A Study to Assess the Experimental Malaria Vaccines R78C and RH5.1 With Matrix-M in Combination With R21/Matrix-M

To assess the protective efficacy against clinical malaria of R78C with Matrix-M™, and the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™, in children living in a malaria-endemic area, for 6 months after the final vaccination.

Primary case definition for clinical malaria:

• 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

Secondary case definitions for clinical malaria:

• Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND EITHER P. falciparum asexual parasitaemia >0 parasites/µL OR positive RDT
• Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia >20,000 parasites/µL

The occurrence of solicited local and systemic reactogenicity signs and symptoms will be assessed for 7 days following each vaccination (day of vaccination and 6 subsequent days)

Foreseeable adverse reactions following vaccination with RH5.1, R78C or R21 and Matrix-MTM adjuvant are:

• Local reactions: pain, erythema, warmth, swelling
• Systemic reactions: drowsiness, fever, irritability/fussiness, loss of appetite

These AEs will be listed as 'solicited AEs' providing they occur within 7 days of the day of vaccination.

The occurrence of unsolicited AEs will be assessed for 7 days following each vaccination (day of vaccination and 6 subsequent days).

Unsolicited AEs' are AEs other than the foreseeable adverse reactions occurring within the first 7 days, or any AEs occurring after the first 7 days after vaccination.

For every unsolicited AE, an assessment of the relationship of the event to the administration of the vaccine will be undertaken by the PI or the PI-delegated clinician. An intervention-related AE refers to an AE for which there is a possible, probable or definite relationship to administration of a vaccine. An interpretation of the causal relationship of the intervention to the AE in question will be made, based on the type of event; the relationship of the event to the time of vaccine administration; and the known biology of the vaccine therapy

The occurrence of SAEs during the whole study duration.

An SAE is an AE that results in any of the following outcomes, whether or not considered related to the study intervention:

• Death.
• Life-threatening event. This does not include an AE that, if it occurred in a more severe form, might have caused death.
• Persistent or significant disability or incapacity.
• Hospitalisation or prolongation of hospitalisation, regardless of length of stay, even if it is a precautionary measure for continued observation. Hospitalisation for a pre-existing condition that has not worsened unexpectedly does not constitute an SAE.
• An important medical event that may, based upon appropriate medical judgment, jeopardise the volunteer and/or require medical or surgical intervention to prevent one of the outcomes listed above.
• Congenital anomaly or birth defect.

Humoral immunogenicity will be assessed from blood samples taken at various timepoints. Immunogenicity will be determined following the quantification of antigen-specific IgG antibody levels (µg/mL readout) over time, as well as by in vitro growth inhibition assays (GIA) against P. falciparum parasites using purified total IgG and a single-cycle pLDH readout assay.

The definition for clinical malaria is as follows:

• Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND EITHER P. falciparum asexual parasitaemia >0 parasites/µL OR positive RDT

or

• Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia >20,000 parasites/µL

Efficacy will be determined following the comparison of mean parasite density in each study arm

The definition for clinical malaria is as follows:

• Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND EITHER P. falciparum asexual parasitaemia >0 parasites/µL OR positive RDT

or

• Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia >20,000 parasites/µL

Efficacy will be determined following the comparison of mean parasite density in each study arm

This will be measured by looking at the following:

• Proportion of participants in each study arm that show presence of parasite density >5000 asexual forms/µL as measured by quantitative reverse-transcriptase PCR (qRT-PCR) from 14 days to 2 and 6 months after administration of the final study vaccination PLUS presence of axillary temperature <37.5°C and absence of history of fever within the last 24 hours
• Proportion of participants in each study arm that show presence of parasite density >0 asexual forms/µL as measured by qRT-PCR from 14 days to 2 and 6 months after administration of the final study vaccination PLUS presence of axillary temperature <37.5°C and absence of history of fever within the last 24 hours
• Parasite density in those with >0 asexual forms/µL as measured by qRT-PCR from 14 days to 2 and 6 after administration of the final study vaccination PLUS presence of axillary temperature <37.5°C and absence of history of fever within the last 24 hours

Protective efficacy against gametocytaemia will be assessed by measuring the proportion of participants in each study arm that show the presence of gametocytes >0 gametocytes/μL as measured by qRT-PCR from 14 days to 2 and 6 months after administration of the final study vaccination

Prevalent severe anaemia is defined as a documented haemoglobin (Hb) level <5.0 g/dL.

Prevalent moderate anaemia is defined as a documented Hb level <8.0 g/dL.