Otimização do cronograma da vacina contra malária infantil
Um estudo randomizado multicêntrico de fase 2b, abrangente, controlado por placebo, duplo-cego, para avaliar a segurança, imunogenicidade e eficácia da vacina de malária R21/Matrix-M em bebês africanos com diferentes cronogramas de imunização
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.
Visão geral do estudo
Status
Intervenção / Tratamento
- Biológico: R21 Matrix-M (R21/MM) Malaria Vaccine
- Biológico: Hexavalent Vaccine
- Biológico: Pneumococcal Polysaccharide Conjugate Vaccine
- Biológico: Rotavirus, Live Attenuated (Oral) Vaccine
- Biológico: Measles and Rubella Vaccine
- Biológico: Meningococcal (A, C, Y, W, X) polysaccharide conjugate vaccine
- Biológico: Yellow Fever vaccine
- Biológico: Typhoid Conjugate vaccine
- Biológico: Placebo
Descrição detalhada
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.
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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Bobo-Dioulasso, Burkina Faso
- Institut de Recherche en Sciences de la Santé (IRSS)
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Ouagadougou, Burkina Faso
- Groupe de Recherche Action en Santé (GRAS)
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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.
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Prevenção
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Triplo
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
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Experimental: 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. |
Administered by intramuscular injection. Each 0.5 mL dose contains R21 Malaria Antigen (5 mcg) and Matrix-M1 (Adjuvant) (50 mcg). Administered by intramuscular injection. Each dose of 0.5 mL contains:
Outros nomes:
Administered by intramuscular injection. Each 0.5 mL dose contains 2 mcg each Saccharide for serotypes 1, 5, 9V, 14, 19A, 19F, 23F, 7F, 6A and 4 mcg Saccharide for serotype 6B.
Outros nomes:
Administered orally. Each 2.0 mL dose contains: Live Attenuated Bovine-Human Rotavirus Reassortant [G1, G2, G3, G4 and G9], 5.6 focus-forming units (FFU) / serotype.
Outros nomes:
Administered by subcutaneous injection. Each 0.5 mL dose contains not less than 1000 cell culture infectious dose 50% (CCID50) of Measles virus and 1000 CCID50 of Rubella virus. Administered by intramuscular injection. Each 0.5 mL dose contains 5 mcg of each Meningococcal A, C, Y, W, and X polysaccharide, 7.8 to 33.4 mcg of TT and 11.7 to 50.1 mcg of recombinant CRM197. Yellow fever vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. Typhoid conjugate vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. |
|
Outro: Compressed 6-10-14 Week Schedule: Placebo / Recommended 5-6-7 Month Schedule: R21/MM Malaria Vaccine
Participants will receive placebo at 6, 10, and 14 weeks of age, co-administered with hexavalent vaccine, PCV, and oral RV. After completion of the 28 day post-Dose 3 visit, these participants will rollover to Cohort 4 (Group 7) to then receive open-label R21/MM vaccine as per the "recommended" schedule at 5-6-7 months 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. |
Administered by intramuscular injection. Each 0.5 mL dose contains R21 Malaria Antigen (5 mcg) and Matrix-M1 (Adjuvant) (50 mcg). Administered by intramuscular injection. Each dose of 0.5 mL contains:
Outros nomes:
Administered by intramuscular injection. Each 0.5 mL dose contains 2 mcg each Saccharide for serotypes 1, 5, 9V, 14, 19A, 19F, 23F, 7F, 6A and 4 mcg Saccharide for serotype 6B.
Outros nomes:
Administered orally. Each 2.0 mL dose contains: Live Attenuated Bovine-Human Rotavirus Reassortant [G1, G2, G3, G4 and G9], 5.6 focus-forming units (FFU) / serotype.
Outros nomes:
Administered by subcutaneous injection. Each 0.5 mL dose contains not less than 1000 cell culture infectious dose 50% (CCID50) of Measles virus and 1000 CCID50 of Rubella virus. Administered by intramuscular injection. Each 0.5 mL dose contains 5 mcg of each Meningococcal A, C, Y, W, and X polysaccharide, 7.8 to 33.4 mcg of TT and 11.7 to 50.1 mcg of recombinant CRM197. Yellow fever vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. Typhoid conjugate vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. Administered by intramuscular injection. Each dose (0.5 mL) contains Normal saline (0.9%). |
|
Experimental: 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. |
Administered by intramuscular injection. Each 0.5 mL dose contains R21 Malaria Antigen (5 mcg) and Matrix-M1 (Adjuvant) (50 mcg). Administered by intramuscular injection. Each dose of 0.5 mL contains:
Outros nomes:
Administered by intramuscular injection. Each 0.5 mL dose contains 2 mcg each Saccharide for serotypes 1, 5, 9V, 14, 19A, 19F, 23F, 7F, 6A and 4 mcg Saccharide for serotype 6B.
