28, D168 (Bamako
Biological: Pfs230D1M-EPA/AS01
Pfs230 is a malaria parasite antigen expressed in gametocytes and on the surface of emerging gametes in the mosquito host and is also a TBV target. Recombinant Pfs230D1M was expressed in P. pastoris. Recombinant EPA was expressed in E. coli. Pfs230D1M and EPA were chemically crosslinked to form Pfs230D1M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs230D1M for a final formulation of either 13mcg conjugated Pfs230D1M, 10mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 2a, 3a or 40mcg conjugated Pfs230D1M, 31mcg conjugated EPA in AS01 for Arms 2b, 3b, 3c, 3d. The fractional dose (Dose #3) in Arm 3d will be 1/5th of the Pfs230D1M dose in AS01 (final formulation of 8mcg conjugated Pfs25M, 2mcg conjugated EPA in AS01 [5mcg MPL+ 5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Experimental: 3a
(n=5), to receive 16 microgram Pfs25M-EPA/AS01 and 13 microgram Pfs230D1M-EPA/AS01 on D0, D28, D168(Bamako)
Biological: Pfs25M-EPA/AS01
Pfs25, a surface antigen of zygotes and ookinetes in the mosquito stages of P.falciparum, is a lead candidate for developing a malaria transmission blocking vaccine. Recombinant Pfs25M was expressed in Pichia pastoris (P.pastoris). Recombinant ExoProtein A (EPA), a mutant, non-toxic protein corresponding to sequence of EPA of Pseudomonas aeruginosa (P.aeruginosa), was expressed in E.coli. Pfs25M and EPA were chemically crosslinked to form Pfs25M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs25M for a final formulation of either 16mcg conjugated Pfs25M, 15mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 1a, 3a or 47mcg conjugated Pfs25M, 45mcg conjugated EPA in AS01 for Arms 1b, 3b, 3c, 3d. The fractional dose (Dose3) in Arm 3d will be 1/5th of the 47mcg conjugated Pfs25M dose in AS01 (final formulation of 9.4mcg conjugated Pfs25M, 3mcg conjugated EPA in AS01 [5mcg MPL+5mcg QS21 liposomal formulation]).

Biological: Pfs230D1M-EPA/AS01
Pfs230 is a malaria parasite antigen expressed in gametocytes and on the surface of emerging gametes in the mosquito host and is also a TBV target. Recombinant Pfs230D1M was expressed in P. pastoris. Recombinant EPA was expressed in E. coli. Pfs230D1M and EPA were chemically crosslinked to form Pfs230D1M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs230D1M for a final formulation of either 13mcg conjugated Pfs230D1M, 10mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 2a, 3a or 40mcg conjugated Pfs230D1M, 31mcg conjugated EPA in AS01 for Arms 2b, 3b, 3c, 3d. The fractional dose (Dose #3) in Arm 3d will be 1/5th of the Pfs230D1M dose in AS01 (final formulation of 8mcg conjugated Pfs25M, 2mcg conjugated EPA in AS01 [5mcg MPL+ 5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Experimental: 3b
(n=10), to receive 47 microgram Pfs25M-EPA/AS01 and 40 microgram Pfs230D1M-EPA/AS01 on D0, D28, D168 (Bamako)
Biological: Pfs25M-EPA/AS01
Pfs25, a surface antigen of zygotes and ookinetes in the mosquito stages of P.falciparum, is a lead candidate for developing a malaria transmission blocking vaccine. Recombinant Pfs25M was expressed in Pichia pastoris (P.pastoris). Recombinant ExoProtein A (EPA), a mutant, non-toxic protein corresponding to sequence of EPA of Pseudomonas aeruginosa (P.aeruginosa), was expressed in E.coli. Pfs25M and EPA were chemically crosslinked to form Pfs25M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs25M for a final formulation of either 16mcg conjugated Pfs25M, 15mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 1a, 3a or 47mcg conjugated Pfs25M, 45mcg conjugated EPA in AS01 for Arms 1b, 3b, 3c, 3d. The fractional dose (Dose3) in Arm 3d will be 1/5th of the 47mcg conjugated Pfs25M dose in AS01 (final formulation of 9.4mcg conjugated Pfs25M, 3mcg conjugated EPA in AS01 [5mcg MPL+5mcg QS21 liposomal formulation]).

