A Phase III randomized controlled multi-centre trial to evaluate the efficacy of the R21/Matrix-M vaccine in African children against clinical malaria

This will be a double-blind, individually randomised trial. In the first phase of the trial, participants were randomised 2:1 to receive R21/Matrix-M malaria vaccine or a control rabies vaccine (Abhayrab). The study groups are as follows:

Standard vaccination regime, 5-36 months olds R21/Matrix-M x 3, n = 1600 Control (rabies) vaccine x 3, n = 800

Seasonal vaccination regime, 5-36 month olds R21/Matrix-M x 3, n = 1600 Control (rabies) vaccine x 3, n = 800

In each group, a booster (4th) dose of the same vaccine will be administered 12 months after the third dose. At certain trial sites, participants in the malaria vaccine group may be further randomised 1:1 to receive a single-vial: two-vial formulation of R21/Matrix-M.

The trial has been extended for two further years to assess safety and efficacy over a longer period of time. During this time, it will also assess the safety, immunogenicity and efficacy of second and third booster doses.

One year after the first booster (fourth dose), participants in the R21/Matrix-M arm will be further randomised 1:1:1:1 to four groups to receive:

1. No booster doses (total of 4 doses of R21/Matrix-M).
2. One booster dose, one year after the first booster dose (total of 5 doses of R21/Matrix-M)
3. One booster dose, two years after the first booster dose (total of 5 doses of R21/Matrix-M)
4. Two booster doses, one year apart (total of 6 doses of R21/Matrix-M)

Participants who are not receiving R21/Matrix-M, will receive a control vaccine at the relevant time point of vaccine administration The control vaccine for the second and the third booster will be a licensed Hepatitis A vaccine.

Participants will be followed up for 12 months after their third booster.

2400 participants will be enrolled for the standard vaccination regime in: Dande, Burkina Faso; Kilifi, Kenya; and Bagamoyo, Tanzania.

In addition, a further 2400 participants will be enrolled for the seasonal vaccination regime in Nanoro, Burkina Faso and Bougouni, Mali.

Study population

Standard vaccination regime:

5-36 month old children living permanently in the study area who are eligible.

Seasonal vaccination regime:

5-36 month old children living permanently in the study area who are eligible.

Primary study objectives

Efficacy:

• To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-36 month old children living in a malaria endemic area, 12 months after completion of the primary course (standard vaccination regime).
• To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-36 month old children living in a malaria endemic area, 12 months after completion of the primary course (seasonal vaccination regime).

Safety:

• To assess the safety and reactogenicity of R21/Matrix-M, in both vaccination regimes, of children living in a malaria endemic area, in the month following each vaccination, and 12 months after completion of the primary course.

Secondary objectives

• Efficacy against clinical malaria after each booster vaccination
• Efficacy against clinical malaria after the primary series and booster vaccination, regardless of vaccination regime
• Efficacy against asymptomatic P. falciparum infection.
• Efficacy against severe malaria disease.
• Efficacy according to different transmission settings.
• Efficacy against incident severe anaemia, blood transfusion requirement and malaria hospitalisation.
• Safety and reactogenicity (including Serious adverse events (SAEs) and any deaths) following each booster vaccination and for the duration of the study.
• Assessment of humoral immunogenicity by anti-CSP antibody concentrations measured 12 months after completion of the primary series of 3 vaccinations and 12 months after booster vaccinations.
• Safety, immunogenicity and efficacy of a single- vial formulation of R21/Matrix-M

This trial is funded by the Serum Institute of India.

The trial has been extended in 2025 for a further two years in both seasonal sites (Nanoro, Burkina Faso and Bougouni, Mali) and one standard site (Dande, Burkina Faso) when children will be of school age.

In this extension, participants who received 4 doses of R21/Matrix-M in the previous part of the trial will be randomised to receive a 5th dose of R21/Matrix-M or a control vaccine and will be followed up for 2 years. Participants in the control group from the previous part of the trial will receive one dose of a control vaccine and will be followed up for 2 years. Participants who have received 5 or 6 doses of R21/Matrix-M will not receive further vaccinations but will be followed up for two more years, (a total of 3 years since the last vaccination (R21/Matrix-M or control vaccine)).

Inclusion Criteria:

All participants must satisfy the following criteria at study entry:

• The child is 5-36 months of age at the time of first vaccination.
• Signed informed consent/thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child to join the trial.
• The investigator believes that the parents/guardians can and will comply with the requirements of the protocol if the child is enrolled in the study.
• The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial.

Exclusion Criteria:

The following criteria should be checked at the time of study entry. If any apply, the participant must not be included:

• The child has previously received a malaria vaccine.
• The child is enrolled in another malaria intervention trial.
• The child has a history of allergic disease or reactions likely to be exacerbated by any component of the malaria or control vaccine.
• The child has a history of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunisations.
• The child has major congenital defects.
• The child has anaemia associated with clinical signs of symptoms of decompensation, or a haemoglobin of ≤ 5.0 g/dL.
• The child has had a blood transfusion within one month of enrolment.
• The child has been administered immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate.
• The child has malnutrition requiring hospital admission.
• The child has an acute or chronic, clinically significant pulmonary, cardiovascular, gastrointestinal, endocrine, neurological, skin, hepatic or renal functional abnormality, as determined by medical history, physical examination or laboratory tests.
• Children currently meeting the WHO criteria for HIV disease of stage 3 or 4 severity. A previous history of stage 3 or 4 disease is not an exclusion. Note: There will be no routine testing for HIV. Positive diagnoses will be recorded at screening if known.
• The child has received an investigational drug or vaccine other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
• The child is currently participating in another clinical trial if likely to affect data interpretation of this trial
• The child has any significant disease, disorder or situation which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

Additional exclusion criteria for second phase of the trial (addition of second and third booster doses)

- Hypersensitivity to neomycin (Hepatitis A vaccine may contain traces of this).

Double blind