Outros nomes:
Administered orally. Each 2.0 mL dose contains: Live Attenuated Bovine-Human Rotavirus Reassortant [G1, G2, G3, G4 and G9], 5.6 focus-forming units (FFU) / serotype.
Outros nomes:
Administered by subcutaneous injection. Each 0.5 mL dose contains not less than 1000 cell culture infectious dose 50% (CCID50) of Measles virus and 1000 CCID50 of Rubella virus. Administered by intramuscular injection. Each 0.5 mL dose contains 5 mcg of each Meningococcal A, C, Y, W, and X polysaccharide, 7.8 to 33.4 mcg of TT and 11.7 to 50.1 mcg of recombinant CRM197. Yellow fever vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. Typhoid conjugate vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. |
|
Experimental: 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. |
Administered by intramuscular injection. Each 0.5 mL dose contains R21 Malaria Antigen (5 mcg) and Matrix-M1 (Adjuvant) (50 mcg). Administered by intramuscular injection. Each dose of 0.5 mL contains:
Outros nomes:
Administered by intramuscular injection. Each 0.5 mL dose contains 2 mcg each Saccharide for serotypes 1, 5, 9V, 14, 19A, 19F, 23F, 7F, 6A and 4 mcg Saccharide for serotype 6B.
Outros nomes:
Administered orally. Each 2.0 mL dose contains: Live Attenuated Bovine-Human Rotavirus Reassortant [G1, G2, G3, G4 and G9], 5.6 focus-forming units (FFU) / serotype.
Outros nomes:
Administered by subcutaneous injection. Each 0.5 mL dose contains not less than 1000 cell culture infectious dose 50% (CCID50) of Measles virus and 1000 CCID50 of Rubella virus. Administered by intramuscular injection. Each 0.5 mL dose contains 5 mcg of each Meningococcal A, C, Y, W, and X polysaccharide, 7.8 to 33.4 mcg of TT and 11.7 to 50.1 mcg of recombinant CRM197. Yellow fever vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. Typhoid conjugate vaccine will be locally sourced by each trial site in accordance with the countries' EPI program. |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Número de participantes com eventos adversos não solicitados
Prazo: 28 dias após cada vacinação de estudo
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28 dias após cada vacinação de estudo
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Number of Participants with Serious Adverse Events
Prazo: Up to 28 days post 4th vaccine dose.
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Up to 28 days post 4th vaccine dose.
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Number of Participants with Adverse Events of Special Interest
Prazo: Up to 28 days post 4th vaccine dose.
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Up to 28 days post 4th vaccine dose.
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Geometric Mean Titers (GMTs) of Anti-circumsporozoite (CS) Immunoglobulin G (IgG) at Baseline and 28 Days after 3rd Vaccine Dose
Prazo: Baseline and 28 days after 3rd vaccine dose
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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. |
Baseline and 28 days after 3rd vaccine dose
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Geometric Mean Fold Rise (GMFR) in Anti-CS IgG 28 Days after 3rd Vaccine Dose Compared to Baseline
Prazo: Baseline and 28 days after 3rd vaccine dose
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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. |
Baseline and 28 days after 3rd vaccine dose
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Number of Participants with Solicited Adverse Events
Prazo: 7 days after each study vaccination
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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). |
7 days after each study vaccination
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Geometric Mean Titers (GMTs) of Anti-CS IgG Before and 28 Days After 4th Vaccine Dose
Prazo: Month 15 predose and 28 days after vaccination
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The anti-CS antibody responses elicited following the 4th dose 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. |
Month 15 predose and 28 days after vaccination
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GMFR in Anti-CS IgG Titer Post 4th Dose Compared to Pre-4th Dose
Prazo: Month 15 predose and 28 days after 4th dose
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The anti-CS antibody responses elicited following the 4th dose 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. |
Month 15 predose and 28 days after 4th dose
|
Colaboradores e Investigadores
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças transmitidas por vetores
- Doenças transmitidas por mosquitos
- Infecções
- Infecções por protozoários
- Doenças Parasitárias
- Malária
- Malária, falciparum
- Produtos biológicos
- Misturas complexas
- Vacinas virais
- Vacinas Protozoárias
- Vacinas
- Vacinas, combinadas
- Vacina da febre amarela
- Vacina contra a Rubéola
- Vacinas Contra a Malária
Outros números de identificação do estudo
- CVIA 108
- PACTR202411825510335 (Identificador de registro: Pan African Clinical Trials Registry)
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
Descrição do plano IPD
PATH as the Sponsor of the Clinical Study will post the Clinical Trial Data in compliance with the Gates Foundation's Open Access policy and the WHO Joint Statement on Clinical Transparency. The Clinical Trial Data will contain no personally identifiable information (PII) and will be fully anonymized and de-identified.
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