Infant Malaria Vaccine Schedule Optimization

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arms had all study procedures discontinued, and were referred to local EPI clinics to receive R21/MM vaccinations and withdrawn from the study.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.

Inclusion criteria

• Signed informed consent or thumb-printed and witnessed informed consent obtained from the parent/legal guardian of the infant.
• Infants must have been born full-term (at ≥37 weeks of gestation) and > 2500 grams at birth.
• Immunization schedule Cohorts 1, 2, and 3: Male and female infants 42-49 days (inclusive) of age at time of enrollment.
• Prior to group randomization, for infants in Cohort 1 randomization to receive vaccine dose 1 (Groups 1 and 2 of R21/MM or placebo, respectively) will occur at 42-49 days of age. Infants in Cohorts 2 and 3 will not be randomized to R21/MM or placebo; placebo will no longer be given. Rather infants in these cohorts will receive open-label R21/MM according to the immunization schedule category to which they have been randomized. Infants in Cohort 2, will receive their open-label R21/MM vaccine dose 1 (Group 3) at 2 months (56-63 days of age). Infants in Cohort 3, will receive their open-label R21/MM vaccine dose 1 (Group 5) at 3 months (84-91 days of age).
• The participant's parent/guardian must be willing to avoid travel, particularly in the 28 days after each study vaccination, must confirm willingness to contact the study team in the event of unexpected/unavoidable travel and, for the safety cohort, must confirm availability for the home visits to be conducted by a field worker or nurse to collect solicited AEs over the 7 days (day of vaccination and 6 subsequent days) following each study vaccine.
• The participant's parent/guardian must confirm willingness to bring their child to the study clinic / local health care clinic, and capacity to contact the study team in the event the subject has any illnesses or other health concerns during the study.
• Participants who the investigator believes that their parent/guardian can and will comply with the requirements of the protocol (e.g. return for follow-up visits) may be enrolled in the study.

Exclusion criteria

• Acute disease at the time of enrolment (acute disease is defined as the presence of a moderate or severe illness with or without fever). This does not include minor illnesses such as diarrhea, mild upper respiratory infection, without low-grade febrile illness, i.e. axillary temperature < 37.5°C or tympanic temperature < 38°C.

(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).

• Clinically significant pulmonary, cardiovascular, gastrointestinal, endocrine, neurological, skin, hepatic or renal functional abnormality, as determined by medical history, physical examination or laboratory tests 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.
• At time of enrollment, any infant who has received any dose of the hexavalent/pentavalent vaccines, pneumococcal vaccine, rotavirus vaccine, IPV or has received more than one dose of oral polio virus or more than one dose of hepatitis B vaccine.
• Weight-for-length/height Z score of less than -3 or other clinical signs of malnutrition.
• Infant with major congenital defects.
• The infant has anaemia associated with clinical signs of symptoms of decompensation, or a haemoglobin of ≤ 5.0 g/dL.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines.
• Any confirmed or suspected immunosuppressive or immunodeficient state (including HIV or asplenia) or known maternal HIV infection (no HIV testing will be routinely done by the study team).
• Administration of immunoglobulins and/or any blood products/blood transfusion from birth to time of planned administration of the vaccine candidate.
• Previous vaccination of participant or biological mother with a malaria vaccine.
• Participation in another research study involving receipt of an investigational product or planned use during the study period.
• Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.