A Phase 2b Multicenter Randomized, Placebo-Controlled Study to Evaluate the Safety and Immunogenicity of R21/Matrix-M Malaria Vaccine in African Infants With Different Immunization Schedules
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- PATH
- 入组人数
- 964
- 试验地点
- 3
- 主要终点
- Number of Participants with Solicited Adverse Events
研究概览
简要总结
The aim of this study is to identify an optimal infant vaccine schedule for a malaria vaccine which is better aligned with the timing of other vaccine interventions.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
964 participants will be randomized to an immunization schedule cohort if eligibility is confirmed by the investigator(s) at 42 to 49 days of age. Both the investigators and parent/legal guardian will know which cohort their infant has been assigned to.
In Part A of the study, infants were randomized within each immunization schedule category to receive R21/MM or placebo; neither the blinded study staff nor the parent/legal guardian knew whether the infant would receive R21/MM or placebo. After the broad introduction of R21/MM for infants from 5 months of age, participants randomized to receive placebo were withdrawn from the study and referred to start R21/MM vaccinations as part of the routine EPI schedule.
In Part B, only infants randomized to the 6-10-14 week immunization schedule will be further randomized to receive R21/MM or placebo for the primary 3 doses; neither the blinded study staff nor the parent/legal guardian will know whether the infant will receive R21/MM or placebo.
入排标准
- 年龄范围
- 42 Days 至 49 Days（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: Measles and Rubella Vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Pneumococcal Polysaccharide Conjugate Vaccine (Biological)
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: R21 Matrix-M (R21/MM) Malaria Vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Hexavalent Vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Yellow Fever vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Typhoid Conjugate vaccine (Biological)
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: Pneumococcal Polysaccharide Conjugate Vaccine (Biological)
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: Hexavalent Vaccine (Biological)
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: Rotavirus, Live Attenuated (Oral) Vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: R21 Matrix-M (R21/MM) Malaria Vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Rotavirus, Live Attenuated (Oral) Vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: R21 Matrix-M (R21/MM) Malaria Vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Hexavalent Vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Rotavirus, Live Attenuated (Oral) Vaccine (Biological)
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: Yellow Fever vaccine (Biological)
Compressed 6-10-14 Week Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, pneumococcal conjugate vaccine (PCV), and oral rotavirus vaccine (RV). At 9 months of age participants will receive measles-rubella (MR) vaccine, yellow fever (YF) vaccine, and typhoid conjugate vaccine (TCV).
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with Meningococcal (A, C, Y, W, X) Polysaccharide Conjugate Vaccine (MenFive) and the 2nd dose of MR vaccine.
干预措施: Typhoid Conjugate vaccine (Biological)
Relaxed 2-4-6 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 2, 4, and 6 months of age co-administered with hexavalent vaccine, PCV, and oral RV. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Measles and Rubella Vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Pneumococcal Polysaccharide Conjugate Vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Measles and Rubella Vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Yellow Fever vaccine (Biological)
Relaxed 3-6-9 Month Schedule: R21/MM Malaria Vaccine
Participants will receive R21/MM malaria vaccination at 3, 6, and 9 months of age. Participants will receive the hexavalent vaccine, PCV, and oral RV at 6 weeks, 10 weeks, and 14 weeks of age. At 9 months of age participants will receive MR and YF vaccines and TCV.
Participants will receive a booster dose of R21/MM malaria vaccine at 15 months of age co-administered with the MenFive vaccine and the 2nd dose of MR vaccine.
干预措施: Typhoid Conjugate vaccine (Biological)
结局指标
主要结局
Number of Participants with Solicited Adverse Events
时间窗: 7 days after each study vaccination
Local (redness, swelling, and pain at the injection site) and systemic (fever, drowsiness, irritability, decreased appetite) reactions will be collected in a subset of participants (the first 40 participants in each immunization schedule category at each site).
Number of Participants with Unsolicited Adverse Events
时间窗: 28 days after each study vaccination
Number of Participants with Serious Adverse Events
时间窗: Up to 27 months of age
Number of Participants with Adverse Events of Special Interest
时间窗: Up to 27 months of age
Geometric Mean Titers (GMTs) of Anti-circumsporozoite (CS) Immunoglobulin G (IgG) at Baseline and 28 Days after 3rd Vaccine Dose
时间窗: Baseline and 28 days after 3rd vaccine dose
The anti-CS antibody responses elicited following the primary 3-dose schedule of R21/MM will be assessed in the "compressed" (6-10-14 week) immunization schedule and the two "relaxed" (2-4-6 month and 3-6-9 month) immunization schedule cohorts.
Geometric Mean Fold Rise (GMFR) in Anti-CS IgG 28 Days after 3rd Vaccine Dose Compared to Baseline
时间窗: Baseline and 28 days after 3rd vaccine dose
The anti-CS antibody responses elicited following the primary 3-dose schedule of R21/MM will be assessed in the "compressed" (6-10-14 week) immunization schedule and the two "relaxed" (2-4-6 month and 3-6-9 month) immunization schedule cohorts.
次要结局
- Fold Increase in Anti-CS IgG Titer Post 4th Dose Compared to Pre-4th Dose(Month 15 predose and 28 days after 4th dose)
- Number of Clinical Malaria Episodes per Person-year Meeting the Primary Case Definition up to 27 Months(From 6 weeks of age to 27 months of age)
- Number of Clinical Malaria Episodes per Person-year Meeting the Primary Case Definition up to 15 Months(From 6 weeks of age to 15 months of age)
- Number of Clinical Malaria Episodes per Person-year Meeting the Primary Case Definition from 15.5 to 27 Months(From 15.5 months (2 weeks after the 4th vaccination) to 27 months of age)
- Number of Clinical Malaria Episodes per Person-year Meeting the Secondary Case Definition up to 27 Months(From 6 weeks of age to 27 months of age)
- Number of Clinical Malaria Episodes per Person-year Meeting the Secondary Case Definition up to 15 Months(From 6 weeks of age to 15 months of age)
- Number of Clinical Malaria Episodes per Person-year Meeting the Secondary Case Definition from 15.5 to 27 Months(From 15.5 months (2 weeks after the 4th vaccination) to 27 months of age)
- Geometric Mean Titers (GMTs) of Anti-CS IgG Before and 28 Days After 4th Vaccine Dose(Month 15 predose and 28 days after vaccination)