This is a dose-escalation, age de-escalation randomised double-blind controlled Phase Ib trial to assess the safety, tolerability and immunogenicity of ChAd63-RH5 administered with MVA-RH5 in a heterologous prime-boost regimen. Adults (18-35 years), young children (1-6 years) and infants (6-11 months) will be enrolled in the study. Safety data will be collected for each of the vaccination regimens. The humoral and cellular immune responses generated by each of these regimens will be assessed.

• Experimental design: Phase Ib, double blind, age de-escalation dose-escalation, randomized (2:1 ratio), controlled trial.
• Healthy adults (18-35 years), young children (1-6 years) and infants (6-11 months) will be screened; those determined to be eligible, based on the inclusion and exclusion criteria, will be enrolled in the study.
• Route of administration of ChAd63-RH5 (day 0) and MVA-RH5 (2 months): both vaccines will be administered by the intramuscular route to the left deltoid.
• Each participant will be observed for at least 1 hour after vaccination to evaluate and treat any acute adverse events (AEs).
• There will be 7-day follow-up period for solicited AEs post-vaccination: Day 0, 2 and 7 evaluations will be carried out by the study clinician at the study centre and day 1, 3, 4, 5 and 6 evaluations will be carried out by a trained community health worker in the participant's home, after each vaccination.
• There will be a 28-day (day of vaccination and 28 subsequent days) follow-up after each vaccine dose for reporting unsolicited symptoms.
• Serious adverse events (SAEs) will be recorded throughout the study period. Prior to vaccination, any SAEs due directly to study procedures will be captured. All SAEs will be captured beginning with the administration of the priming dose of ChAd63 RH5 and ending 4 months after the booster dose with MVA RH5.
• Antibodies to RH5_FL will be determined at baseline and 14, 28, 56, 63, 84, 112, 140 and 168 days after ChAd63 RH5 in all participants.
• Cellular immune responses to RH5 will be evaluated at baseline and 14 (adults only), 28, 56, 63, 84 and 168 days after ChAd63 RH5 in all participants.
• The duration of involvement in the study from enrolment will be approximately 6 months. The vaccination phase of the study takes 9 weeks and the post-vaccination follow-up lasts for 4 months after the last dose.

Inclusion Criteria:

Only participants who meet all the inclusion criteria will be enrolled into the trial;

• Group 1: Healthy male or female adults aged 18-35 years at the time of enrolment with signed consent.
• Group 1 (Female only participants): Must be non-pregnant (as demonstrated by a negative urine pregnancy test), and provide consent of their willingness to take Depo-Provera contraceptive during the study and safety follow-up period.
• Groups 2a & 2b: Healthy male or female young children aged 1-6 years at the time of enrolment with signed consent obtained from parents or guardians.
• Groups 3a & 3b: Healthy male or female infants aged 6-11 months at the time of enrolment with signed consent obtained from parents or guardians.
• Planned long-term (at least 9 months from the date of recruitment) or permanent residence in Bagamoyo town.
• Adults with a Body Mass Index (BMI) 18 to 30 Kg/m2; or young children and infants with Z-score of weight-for-age within ±2SD.

Exclusion Criteria:

The participant may not enter the trial if ANY of the following apply:

• Clinically significant congenital abnormalities as judged by the PI or other delegated individual.
• Clinically significant history of skin disorder (psoriasis, contact dermatitis etc.), allergy, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease and neurological illness as judged by the PI or other delegated individual.
• Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed).
• History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ).
• Weight for age z-scores below 2 standard deviations of normal for age.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, e.g. egg products, Kathon, neomycin, betapropiolactone.
• Any history of anaphylaxis in relation to vaccination.
• Clinically significant laboratory abnormality as judged by the PI or other delegated individual.
• Blood transfusion within one month of enrolment.
• History of vaccination with previous experimental malaria vaccines.
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate.
• Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period.
• Seropositive for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV IgG).
• Any other finding which in the opinion of the PI or other delegated individual would increase the risk of an adverse outcome from participation in the trial.
• Likelihood of travel away from the study area.
• Positive malaria by blood smear at screening.
• Female participant who is pregnant, lactating or planning pregnancy during the course of the trial.
• Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
• Any other 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.

Double-blind.