Biological: Pfs230D1M-EPA/AS01
Pfs230 is a malaria parasite antigen expressed in gametocytes and on the surface of emerging gametes in the mosquito host and is also a TBV target. Recombinant Pfs230D1M was expressed in P. pastoris. Recombinant EPA was expressed in E. coli. Pfs230D1M and EPA were chemically crosslinked to form Pfs230D1M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs230D1M for a final formulation of either 13mcg conjugated Pfs230D1M, 10mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 2a, 3a or 40mcg conjugated Pfs230D1M, 31mcg conjugated EPA in AS01 for Arms 2b, 3b, 3c, 3d. The fractional dose (Dose #3) in Arm 3d will be 1/5th of the Pfs230D1M dose in AS01 (final formulation of 8mcg conjugated Pfs25M, 2mcg conjugated EPA in AS01 [5mcg MPL+ 5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Experimental: 3c
(n=60), to receive 47 microgram Pfs25M-EPA/AS01 and 40 microgram Pfs230D1M-EPA/AS01 on D0, D28, D168 (Bancoumana & Doneguebougou)
Biological: Pfs25M-EPA/AS01
Pfs25, a surface antigen of zygotes and ookinetes in the mosquito stages of P.falciparum, is a lead candidate for developing a malaria transmission blocking vaccine. Recombinant Pfs25M was expressed in Pichia pastoris (P.pastoris). Recombinant ExoProtein A (EPA), a mutant, non-toxic protein corresponding to sequence of EPA of Pseudomonas aeruginosa (P.aeruginosa), was expressed in E.coli. Pfs25M and EPA were chemically crosslinked to form Pfs25M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs25M for a final formulation of either 16mcg conjugated Pfs25M, 15mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 1a, 3a or 47mcg conjugated Pfs25M, 45mcg conjugated EPA in AS01 for Arms 1b, 3b, 3c, 3d. The fractional dose (Dose3) in Arm 3d will be 1/5th of the 47mcg conjugated Pfs25M dose in AS01 (final formulation of 9.4mcg conjugated Pfs25M, 3mcg conjugated EPA in AS01 [5mcg MPL+5mcg QS21 liposomal formulation]).

Biological: Pfs230D1M-EPA/AS01
Pfs230 is a malaria parasite antigen expressed in gametocytes and on the surface of emerging gametes in the mosquito host and is also a TBV target. Recombinant Pfs230D1M was expressed in P. pastoris. Recombinant EPA was expressed in E. coli. Pfs230D1M and EPA were chemically crosslinked to form Pfs230D1M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs230D1M for a final formulation of either 13mcg conjugated Pfs230D1M, 10mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 2a, 3a or 40mcg conjugated Pfs230D1M, 31mcg conjugated EPA in AS01 for Arms 2b, 3b, 3c, 3d. The fractional dose (Dose #3) in Arm 3d will be 1/5th of the Pfs230D1M dose in AS01 (final formulation of 8mcg conjugated Pfs25M, 2mcg conjugated EPA in AS01 [5mcg MPL+ 5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Drug: Coartem
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. All antimalarial medications used for the study, including Coartem which is used for pre-emptive treatment of all subjects in Arms and will be maintained at the study site. Coartem(R) will be provided as tablets for oral administration; and will be purchased from commercial sources and provided by the MRTC study team to subjects.

Experimental: 3d
(n=60), to receive 47 microgram Pfs25M-EPA/AS01 and 40 g Pfs230D1M-EPA/AS01 on D0, D28, then 9 microgram Pfs25M-EPA/AS01 and 8 microgram Pfs230D1M-EPA/AS01 (fractional dose) on D168 (Bancoumana & Doneguebougou)
Biological: Pfs25M-EPA/AS01
Pfs25, a surface antigen of zygotes and ookinetes in the mosquito stages of P.falciparum, is a lead candidate for developing a malaria transmission blocking vaccine. Recombinant Pfs25M was expressed in Pichia pastoris (P.pastoris). Recombinant ExoProtein A (EPA), a mutant, non-toxic protein corresponding to sequence of EPA of Pseudomonas aeruginosa (P.aeruginosa), was expressed in E.coli. Pfs25M and EPA were chemically crosslinked to form Pfs25M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs25M for a final formulation of either 16mcg conjugated Pfs25M, 15mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 1a, 3a or 47mcg conjugated Pfs25M, 45mcg conjugated EPA in AS01 for Arms 1b, 3b, 3c, 3d. The fractional dose (Dose3) in Arm 3d will be 1/5th of the 47mcg conjugated Pfs25M dose in AS01 (final formulation of 9.4mcg conjugated Pfs25M, 3mcg conjugated EPA in AS01 [5mcg MPL+5mcg QS21 liposomal formulation]).

