Malaria Vaccines
Conditions
Keywords
Plasmodium falciparum, R21/Matrix-M Malaria Vaccine
Brief summary
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.
Detailed description
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 and the ensuant efficacy in protecting infants against clinical Plasmodium falciparum malaria. 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. Participants in each immunization schedule cohort will be randomized in a ratio of 3:1 to receive 4 doses of either R21/MM or placebo with a 4th dose to be administered at 15 months of age. Infants randomized to the respective immunization schedule categories will receive co-administered routine EPI vaccines. The study will include the provision of a three dose R21/MM compressed schedule to all participants randomized to the placebo arms upon completion of the study at Month 27 of life.
Interventions
BIOLOGICALR21 Matrix-M (R21/MM) Malaria Vaccine
Administered by intramuscular injection. Each 0.5 mL dose contains R21 Malaria Antigen (5 mcg) and Matrix-M1 (Adjuvant) (50 mcg).
BIOLOGICALPlacebo
Administered by intramuscular injection. Each dose (0.5 mL) contains Normal saline (0.9%).
BIOLOGICALHexavalent Vaccine
Administered by intramuscular injection. Each dose of 0.5 mL contains: * Diphtheria Toxoid \> 30 IU * Tetanus Toxoid \> 40 IU * B. pertussis (whole cell) \> 4 IU * Hepatitis B surface antigen (HBsAg) (recombinant DNA) 15 mcg * Inactivated polio vaccine (Salk strains grown on vero cells): Type - 1 (Mahoney strain) 40 D antigen units (DU); Type - 2 (MEF-1 strain) 8 DU; Type - 3 (Saukett strain) 32 DU * Haemophilus influenzae Type b (Hib) Conjugate Vaccine (Adsorbed) polyribosylribitol phosphate (PRP) 10 mcg conjugated to tetanus toxoid (TT) (carrier protein) 19 to 33 mcg\]
BIOLOGICALPneumococcal Polysaccharide Conjugate Vaccine
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.
BIOLOGICALRotavirus, Live Attenuated (Oral) Vaccine
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.
BIOLOGICALMeasles and Rubella Vaccine
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.
BIOLOGICALMeningococcal A conjugate vaccine
Administered by intramuscular injection. Each 0.5 mL dose contains Meningococcal A polysaccharide 10 mcg and tetanus toxoid (TT) (carrier protein) 10 to 33 mcg.
BIOLOGICALYellow Fever vaccine
Yellow fever vaccine will be locally sourced by each trial site in accordance with the countries' EPI program.
BIOLOGICALTyphoid Conjugate vaccine
Typhoid conjugate vaccine will be locally sourced by each trial site in accordance with the countries' EPI program.
Sponsors
Serum Institute of India PVT LTD (SII)
Agilis
Pharmassist Ltd
MCT-CRO
Cytespace
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
1200 healthy participants will be randomized to an immunization schedule cohort if eligibility is confirmed by the investigator(s) at 42 to 49 days of age. The investigators and parent/legal guardian will both know which immunization schedule cohort their infant has been assigned to. Infants will be randomized within each immunization schedule category to a group assignment to either receive the R21/MM or placebo; neither the blinded study staff nor the parent/legal guardian will know whether the infant will receive the R21/MM or placebo.
Eligibility
Sex/Gender
ALL
Age
42 Days to 49 Days
Healthy volunteers
Yes
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. 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. For infants in Cohort 2, randomization to receive vaccine dose 1 (Groups 3 and 4 of R21/MM or placebo, respectively) will occur at 2 months (56-63 days of age). For infants in Cohort 3, randomization to receive vaccine dose 1 (Groups 5 and 6 of R21/MM or placebo, respectively) will occur 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 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. All vaccines can be administered to participants with a minor illness such as diarrhea, mild upper respiratory infection, without low-grade febrile illness, i.e. axillary temperature \< 37.5°C). * 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-height/length 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Titers (GMTs) of Anti-circumsporozoite (CS) Immunoglobulin G (IgG) at Baseline and 28 Days after 3rd Vaccine Dose | Baseline and 28 days after 3rd vaccine dose | — |
| Geometric Mean Fold Rise (GMFR) in Anti-CS IgG 28 Days after 3rd Vaccine Dose Compared to Baseline | Baseline and 28 days after 3rd vaccine dose | — |
| Number of Participants with Solicited Adverse Events | 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 | 28 days after each study vaccination | — |
| Number of Participants with Serious Adverse Events | Up to 27 months of age | — |
| Number of Participants with Adverse Events of Special Interest | Up to 27 months of age | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | The secondary case definition will be P. falciparum asexual parasitemia \> 0 parasites/µL detected by blood slide reading and presence of fever (axillary temperature ≥ 37.5°C or tympanic temperature ≥ 38°C) or history of fever within 48 hours of presentation AND occurring in an infant/child who is unwell and brought for treatment to a healthcare facility. |
| Geometric Mean Titers (GMTs) of Anti-CS IgG Before and 28 Days After 4th Vaccine Dose | Month 15 predose and 28 days after vaccination | — |
| 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 | The secondary case definition will be P. falciparum asexual parasitemia \> 0 parasites/µL detected by blood slide reading and presence of fever (axillary temperature ≥ 37.5°C or tympanic temperature ≥ 38°C) or history of fever within 48 hours of presentation AND occurring in an infant/child who is unwell and brought for treatment to a healthcare facility. |
| 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 | The primary case definition will be P. falciparum asexual parasitemia \> 5000 parasites/µL detected by blood slide reading AND presence of fever (axillary temperature ≥ 37.5°C or tympanic temperature ≥ 38°C) or history of fever within 48 hours of presentation at the time of presentation AND occurring in an infant/child who is unwell and brought for treatment to a healthcare facility. |
| 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 | The primary case definition will be P. falciparum asexual parasitemia \> 5000 parasites/µL detected by blood slide reading AND presence of fever (axillary temperature ≥ 37.5°C or tympanic temperature ≥ 38°C) or history of fever within 48 hours of presentation at the time of presentation AND occurring in an infant/child who is unwell and brought for treatment to a healthcare facility. |
| 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 | The primary case definition will be P. falciparum asexual parasitemia \> 5000 parasites/µL detected by blood slide reading AND presence of fever (axillary temperature ≥ 37.5°C or tympanic temperature ≥ 38°C) or history of fever within 48 hours of presentation at the time of presentation AND occurring in an infant/child who is unwell and brought for treatment to a healthcare facility. |
| 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 | The secondary case definition will be P. falciparum asexual parasitemia \> 0 parasites/µL detected by blood slide reading and presence of fever (axillary temperature ≥ 37.5°C or tympanic temperature ≥ 38°C) or history of fever within 48 hours of presentation AND occurring in an infant/child who is unwell and brought for treatment to a healthcare facility. |
Countries
Burkina Faso
Contacts
Primary ContactMichael Thigpen, MD
Outcome results
None listed