A Phase 2 interventional study of R21 Matrix-M (R21/MM) Malaria Vaccine and Placebo in Malaria Vaccines, sponsored by PATH. Recruiting at 2 sites in Burkina Faso. Open to participants aged 42 Days to 49 Days, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-05-15.
Sponsored by PATH · Phase 2, Interventional, and Prevention
The aim of this study is to identify an optimal infant vaccine schedule for a malaria vaccine which is better aligned with the timing of other vaccine interventions.
The R21/Matrix-M (R21/MM) vaccine has been recommended by the World Health Organization (WHO) to prevent clinical malaria in young children living in moderate to high transmission areas of Sub-Saharan Africa. R21/MM is based on the circumsporozoite protein (CSP) targeting the pre-erythrocytic stage of Plasmodium falciparum. R21/MM elicits high levels of antibodies against the central repeat (Asn-Ala-Asn-Pro [NANP]) of the circumsporozoite protein (CSP) which has been shown to correlate with protection. Currently, R21/MM is recommended to be delivered to young children starting at 5-6 months of age with 3 doses given at monthly intervals, however, there are no existing Essential Programme on Immunization (EPI) vaccine visits scheduled at these ages.
We plan to evaluate, using the R21/MM malaria vaccine as a model system, how age at first vaccine dose and time intervals between doses modify the immunogenicity of the vaccine.
Healthy male or female infants 6 to 7 weeks of age will be randomized to one of three different immunization schedule cohorts: a) a "compressed" conventional schedule at 6-10-14 weeks of age; b) a "relaxed" schedule at 2-4-6 months of age; c) a "relaxed" schedule at 3-6-9 months of age.
In the original study design (Part A of the study), participants in each immunization schedule cohort were randomized in a ratio of 3:1 to receive either R21/MM or placebo - up until September 1, 2025, where upon confirmation of R21/MM rollout into the EPI schedule in the study districts, all participants already enrolled in the "relaxed" 2-4-6 month and "relaxed" 3-6-9 month schedules who had not yet received the first study vaccination, were assigned automatically to receive open-label R21/MM. Recruitment into the study was also paused while the protocol amendment with the revised study design was being developed. At the time of the recruitment being paused, the study had enrolled 644 participants.
All study participants enrolled during Part A of the study were unblinded as they approached 5 months of age and those who were randomized to the placebo arms had all study procedures discontinued, and were referred to local EPI clinics to receive R21/MM vaccinations and withdrawn from the study. Participants who had been randomized and who had received R21/MM at their first study vaccination, were kept on study and continued to receive open-label R21/MM, as per the protocol.
In Part B of the study, as per the revised study design, an additional 320 infants will be enrolled and randomized to the "compressed" 6-10-14 weeks (Cohort 1), "relaxed" 2-4-6 month (Cohort 2) and "relaxed" 3-6-9 month (Cohort 3) immunization schedules initially in a 2:1:1 ratio. Participants enrolled into Cohorts 2 and 3 will all be assigned to receive open-label R21/MM, while those enrolled into Cohort 1 will be randomized (blinded) 1:1 to receive 3 doses of either R21/MM or placebo. Once participants in Cohort 1 complete their 28 day post-3rd dose visit, they will be unblinded. Participants randomized to placebo will rollover to a new cohort, Cohort 4, to receive 3 doses of R21/MM on a 5-6-7-month schedule, aligning with WHO guidelines. Participants randomized into the "relaxed" 2-4-6 month schedule (Cohort 2) and "relaxed" 3-6-9 month schedule (Cohort 3) will receive 3 doses of open-label R21/MM; no placebo participants will be enrolled into Cohorts 2 and 3.
Infants randomized to the respective immunization schedule categories will receive co-administered routine EPI vaccines and participants in all cohorts will receive a 4th dose of R21/MM at Month 15.
Exclusion Criteria:
(Note: In case of acute disease, participants may be re-assessed by a study physician for resolution of the condition and enrolled if eligible and still within the visit window).
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV). Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
Biological: R21 Matrix-M (R21/MM) Malaria Vaccine · Biological: Hexavalent Vaccine · Biological: Pneumococcal Polysaccharide Conjugate Vaccine · Biological: Rotavirus, Live Attenuated (Oral) Vaccine · Biological: Measles and Rubella Vaccine · Biological: Meningococcal (A, C, Y, W, X) polysaccharide conjugate vaccine · Biological: Yellow Fever vaccine · Biological: Typhoid Conjugate vaccine
Participants will receive placebo at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, PCV, and oral RV. After completion of the 28 day post-Dose 3 visit, these participants will rollover to Cohort 4 (Group 7) to then receive open-label R21/MM vaccine as per the "recommended" schedule at 5-6-7 months of age. At 9 months of age participants will receive MR and YF vaccines and TCV. Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
Biological: R21 Matrix-M (R21/MM) Malaria Vaccine · Biological: Placebo · Biological: Hexavalent Vaccine · Biological: Pneumococcal Polysaccharide Conjugate Vaccine · Biological: Rotavirus, Live Attenuated (Oral) Vaccine · Biological: Measles and Rubella Vaccine · Biological: Meningococcal (A, C, Y, W, X) polysaccharide conjugate vaccine · Biological: Yellow Fever vaccine · Biological: Typhoid Conjugate vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV. Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
Biological: R21 Matrix-M (R21/MM) Malaria Vaccine · Biological: Hexavalent Vaccine · Biological: Pneumococcal Polysaccharide Conjugate Vaccine · Biological: Rotavirus, Live Attenuated (Oral) Vaccine · Biological: Measles and Rubella Vaccine · Biological: Meningococcal (A, C, Y, W, X) polysaccharide conjugate vaccine · Biological: Yellow Fever vaccine · Biological: Typhoid Conjugate vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV. Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
Biological: R21 Matrix-M (R21/MM) Malaria Vaccine · Biological: Hexavalent Vaccine · Biological: Pneumococcal Polysaccharide Conjugate Vaccine · Biological: Rotavirus, Live Attenuated (Oral) Vaccine · Biological: Measles and Rubella Vaccine · Biological: Meningococcal (A, C, Y, W, X) polysaccharide conjugate vaccine · Biological: Yellow Fever vaccine · Biological: Typhoid Conjugate vaccine
Administered by intramuscular injection. Each 0.5 mL dose contains R21 Malaria Antigen (5 mcg) and Matrix-M1 (Adjuvant) (50 mcg).
