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
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
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.
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
 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 approximately 137 compounds/vaccine units (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 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 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.

 In Year 2, those who received vaccination during Year 1 (5 years of age and older at
 enrollment), if eligible and still on study, will receive a single fourth vaccination per
 their vaccine unit (VU) blinded arm assignment. No new individuals will be enrolled. Again,
 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 BS along with all vaccinated children. Children 9-18 years of
 age will also be assessed for vaccine efficacy against parasitemia, but as a separate
 analysis from those 1-8 years of age. Immunogenicity outcomes will be antibody responses as
 measured by 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 DSF starting 2 weeks
 post vaccination #4 for a total of 10 DSFs.
-  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.

 Inclusion Criteria for Groups 1, 2, 3, (Year 2)

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

 1. Previously enrolled in the study and has received at least 1 vaccination. 2. Available
 for the duration of the trial.

 3. In good general health and without clinically significant medical history in the opinion
 of the investigator.

 4. Females of childbearing potential must be willing to use reliable contraception from 21
 days prior to scheduled vaccine dose #4 and until 1 month after the 4th 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 menstruatingOR 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 greater than or equal
 to 18 years of age, married, or sexually active), the female will be required to start
 reliable contraception

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

 Inclusion Criteria for Group 4 (Year 2):

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

 1. Previously enrolled in the study

 2. Available for the duration of the trial.

 3. In good general health and without clinically significant medical history in the
 opinion of the investigator.

 4. 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 (>450 milliseconds) 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 and/or meningococcal 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.

 Exclusion Criteria for Groups 1, 2, 3 (Year 2):

 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 less than or equal to 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 less than or equal to
 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. History of receiving any investigational product within the past 30 days.

 9. Medical, occupational, or family problems as a result of alcohol or illicit drug use
 during the past 12 months.

 10. History of a severe allergic reaction or anaphylaxis.

 11. 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, Sjogren s syndrome, or
 autoimmune thrombocytopenia.

 -  Immunodeficiency syndrome.

 -  Seizure disorder (exception: history of simple febrile seizures)

 -  Asplenia or functional asplenia.

 -  Use of chronic (greater than or equal to 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 and/or meningococcal vaccine in
 the past

 -  Adverse reaction to artemether/lumefantrine in the past

 12. 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.

 13. 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.

 Exclusion Criteria for Group 4 (Year 2):

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

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

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

 6. Receipt of:

 -  Investigational malaria vaccine in the last 2 years.

 7. 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.