This is a randomized, double-blind, placebo-controlled trial in 2 parts evaluating theeffect of 1-time administration of the monoclonal antibody (MAb) L9LS to healthy Malianparticipants on the immunogenicity of subsequent administration of the R21/Matrix-M™vaccine. L9LS will be administered subcutaneously (SC) for adults and infants. The studywill assess how the timing of L9LS administration impacts immunogenicity followingsubsequent intramuscular (IM) R21/Matrix-M™ vaccination. Twenty-four adult participantsand 333 infant participants will be enrolled.
In Part 1, 24 adult participants will be randomized 1:1 to receive 1800 mg of L9LS or
normal saline placebo at enrollment, followed by the R21/Matrix-M™ 3-dose initial vaccine
series starting on day 7. Adult participants will be followed at study visits 7 days
after L9LS administration and 7 days after each R21/Matrix-M™ vaccination. If no
significant safety concerns arise through 7 days after administration of the first
R21/Matrix-M™ vaccine (day 14) per an interim safety review, the study will proceed to
Part 2. There will also be study visits 28 and 84 days following the last R21/Matrix-M™
vaccine to assess immune responses.
In Part 2, 333 infant participants will be randomized into 1 of 3 cohorts, each with an
L9LS arm and a placebo arm (2:1). The individual cohorts will differ in the timing of the
R21/Matrix-M™ 3-dose initial vaccine series (7 days, 2 months, and 4 months between L9LS
and first R21/Matrix-M™ respectively). Infant participants will be followed at study
visits 7 days after L9LS administration and 7 days after each R21/Matrix-M™ vaccination,
after which they will continue to be followed every 28 days through the fourth (booster)
dose of the R21/Matrix-M™ vaccine. There will also be study visits 28 and 84 days
following the last R21/Matrix-M™ vaccine to assess immune responses. Primary study
assessments include medical history, physical examination, and blood collection to assess
antibody responses to the R21/Matrix-M™ vaccine, L9LS pharmacokinetics (PK), anti-drug
antibody (ADA) assessments, identification of Plasmodium falciparum (Pf) infection by
microscopic examination of thick blood smears and reverse transcription polymerase chain
reaction (RT-PCR), and other research laboratory evaluations.
Drug: Single dose of 1800 mg L9LS SC (12mL)
A human monoclonal antibody to protect against Plasmodium falciparum.
Other: Placebo 12 mL SC
Normal saline.
Drug: Single dose of 225 mg L9LS SC (1.5mL)
A human monoclonal antibody to protect against Plasmodium falciparum.
Other: Placebo 1.5 mL SC
Normal saline.
Inclusion Criteria:
Part 1: Healthy Adults
Individuals must meet all of the following criteria to be eligible for study
participation:
1. Male aged ≥18 and ≤50 years weighing ≥50.0 and ≤100.0 kg or female aged ≥18 and ≤50
years weighing ≥45.0 and ≤90.0 kg.
2. Able to provide proof of identity to the satisfaction of the study clinician
completing the enrollment process.
3. In good general health and without clinically significant medical history.
4. Able to provide informed consent.
5. Willing to have blood samples and data stored for future research.
6. Resides in or near Sotuba, Mali, and available for the duration of the study.
7. Females of childbearing potential must be willing to use reliable contraception from
21 days prior to study day 0 through the final study visit as described below.
1. Reliable methods of birth control include 1 of the following: confirmed
pharmacologic contraceptives via parenteral delivery or intrauterine or
implantable device.
2. Nonchildbearing women will be required to report date of last menstrual period,
history of surgical sterility (i.e., tubal ligation, hysterectomy) or premature
ovarian insufficiency, and will have serum pregnancy test performed per
protocol.
Part 2: Healthy Infants
Individuals must meet all of the following criteria to be eligible for study
participation:
1. Aged ≥5 and ≤12 months at enrollment.
2. Born at ≥37 weeks gestation (at term).
3. Parent and/or guardian 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.
5. Parent and/or guardian able to provide informed consent.
6. Willing to have blood samples and data stored for future research.
7. Resides in or near Sotuba, Mali, and available for the duration of the study.
Exclusion Criteria:
Part 1: Healthy Adults
Individuals meeting any of the following criteria will be excluded from study
participation:
1. Pregnancy, as determined by a positive urine or serum beta-human choriogonadotropin
test (if female).
2. Currently breastfeeding.
3. Behavioral, cognitive, or psychiatric disease that in the opinion of the
investigator affects the ability of the prospective participant to understand and
comply with the study protocol.
4. Study comprehension examination score of <80% correct or per investigator
discretion.
5. Hemoglobin, WBC, absolute neutrophil, or platelet count outside the local
laboratory-defined limits of normal. Individuals may be included at the
investigator's discretion for "not clinically significant" values.
6. ALT or creatinine (Cr) level above the local laboratory-defined upper limit of
normal. Individuals may be included at the investigator's discretion for "not
clinically significant" values.
7. Infection with HIV virus.
8. Known or documented sickle cell disease by history. (Note: Known sickle cell trait
is NOT exclusionary.)
9. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,
endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by
history, physical examination, and/or laboratory studies.
