Malaria,Falciparum
Conditions
Brief summary
This is a Phase IIb randomised controlled trial of the safety, immunogenicity and efficacy of the malaria vaccine candidates R78C with Matrix-M™, and the combination of RH5.1 and R21 with Matrix-M™, in children aged 5-36 months in Burkina Faso.
Detailed description
There will be three study groups, each comprising of 120 children aged between 5 and 36 months at the time of first vaccination living in a malaria endemic area and will be recruited at one site in Burkina Faso. Participants will be randomised to receive either three doses of the malaria candidate vaccines R78C/Matrix-M and three doses of a commercially available rabies vaccine, three doses of RH5.1+R78C/Matrix-M and three doses of R21/Matrix-M or six doses of commercially available control vaccines. Follow up will be for six months following the last vaccination.
Interventions
BIOLOGICALR21
A protein particle comprising recombinant HBsAg fused to the central repeat and the C-terminus of the circumsporozoite protein
BIOLOGICALRH5.1
A soluble protein vaccine against the RH5 antigen
BIOLOGICALR78C
A soluble RIPR EGF-CyRPA fusion protein vaccine
BIOLOGICALMatrix-M™
A saponin-based vaccine adjuvant
BIOLOGICALRabivax-S
Rabivax-S is an inactivated, freeze-dried, single-dose vaccine. The vaccine contains purified, inactivated rabies antigen produced using Vero ATCC CCL 81 cells as the cell substrate, Pitman Moore (PM3218) as the virus strain, and sucrose, glycine and HSA (Human Serum Albumin) as excipients
BIOLOGICALMenveo
Menveo is a tetravalent meningitis vaccine that consists of one vial of MenA powder and one vial of Men CWY solution.
BIOLOGICALAvaxim 80
Avaxim 80 is an inactivated, adsorbed hepatitis A vaccine. Each immunising dose contains 80 antigen units of inactivated hepatitis A virus (GBM strain).
Sponsors
University of Oxford
Institut de Recherche en Sciences de la Sante, Burkina Faso
European and Developing Countries Clinical Trials Partnership (EDCTP)
European Vaccine Initiative
Bundesministerium für Forschung, Technologie und Raumfahrt (BMFTR)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blinding will be used to reduce bias in evaluating the study endpoints. This means that the vaccine recipient, their parent(s)/guardian(s), all investigators and the study team responsible for the evaluation of efficacy, safety and immunogenicity endpoints will all be unaware of the exact treatment given to the participant. The vaccines will be different in terms of volume and colour. Therefore, the contents of the syringe will be masked with an opaque label to ensure that parent(s)/guardian(s), as well as nurse administering the vaccine are blinded. The central study team will remain blinded. The laboratory team involved in the immunogenicity analysis will be blinded also. The Local Safety Monitor (LSM) and Data Safety Monitoring Board (DSMB), will also be provided with the randomisation sequence. If deemed necessary for reasons such as safety, the LSM or DSMB will unblind the specific enrolled participant without revealing the study group to the investigators.
Intervention model description
This is a Phase IIb, double-blinded, block randomised, controlled trial to assess the safety, immunogenicity and efficacy of the blood-stage malaria vaccine candidate R78C in Matrix-M and the multi-stage combination of the blood-stage malaria vaccine candidates RH5.1 and R78C in Matrix-M and the pre-erythrocytic malaria vaccine R21 in Matrix-M. 360 healthy children aged between 5 and 36 months at the time of first vaccination living in a malaria endemic area will be recruited at one site in Burkina Faso. Participants will be randomised to receive either three doses of the malaria candidate vaccines R78C/Matrix-M and three doses of a commercially available rabies vaccine, three doses of RH5.1+R78C/Matrix-M and three doses of R21/Matrix-M or six doses of commercially available control vaccines. Follow up will be for six months following the last vaccination.
Eligibility
Sex/Gender
ALL
Age
5 Months to 36 Months
Healthy volunteers
Yes
Inclusion criteria
Only participants who meet all the inclusion criteria will be enrolled into the trial: * Healthy infant aged 5-36 months at the time of first study vaccination * Parent/guardian provides signed/thumb-printed informed consent * Infant and parent/guardian resident in the study area villages and anticipated to be available for vaccination and the duration of follow-up
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 skin disorder (psoriasis, contact dermatitis etc.), cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, neurological illness as judged by the PI or other delegated individual. * 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. * Sickle cell disease. * Clinically significant laboratory abnormality at grade 2 or above as judged by the PI or other delegated individual. * Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate. * Receipt of any vaccine in the 14 days preceding enrolment, or planned receipt of any other vaccine within 28 days following each study vaccination. * History of vaccination with another malaria vaccine. * Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period. * 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. The following adverse events associated with vaccine immunisation constitute absolute contraindications to further administration of vaccine. If any of these events occur during the study, the participant must be withdrawn and followed until resolution of the event, as with any adverse event: • Anaphylactic reaction following administration of vaccine. The following adverse events constitute contraindications to administration of vaccine at that point in time; if any one of these adverse events occurs at the time scheduled for vaccination, the participant may be vaccinated at a later date, or withdrawn at the discretion of the Investigator. The participant must be followed until resolution of the event as with any adverse event: * Acute disease at the time of vaccination (acute disease is defined as the presence of a moderate or severe illness with or without fever or symptoms suggestive of possible COVID-19 disease). All vaccines can be administered to persons with a minor illness such as diarrhoea or mild upper respiratory infection without fever, i.e. axillary temperature \< 37.5°C. * Temperature of \>37.5°C (99.5°F) at the time of vaccination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: The primary efficacy outcome is clinical malaria, defined as the presence of axillary temperature ≥37.5°C and P. falciparum parasite density >5000 asexual forms/µL. | Clinical malaria will be assessed 6 months post final vaccination | To assess the protective efficacy against clinical malaria of R78C with Matrix-M™, and the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™, in children living in a malaria-endemic area, for 6 months after the final vaccination. Primary case definition for clinical malaria: • Presence of axillary temperature ≥37.5°C and/or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia \> 5000 parasites/µL Secondary case definitions for clinical malaria: * Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND EITHER P. falciparum asexual parasitaemia \>0 parasites/µL OR positive RDT * Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia \>20,000 parasites/µL |
| Safety: To assess the safety and reactogenicity of R78C, RH5.1 and R21 with Matrix-M™ by assessing solicited adverse events (AEs) in children living in a malaria-endemic area until 6 months after administration of the final dose of vaccine. | Day 0,1-6,28,29-34,98,99-104,126,127-132,154,155-160,182,183-188. | The occurrence of solicited local and systemic reactogenicity signs and symptoms will be assessed for 7 days following each vaccination (day of vaccination and 6 subsequent days) Foreseeable adverse reactions following vaccination with RH5.1, R78C or R21 and Matrix-MTM adjuvant are: * Local reactions: pain, erythema, warmth, swelling * Systemic reactions: drowsiness, fever, irritability/fussiness, loss of appetite These AEs will be listed as 'solicited AEs' providing they occur within 7 days of the day of vaccination. |
| Safety: To assess the safety and reactogenicity of R78C, RH5.1 and R21 with Matrix-M™ by assessing unsolicited adverse events (AEs) in children living in a malaria-endemic area until 6 months after administration of the final dose of vaccine. | Day 0,1-6,14,28,29-34,42,56,98,99-104,112,126,127-132,140,154,155-160,168,182,183-188,196. | The occurrence of unsolicited AEs will be assessed for 7 days following each vaccination (day of vaccination and 6 subsequent days). Unsolicited AEs' are AEs other than the foreseeable adverse reactions occurring within the first 7 days, or any AEs occurring after the first 7 days after vaccination. For every unsolicited AE, an assessment of the relationship of the event to the administration of the vaccine will be undertaken by the PI or the PI-delegated clinician. An intervention-related AE refers to an AE for which there is a possible, probable or definite relationship to administration of a vaccine. An interpretation of the causal relationship of the intervention to the AE in question will be made, based on the type of event; the relationship of the event to the time of vaccine administration; and the known biology of the vaccine therapy |
| Safety: To assess the safety and reactogenicity of R78C, RH5.1 and R21 with Matrix-M™ by assessing serious adverse events (SAEs) in children living in a malaria-endemic area until 6 months after administration of the final dose of vaccine. | Throughout study completion, an average of 1 year | The occurrence of SAEs during the whole study duration. An SAE is an AE that results in any of the following outcomes, whether or not considered related to the study intervention: * Death. * Life-threatening event. This does not include an AE that, if it occurred in a more severe form, might have caused death. * Persistent or significant disability or incapacity. * Hospitalisation or prolongation of hospitalisation, regardless of length of stay, even if it is a precautionary measure for continued observation. Hospitalisation for a pre-existing condition that has not worsened unexpectedly does not constitute an SAE. * An important medical event that may, based upon appropriate medical judgment, jeopardise the volunteer and/or require medical or surgical intervention to prevent one of the outcomes listed above. * Congenital anomaly or birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity:To assess the humoral immunogenicity of R78C with Matrix-M™, and the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™ in children living in a malaria-endemic area. | Blood samples for immunogenicity will be taken at Day -30 to 0, 0, 42, 56, 182, 196, 238, and 350. | Humoral immunogenicity will be assessed from blood samples taken at various timepoints. Immunogenicity will be determined following the quantification of antigen-specific IgG antibody levels (µg/mL readout) over time, as well as by in vitro growth inhibition assays (GIA) against P. falciparum parasites using purified total IgG and a single-cycle pLDH readout assay. |
| Efficacy: To assess the protective efficacy against clinical malaria of R78C with Matrix-M™, in children living in a malaria-endemic area, for 3 months after the final vaccination | 3 months after the final vaccination | The definition for clinical malaria is as follows: 1. Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND EITHER P. falciparum asexual parasitaemia \>0 parasites/µL OR positive RDT or 2. Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia \>20,000 parasites/µL Efficacy will be determined following the comparison of mean parasite density in each study arm |
| Efficacy: To assess the protective efficacy against clinical malaria of the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™, in children living in a malaria-endemic area, for 3 months after the final vaccination | 3 months after the final vaccination | The definition for clinical malaria is as follows: 1. Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND EITHER P. falciparum asexual parasitaemia \>0 parasites/µL OR positive RDT or 2. Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia \>20,000 parasites/µL Efficacy will be determined following the comparison of mean parasite density in each study arm |
| Efficacy: To assess the protective efficacy against asymptomatic P. falciparum infection of R78C with Matrix-M™, and the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™, in children living in a malaria-endemic area. | 2 and 6 months after administration of the final dose of vaccine | This will be measured by looking at the following: * Proportion of participants in each study arm that show presence of parasite density \>5000 asexual forms/µL as measured by quantitative reverse-transcriptase PCR (qRT-PCR) from 14 days to 2 and 6 months after administration of the final study vaccination PLUS presence of axillary temperature \<37.5°C and absence of history of fever within the last 24 hours * Proportion of participants in each study arm that show presence of parasite density \>0 asexual forms/µL as measured by qRT-PCR from 14 days to 2 and 6 months after administration of the final study vaccination PLUS presence of axillary temperature \<37.5°C and absence of history of fever within the last 24 hours * Parasite density in those with \>0 asexual forms/µL as measured by qRT-PCR from 14 days to 2 and 6 after administration of the final study vaccination PLUS presence of axillary temperature \<37.5°C and absence of history of fever within the last 24 hours |
| Efficacy: To assess the protective efficacy against gametocytaemia of R78C with Matrix-M™, and the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™, in children living in a malaria-endemic area | 2 and 6 months after administration of the final dose of vaccine | Protective efficacy against gametocytaemia will be assessed by measuring the proportion of participants in each study arm that show the presence of gametocytes \>0 gametocytes/μL as measured by qRT-PCR from 14 days to 2 and 6 months after administration of the final study vaccination |
| Efficacy: To assess the protective efficacy of R78C with Matrix-M™, and the combination of RH5.1 with Matrix-M™ and R21 with Matrix-M™, against prevalent moderate or severe anaemia at 6 months after administration of the final dose of vaccine | 6 months after administration of the final dose of vaccine | Prevalent severe anaemia is defined as a documented haemoglobin (Hb) level \<5.0 g/dL. Prevalent moderate anaemia is defined as a documented Hb level \<8.0 g/dL. |
Countries
Burkina Faso
Contacts
PRINCIPAL_INVESTIGATORHalidou Tinto
Institut de Recherche en Sciences de la Sante, Burkina Faso
Outcome results
None listed