Biological: Pfs230D1M-EPA/AS01
Pfs230 is a malaria parasite antigen expressed in gametocytes and on the surface of emerging gametes in the mosquito host and is also a TBV target. Recombinant Pfs230D1M was expressed in P. pastoris. Recombinant EPA was expressed in E. coli. Pfs230D1M and EPA were chemically crosslinked to form Pfs230D1M-EPA conjugate. AS01B will be mixed directly with the vialed conjugated Pfs230D1M for a final formulation of either 13mcg conjugated Pfs230D1M, 10mcg conjugated EPA in AS01 (25mcg MPL+ 25mcg QS21 liposomal formulation) for Arms 2a, 3a or 40mcg conjugated Pfs230D1M, 31mcg conjugated EPA in AS01 for Arms 2b, 3b, 3c, 3d. The fractional dose (Dose #3) in Arm 3d will be 1/5th of the Pfs230D1M dose in AS01 (final formulation of 8mcg conjugated Pfs25M, 2mcg conjugated EPA in AS01 [5mcg MPL+ 5mcg QS21 liposomal formulation]).

Other: AS01
AS01 is a liposome-based Adjuvant System containing the immunoenhancers MPL (3- Odesacyl- 4'-monophosphoryl lipid A) and QS- 21 (a saponin molecule purified from the bark extract of Quillaja saponaria Molina tree). There are two formulations in the AS01 family: AS01B Adjuvant System and AS01E Adjuvant System. While AS01B contains 50 microgram of MPL and 50 microgram of QS-21 per one human dose, AS01E contains half the quantity of each immunoenhancer, i.e. 25 microgram of MPL and 25 microgram of QS- 21. For this study, the AS01B adjuvant will be used at a diluted concentration similar to the concentration of AS01E.

Drug: Coartem
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. All antimalarial medications used for the study, including Coartem which is used for pre-emptive treatment of all subjects in Arms and will be maintained at the study site. Coartem(R) will be provided as tablets for oral administration; and will be purchased from commercial sources and provided by the MRTC study team to subjects.

Active Comparator: 4a
(n=10), to receive Bexsero on D0, D28 and Fluarix on D168 (Bamako)
Biological: Bexsero (Comparator Vaccine)
Bexsero(R) is a FDA approved vaccine manufactured by GSK and is used to prevent invasive disease caused by Neisseria meningitidis serogroup B. It is approved for use in individuals aged 10 through 25 years and also has been provided to individuals at risk of meningococcal Group B infection. The vaccine is given at the standard dose of 0.5mL each given in 2 vaccinations.

Biological: Fluarix
Fluarix(TM) is a FDA approved influenza vaccine indicated for the prevention of disease caused by influenza A. It is approved for use in persons 3 years of age and older. Fluarix(TM) is given at the standard dosing of 0.5mL in 1 vaccination.

Active Comparator: 4b
(n=10), to receive Bexsero on D0, D28 and Fluarix on D168 (Bamako)
Biological: Bexsero (Comparator Vaccine)
Bexsero(R) is a FDA approved vaccine manufactured by GSK and is used to prevent invasive disease caused by Neisseria meningitidis serogroup B. It is approved for use in individuals aged 10 through 25 years and also has been provided to individuals at risk of meningococcal Group B infection. The vaccine is given at the standard dose of 0.5mL each given in 2 vaccinations.

Biological: Fluarix
Fluarix(TM) is a FDA approved influenza vaccine indicated for the prevention of disease caused by influenza A. It is approved for use in persons 3 years of age and older. Fluarix(TM) is given at the standard dosing of 0.5mL in 1 vaccination.