10. Receipt of any investigational product within the past 30 days.
11. Participation or planned participation in an interventional trial with an
investigational product until the last required protocol visit. (Note: Past,
current, or planned participation in observational studies is NOT exclusionary;
participation in the placebo arm of the Mali adult CIS43LS MAb trial
[ClinicalTrials.gov Identifier: NCT04329104] or L9LS MAb trials [NCT05816330] is NOT
exclusionary.)
12. Medical, occupational, or family problems as a result of alcohol or illicit drug use
during the past 12 months.
13. History of a severe allergic reaction or anaphylaxis, including history of
generalized urticaria and angioedema from prior allergic reactions.
14. Hypersensitivity to the active substances or to any of the excipients included in
the vaccines.
15. Hypersensitivity to hepatitis B vaccines.
16. 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).
17. Pre-existing autoimmune or antibody-mediated diseases including but not limited to:
systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's
syndrome, or autoimmune thrombocytopenia.
18. Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis,
sialolithiasis, salivary gland tumors).
19. Known immunodeficiency syndrome.
20. Known asplenia or functional asplenia.
21. Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at
immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs
within 30 days of day 0.
22. Receipt of a live vaccine within the past 4 weeks or a killed vaccine within the
past 2 weeks prior to study agent administration.
23. Receipt of immunoglobulins and/or blood products within the past 6 months.
24. Previous receipt of an investigational malaria vaccine or MAb in the last 5 years.
25. Other condition(s) that, in the opinion of the investigator, would jeopardize the
safety or rights of an individual participating in the trial, interfere with the
evaluation of the study objectives, or render the participant unable to comply with
the protocol.
Part 2: Healthy Infants
Individuals meeting any of the following criteria will be excluded from study
participation:
1. Body weight <5.5 kg.
2. Behavioral, cognitive, or psychiatric disease in the parent and/or guardian that in
the opinion of the investigator affects the ability of the parent and/or guardian to
understand and comply with the study protocol.
3. Any fever (≥ 37.5°C, regardless of route) or acute illness within 7 days prior to
randomization.
4. Clinically significant congenital anomaly or documented or suspected serious medical
illness (e.g., history of epilepsy), serious congenital anomaly, or immediate
life-threatening condition in the infant that may interfere with the ability to
complete study requirements, as judged by the examining clinician.
5. Prior history of a suspected or actual acute medically life-threatening event.
6. Receipt of any blood products, monoclonal or polyclonal antibody/immunoglobulin
(e.g., hepatitis B immune globulin, IV immunoglobulin), or anticipated use during
the study.
7. Any suspected or actual life-threatening acute or chronic illnesses known in the
mother during her pregnancy.
8. Parent or guardian study comprehension examination score of <80% correct or per
investigator discretion.
9. Hemoglobin, WBC, absolute neutrophil, or platelet count outside the local
laboratory-defined limits of normal. Individuals may be included at the
investigator's discretion for "not clinically significant" values.
10. ALT or Cr level above the local laboratory-defined upper limit of normal.
Individuals may be included at the investigator's discretion for "not clinically
significant" values.
11. Mother and/or infant infected with HIV.
12. Sickle cell disease by testing. (Note: Known sickle cell trait is NOT exclusionary.)
13. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,
endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by
history, physical examination, and/or laboratory studies.
14. Receipt of any investigational product within the past 30 days.
15. Participation or planned participation in an interventional trial with an
investigational product until the last required protocol visit. (Note: Past,
current, or planned participation in observational studies is NOT exclusionary.)
16. History of a severe allergic reaction or anaphylaxis, including history of
generalized urticaria and angioedema from prior allergic reactions.
17. Hypersensitivity to the active substances or to any of the excipients included in
the vaccines.
18. Hypersensitivity to hepatitis B vaccines.
19. Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis,
sialolithiasis, salivary gland tumors).
20. Pre-existing autoimmune or antibody-mediated diseases including but not limited to
systemic lupus erythematosus or autoimmune thrombocytopenia.
21. Known immunodeficiency syndrome.
22. Known asplenia or functional asplenia.
23. Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at
immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs
within 30 days of day 0.
24. Previous receipt of the R21/Matrix-MTM or RTS,S/AS01 vaccine.
25. Receipt of a live or killed vaccine within the past 1 week prior to study agent
administration.
26. Previous receipt of an investigational malaria vaccine or MAb.
27. Previous receipt of L9LS MAb by the mother.
28. Clinical signs of malnutrition.
29. Other condition(s) that, in the opinion of the investigator, might jeopardize the
safety or rights of an individual participating in the trial, interfere with the
evaluation of the study objectives, or render the participant unable to comply with
the protocol.
Sotuba Malaria Research and Training Center (MRTC)
Sotouba 2450702, Mali
Investigator: Kassoum Kayentao, MD, MPH, PhD
Contact: +223 7646 0173
kayentao@icermali.org
Kassoum Kayentao, MD, MPH, PhD
+223 7646 0173
kayentao@icermali.org
Boubacar Traore, PharmD, PhD
+223 2022 1417
bouba.traore@mrtcbko.org