Administered by intramuscular injection. Each dose (0.5 mL) contains Normal saline (0.9%).
Administered by intramuscular injection. Each dose of 0.5 mL contains: * Diphtheria Toxoid \> 30 IU * Tetanus Toxoid \> 40 IU * B. pertussis (whole cell) \> 4 IU * Hepatitis B surface antigen (HBsAg) (recombinant DNA) 15 mcg * Inactivated polio vaccine (Salk strains grown on vero cells): Type - 1 (Mahoney strain) 40 D antigen units (DU); Type - 2 (MEF-1 strain) 8 DU; Type - 3 (Saukett strain) 32 DU * Haemophilus influenzae Type b (Hib) Conjugate Vaccine (Adsorbed) polyribosylribitol phosphate (PRP) 10 mcg conjugated to tetanus toxoid (TT) (carrier protein) 19 to 33 mcg\]
Also known as: HEXASIIL
Administered by intramuscular injection. Each 0.5 mL dose contains 2 mcg each Saccharide for serotypes 1, 5, 9V, 14, 19A, 19F, 23F, 7F, 6A and 4 mcg Saccharide for serotype 6B.
Also known as: PNEUMOSIL
Administered orally. Each 2.0 mL dose contains: Live Attenuated Bovine-Human Rotavirus Reassortant \[G1, G2, G3, G4 and G9\], 5.6 focus-forming units (FFU) / serotype.
Also known as: ROTASIIL
Administered by subcutaneous injection. Each 0.5 mL dose contains not less than 1000 cell culture infectious dose 50% (CCID50) of Measles virus and 1000 CCID50 of Rubella virus.
Administered by intramuscular injection. Each 0.5 mL dose contains 5 mcg of each Meningococcal A, C, Y, W, and X polysaccharide, 7.8 to 33.4 mcg of TT and 11.7 to 50.1 mcg of recombinant CRM197.
Yellow fever vaccine will be locally sourced by each trial site in accordance with the countries' EPI program.
Typhoid conjugate vaccine will be locally sourced by each trial site in accordance with the countries' EPI program.
Geometric Mean Titers (GMTs) of Anti-circumsporozoite (CS) Immunoglobulin G (IgG) at Baseline and 28 Days after 3rd Vaccine Dose
The anti-CS antibody responses elicited following the primary 3-dose schedule of R21/MM will be assessed in the "compressed" (6-10-14 week) immunization schedule and the two "relaxed" (2-4-6 month and 3-6-9 month) immunization schedule cohorts.
Time frame: Baseline and 28 days after 3rd vaccine dose
Geometric Mean Fold Rise (GMFR) in Anti-CS IgG 28 Days after 3rd Vaccine Dose Compared to Baseline
The anti-CS antibody responses elicited following the primary 3-dose schedule of R21/MM will be assessed in the "compressed" (6-10-14 week) immunization schedule and the two "relaxed" (2-4-6 month and 3-6-9 month) immunization schedule cohorts.
Time frame: Baseline and 28 days after 3rd vaccine dose
Number of Participants with Solicited Adverse Events
Local (redness, swelling, and pain at the injection site) and systemic (fever, drowsiness, irritability, decreased appetite) reactions will be collected in a subset of participants (the first 40 participants in each immunization schedule category at each site).
Time frame: 7 days after each study vaccination
Number of Participants with Unsolicited Adverse Events
Time frame: 28 days after each study vaccination
Number of Participants with Serious Adverse Events
Time frame: Up to 28 days post 4th vaccine dose.
Number of Participants with Adverse Events of Special Interest
Time frame: Up to 28 days post 4th vaccine dose.
Geometric Mean Titers (GMTs) of Anti-CS IgG Before and 28 Days After 4th Vaccine Dose
The anti-CS antibody responses elicited following the 4th dose of R21/MM will be assessed in the "compressed" (6-10-14 week) immunization schedule and the two "relaxed" (2-4-6 month and 3-6-9 month) immunization schedule cohorts.
Time frame: Month 15 predose and 28 days after vaccination
GMFR in Anti-CS IgG Titer Post 4th Dose Compared to Pre-4th Dose
The anti-CS antibody responses elicited following the 4th dose of R21/MM will be assessed in the "compressed" (6-10-14 week) immunization schedule and the two "relaxed" (2-4-6 month and 3-6-9 month) immunization schedule cohorts.
Time frame: Month 15 predose and 28 days after 4th dose
Plan to share: Yes — PATH as the Sponsor of the Clinical Study will post the Clinical Trial Data in compliance with the Gates Foundation's Open Access policy and the WHO Joint Statement on Clinical Transparency. The Clinical Trial Data will contain no personally identifiable information (PII) and will be fully anonymized and de-identified.
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