Active Comparator: 4c
(n=120), to receive Bexsero and normal saline on D0, D28 and Fluarix and normal saline on D168 (start study with Arm 3c and 3d in Bancoumana & Doneguebougou)
Biological: Bexsero (Comparator Vaccine)
Bexsero(R) is a FDA approved vaccine manufactured by GSK and is used to prevent invasive disease caused by Neisseria meningitidis serogroup B. It is approved for use in individuals aged 10 through 25 years and also has been provided to individuals at risk of meningococcal Group B infection. The vaccine is given at the standard dose of 0.5mL each given in 2 vaccinations.

Biological: Fluarix
Fluarix(TM) is a FDA approved influenza vaccine indicated for the prevention of disease caused by influenza A. It is approved for use in persons 3 years of age and older. Fluarix(TM) is given at the standard dosing of 0.5mL in 1 vaccination.

Other: Normal Saline
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.

Drug: Coartem
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. All antimalarial medications used for the study, including Coartem which is used for pre-emptive treatment of all subjects in Arms and will be maintained at the study site. Coartem(R) will be provided as tablets for oral administration; and will be purchased from commercial sources and provided by the MRTC study team to subjects.




Primary Outcome Measures :
  1. Incidence of local and systemic adverse events and SAEs (Bamako Arms 1a, 2a, 3a and Bamako Arms 1b, 2b, 3b, 4a, 4b) [ Time Frame: Assessment on Study days 0,1,3,7,14,28,29,31,35,42,56,84,112, 140,168,169,171,175,182,196,224, 252,280,308,336 ]
    Bamako Arms 1a, 2a, 3a: Assessment on Study days 0, 1, 3, 7, 14, 28, 29, 31, 35, 42, 56, 84, 112, 140, 168, 169, 171, 175, 182, 196, 224, 252, 280, 308, 336Bamako Arms 1b, 2b, 3b, 4a, 4b: Assessment on Study days 0, 1, 3, 7, 14, 28, 29, 31, 35, 42, 56, 84, 112, 140, 168, 169, 171, 175, 182, 196, 224, 252, 280, 308, 336

  2. Incidence of local and systemic adverse events and SAEs. (Field Arms 3c, 3d, 4c) [ Time Frame: Assessment of Study days - 7, 0, 1, 3, 7, 14, 28, 29, 31, 35, 42, 56, 84, 112, 140, 168, 169, 171, 175, 178, 182, 185, 189, 192, 196, 199, 203, 206, 210, 213, 217, 224, 252, 280, 308, 336 ]

Secondary Outcome Measures :
  1. To assess the antibody response to the Pfs25 and Pfs230 protein asmeasured by ELISA. (All arms) [ Time Frame: Study days - 0, 14, 28, 42, 112, 168, 182, 196, 224, 280, 336 ]
  2. To assess the functional antibody response to the Pfs25 and Pfs230protein as measured by standard membrane feeding assay (SMFA).(All arms except 1a, 2a, 3a) [ Time Frame: SMFA will be completed on all eligible subjects on study day 0 and 182. Assessment for other SMFA time points will be completed depending on associated ELISA results at time points. ]
  3. To assess the functional antibody response to the Pfs25 and Pfs230protein as measured by direct skin feeds (DSF). (Arms 3c, 3d, 4c only) [ Time Frame: Assessed twice a week from day 7 post vaccination No.3 thru day 45 post vaccination #3. If insufficient mosquitoes are available for twice a week feeds, once a week feeds will be completed on the following study days: 175, 182, 189, 196, 203, 210 ]


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.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

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): NCT02942277


Locations
Mali
Bancoumana Malaria Vaccine Center
Bamako, Mali
Doneguebougou Malaria Research Center
Bamako, Mali
Sotuba
Bamako, Mali
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Patrick E Duffy, M.D. National Institute of Allergy and Infectious Diseases (NIAID)

Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02942277     History of Changes
Other Study ID Numbers: 999917006
17-I-N006
First Posted: October 24, 2016    Key Record Dates
Last Update Posted: August 22, 2018
Last Verified: August 20, 2018

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) ):
Malaria
Reactogenicity
Antibody
Direct Skin Feed
Mosquito

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Vaccines
Artemether-lumefantrine combination
Immunologic Factors
Physiological Effects of Drugs
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents