R21/Matrix-M in African Children Against Clinical Malaria

A Phase III Randomized Controlled Multi-centre Trial to Evaluate the Efficacy of the R21/Matrix-M Vaccine in African Children Against Clinical Malaria

Institut de Recherche en Sciences de la Sante - Clinical Research Unit of Nanoro (IRSS-URCN), Nanoro, Burkina Faso, Institut de Recherche en Sciences de la Sante-Direction Regionale de l'Ouest, Malaria Research and Training Center, Bamako, Mali, KEMRI-Wellcome Trust Collaborative Research Program, Ifakara Health Institute Clinical Trial Facility, Bagamoyo Research and Training Centre, PO Box 74, Bagamoyo, Tanzania, London School of Hygiene and Tropical Medicine

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, with 2:1 randomisation with the 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 Rabies vaccine x 3, n = 800 Seasonal vaccination regime, 5-36 month olds R21/Matrix-M x 3, n = 1600 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. Initial follow-up will be for two years after dose three, with a primary analysis at 12 months after dose 3. Extension of the trial will be considered to allow for longer follow-up as indicated by the 12-month safety and efficacy data. 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 a 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 the 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 vaccination Safety, immunogenicity and efficacy of a single- vial formulation of R21/Matrix-M This trial is funded by the Serum Institute of India.

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.

The primary efficacy outcome is clinical malaria, according to the primary case definition: the presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours, and P. falciparum asexual parasitaemia >5000 parasites/μL.This will assessed separately for seasonal and standard vaccination regimes.

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.

Occurrence of solicited local reactogenicity signs and symptoms for 7 days following the vaccination. Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days following the vaccination. Occurrence of unsolicited adverse events for 28 days following the vaccination. Change from baseline for safety laboratory measures thought to be clinically significant. Occurrence of serious adverse events for the whole study duration.

Protective efficacy of R21/Matrix-M against clinical malaria caused by P.falciparum, in 5-36 month old children living in a malaria endemic area, following the primary vaccination series across both vaccination regimes and following booster vaccination.

Efficacy against clinical malaria following the primary series, regardless of vaccination regime. Efficacy against clinical malaria after a booster vaccination. This will be assessed for the seasonal vaccination regime, standard vaccination regime and across both vaccination regimes together. Clinical malaria is defined (according to the primary case definition) as the presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours, and P. falciparum asexual parasitaemia >5000 parasites/μL.

Efficacy of R21/Matrix-M against asymptomatic P.falciparum malaria infection in either vaccination regime, following the primary vaccination series and following booster vaccination.

Asymptomatic malaria, defined by: Presence of axillary temperature <37.5°C and absence history of fever within the last 24 hours AND P. falciparum asexual parasitaemia > 0 parasites/μL.

Efficacy of R21/Matrix-M against severe malaria disease in either vaccination regime, following the primary vaccination series and following booster vaccination.

Severe malaria, defined by the primary case definition: Presence of P. falciparum asexual parasitaemia > 5000 parasites/μL AND one of more of the following criteria of disease severity: Prostration Respiratory distress Blantyre coma score ≤ 2 Seizures: 2 or more Hypoglycaemia < 2.2 mmol/L Acidosis BE ≤-10.0 mmol/L Lactate ≥ 5.0 mmol/L Anaemia < 5.0 g/dL AND without any of the following diagnosis of co-morbidity Pneumonia (confirmed by X-ray) Meningitis (confirmed by Cerebrospinal Fluid examination) Sepsis (with Positive blood culture) Gastroenteritis with dehydration

Efficacy of R21/Matrix-M against clinical malaria according to different transmission settings (seasonal and standard vaccination regimes).

Clinical malaria is defined (according to the primary case definition) as the presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours, and P. falciparum asexual parasitaemia >5000 parasites/μL.

Efficacy of R21/Matrix-M against incident severe anaemia and the need for blood transfusion in both vaccination regimes following the primary vaccination series and booster vaccination.

Incident severe anaemia according to the primary case definition: Documented Hb <5.0 g/dL identified at clinical presentation in association with P. falciparum asexual parasitaemia > 5000 parasites/μL. Incident severe anaemia according to the secondary case definitions: Documented Hb <5.0 g/dL identified at clinical presentation in association with P. falciparum asexual parasitaemia > 0 parasites/μL Documented Hb <5.0 g/dL identified at clinical presentation and requirement for a blood transfusion Documented Hb <5.0 g/dL identified at clinical presentation Prevalent severe anaemia defined as: Documented Hb <5.0 g/dL Prevalent moderate anaemia defined as: Documented Hb <8.0 g/dL Prevalent mild anaemia defined as: Documented Hb <10.0 g/dl

Efficacy of R21/Matrix-M against malaria hospitalisation following the primary vaccination series and booster vaccination.

Malaria hospitalisation defined by the primary case definition: Medical hospitalisation with confirmed P. falciparum asexual parasitaemia > 5000 parasites/μL. Malaria hospitalisation defined by the secondary case definition: Medical hospitalisation which, in the judgement of the principal investigator, P. falciparum was the sole reason or major contributing factor.

Safety, reactogenicity, humoral immunogenicity and efficacy of R21/Matrix-M as a single-vial formulation, compared with the two-vial formulation.

Safety and reactogenicity of the single-vial formulation will be assessed as per the primary safety outcome (#2). Efficacy of the single-vial formulation will be assessed as per the primary efficacy outcome (#1). Immunogenicity will be assessed as per the secondary immunogenicity outcome (#11).

Safety and reactogenicity (including Serious adverse events (SAEs) and any deaths) following the booster vaccination and for the duration of the study.

Humoral immunogenicity by anti-CSP antibody concentrations measured 12 months after completion of the primary series of 3 vaccinations and 12 months after booster vaccination

Comparison of immunogenicity (antibody responses to CSP) in the R21/Matrix-M vaccination groups with those in the rabies vaccine groups and the durability of responses Serology to quantify antibodies to the vaccine components (regions of the CS antigen including the NANP repeat region and other elements of the protein as well as antibodies to HBsAg).

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.