A Phase Ib/IIb Randomised Controlled Trial of the Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine, R21 Adjuvanted With Matrix-M (R21/MM), in 5-17 Month Old Children in Nanoro, Burkina Faso
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 450
- 试验地点
- 1
- 主要终点
- The protective efficacy (number of cases) against clinical malaria of R21 adjuvanted with Matrix-M in 5-17 month old children living in a malaria-endemic area
研究概览
简要总结
This is a double blind randomised controlled clinical trial to evaluate the efficacy of R21 adjuvanted with Matrix-M in healthy 5-17 month old children in a malaria endemic area.
详细描述
In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months.
From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated.
Please see publication for more details: Lancet. 2021 May 15;397(10287):1809-1818. doi: 10.1016/S0140-6736(21)00943-0
After the first booster vaccination, participants in Groups 1 and 2 were further randomised 2:1 to receive R21 with Matrix-M: control. The trial was extended by a further two years with yearly boosters of R21/MM or rabies vaccine. Groups 1 and 2 were subdivided and randomized 2:1 to receive R21/MM or rabies vaccine as the second booster. Group 3 received control rabies vaccine as they had done previously. The second boosting occurred between June and July 2021 where 368 participants were boosted. In May 2022 it was decided to amend the protocol to allow for groups 1a and 2a (malaria vaccine groups) to be randomised 1:1 to receive either the R21/Matrix-M vaccine or a control rabies vaccine a year after the previous booster vaccine. The third boosting occurred between June and July 2022 where 357 participants were boosted.
Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and 140 received the control vaccine.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 5 Months 至 17 Months（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy child aged 5-17 months at the time of first study vaccination
- •Provide written Informed consent of parent/guardian
- •Child and parent/guardian resident in the study area villages and anticipated to be available for vaccination and follow-up for 2 years following last dose of vaccination
排除标准
- •Clinically significant skin disorder (psoriasis, contact dermatitis etc.), immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, neurological illness.
- •Weight-for-age Z score of less than -3 or other clinical signs of malnutrition.
- •History of allergic reaction, significant IgE-mediated event, or anaphylaxis to immunisation.
- •History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, e.g. neomycin.
- •Sickle cell disease.
- •Clinically significant laboratory abnormality as judged by the study clinician.
- •Blood transfusion within one month of enrolment.
- •Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate.
- •Previous vaccination with experimental malaria vaccines.
- •Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period.
- •Current participation in another clinical trial, or within 12 weeks of this study.
- •Known maternal HIV infection (No testing will be done by the study team).
- •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 (For corticosteroids, this will mean prednisone, or equivalent, >= 0.5 mg/kg/day. Inhaled and topical steroids are allowed).
- •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.
研究组 & 干预措施
Group 1
n=150. Age 5-17 month-old. 5mcg R21/25mcg Matrix-M at Day 0, 28 and 56 and 1 year.
Following the initial booster, Group 1 will be randomised 2:1 into Groups1a and 1b for 5ug R21/50ug Matrix-M: control. Groups 1a and 1b will receive these second and third booster vaccinations each year prior to the malaria season
干预措施: R21 adjuvanted with 25mcg Matrix-M (Biological)
Group 1
n=150. Age 5-17 month-old. 5mcg R21/25mcg Matrix-M at Day 0, 28 and 56 and 1 year.
Following the initial booster, Group 1 will be randomised 2:1 into Groups1a and 1b for 5ug R21/50ug Matrix-M: control. Groups 1a and 1b will receive these second and third booster vaccinations each year prior to the malaria season
干预措施: Rabies Vaccine (Biological)
Group 1
n=150. Age 5-17 month-old. 5mcg R21/25mcg Matrix-M at Day 0, 28 and 56 and 1 year.
Following the initial booster, Group 1 will be randomised 2:1 into Groups1a and 1b for 5ug R21/50ug Matrix-M: control. Groups 1a and 1b will receive these second and third booster vaccinations each year prior to the malaria season
干预措施: R21 adjuvanted with 50mcg Matrix-M (Biological)
Group 2
n=150. Age 5-17 month-old. 5mcg R21/50mcg Matrix-M at Day 0, 28 and 56 and 1 year.
Following the initial booster, Group 2 will be randomised 2:1 into Groups 2a and 2b or 5ug R21/50ug Matrix-M:ccontrol. Groups 2a and 2b will receive these second and third booster vaccinations each year prior to the malaria season
干预措施: Rabies Vaccine (Biological)
Group 2
n=150. Age 5-17 month-old. 5mcg R21/50mcg Matrix-M at Day 0, 28 and 56 and 1 year.
Following the initial booster, Group 2 will be randomised 2:1 into Groups 2a and 2b or 5ug R21/50ug Matrix-M:ccontrol. Groups 2a and 2b will receive these second and third booster vaccinations each year prior to the malaria season
干预措施: R21 adjuvanted with 50mcg Matrix-M (Biological)
Group 3 (control group)
n=150. Age 5-17 month-old. Rabies Vaccine by the end of the trial.
干预措施: Rabies Vaccine (Biological)
结局指标
主要结局
The protective efficacy (number of cases) against clinical malaria of R21 adjuvanted with Matrix-M in 5-17 month old children living in a malaria-endemic area
时间窗: for 6 months after the last vaccination
We will look for the presence of axillary temperature ≥37.5°C AND P. falciparum parasites density \> 5000 asexual forms/µL as a primary case definition of clinical malaria. - We will look for the presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum parasites density \> 0 for a secondary case definition of clinical malaria.
次要结局
- Efficacy (number of cases) against asymptomatic P. falciparum infection(at 6 and 12 months after administration of the third dose of vaccine, and for 12 months after each booster vaccination)
- Duration of Protective efficacy (number of cases) against clinical malaria(for 12 months after administration of the third dose of vaccine, and for 6 and 12 months after each booster vaccination)
- The safety and reactogenicity (number of adverse events) of R21 adjuvanted with Matrix-M in 5-17 month olds living in a malaria-endemic area in the month following each vaccination and at 12 months after administration of the final dose of vaccine(for 6 and 12 months after administration of the third dose of vaccine, and for 12 months after each booster vaccination)
- The humoral immunogenicity (antibody response) of R21 adjuvanted with Matrix-M in 5-17 months old children living in a malaria-endemic area(for 6 and 12 months after administration of the third dose of vaccine, and for 6 months after each booster vaccination)