This is a Phase 2, randomized, double-blind, controlled study designed to evaluate the safety, tolerability, immunogenicity, vaccine efficacy, and functional activity of Pfs230D1-CRM197 conjugate vaccine with R21 nanoparticle vaccine formulated on Matrix-M1. Participants (9-50 years of age) will be drawn from Bancoumana, Mali and the surrounding areas.
Participants aged 9 - 17 years in the immunobridging cohort (n=540) will be randomized to one of the study arms ( 2:2:1:1) to receive 10μg R21 alone in 50μg of Matrix-M1, control vaccine (RABIVAX-S), or 6μg Pfs230D1-CRM197 with 10μg R21 in 50μg of Matrix-M1 as either a bedside mixture or a single-vial coformulation. Participants in the main cohort who are aged 9-17 years will be randomized to one of the study arms (1:1:1) to receive 10μg R21 alone in 50μg of Matrix-M1, control vaccine (RABIVAX-S), or 6μg Pfs230D1-CRM197 with 10 μg R21 in 50μg of Matrix-M1 single-vial coformulation. Enrollment of participants aged 9-17 years in the main cohort will be done after DSMB reviews the 7-day safety data post dose 1 from the immunobridging cohort. Participants in the main cohort who are aged 18 - 50 years will be randomized to one of the study arms (1:1:1) to receive either 10μg R21 alone in 50μg of Matrix-M1, control vaccine (RABIVAX-S), or 6μg Pfs230D1-CRM197 with 10μg R21 in 50μg of Matrix-M1 single-vial coformulation. Enrollment of adult participants aged 18 -50 years in the main cohort (n=300) will be done from the start of the study and will be independent of enrollment into of the pediatric cohort (9-17 years). All vaccines will be administered as an intramuscular (IM) injection on a 0, 28, 56 day schedule with an option for additional follow-up for a subsequent malaria transmission season with or without a fourth dose approximately 52 weeks after the third vaccine dose (based on year 1 results). Initial enrollment will be staggered over time for safety, but all participants will be analyzed together for primary, secondary, and exploratory endpoints. A total 1200 participants will be randomized into the study as below: Immunobridging cohort (Participants 9-17 years of age, n = 540) (2:2:1:1 randomization) * Arm 1a (n = 180): 10µg of R21 with 50µg Matrix-M1 on study day 0, 28, 56 +/- 392 * Arm 2a (n = 180): Control vaccine (rabies vaccine) on study day 0, 28, 56 +/- 392 * Arm 3a (n = 90): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 single vial coformulation on study day 0, 28, 56 +/- 392 * Arm 4a (n = 90): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 bedside mix on study day 0, 28, 56 +/- 392 Main cohort: Participants 9-17 years of age (n = 360) (1:1:1 randomization): * Arm 1b (n=120): 10µg of R21 with 50µg Matrix-M1 on study day 0, 28, 56 +/- 392 * Arm 2b (n = 120): Control vaccine (rabies vaccine) on study day 0, 28, 56 +/- 392 * Arm 3b (n = 120): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 single vial coformulation on study day 0, 28, 56 +/- 392 Participants 18-50 years of age (n = 300) (1:1:1 randomization): * Arm 1c (n=100): 10µg of R21 with 50µg Matrix-M1 on study day 0, 28, 56 +/- 392 * Arm 2c (n = 100): Control vaccine (rabies vaccine) on study day 0, 28, 56 +/- 392 * Arm 3c (n = 100): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 single vial coformulation on study day 0, 28, 56 +/- 392
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
1,200
R21 is a portion of Pf circumsporozoite protein fused with hepatitis B surface antigen in the form of non-infectious virus-like particles (VLPs) produced in yeast cells (Hansenula) by recombinant DNA technology. Matrix-M1 (Adjuvanted) is cGMP manufactured by Serum Institute of India, PVD, LTD (SIIPL), Pune.
R21 Malaria antigen is expressed in a recombinant high expressing Hansenula polymorpha production strain. The R21 Malaria drug substance lots/batches were cGMP manufactured at SIIPL, India. Recombinant CRM197 is a recombinant protein, and its drug substance lots/batches cGMP manufactured using Pseudomonas fluorescens production strain at SIIPL, India. Recombinant Pfs230D1M drug substance lots/batches of cGMP were manufactured using Hansenula Polymorpha and manufactured at the SIIPL. A single vial coformulation containing 10µg R21 and 6µg Pfs230D1-CRM197 conjugate mixed with 50µg Matrix-M1 has been developed and is manufactured by SIIPL.
University of Science, Technique and Technology of Bamako (Usttb)
Bamako, Mali
RECRUITINGNumber of Participants with Immediate adverse events in all participants
Occurrence of immediate adverse events
Time frame: Up to 30-minutes following each dose
Number of Participants with solicited local adverse events in reactogenicity group
Occurrence of solicited local adverse events
Time frame: Up to 7 days following each dose
Number of Participants with Solicited systemic adverse events in reactogenicity group
Occurrence of solicited systemic adverse events
Time frame: Up to 7 days following each dose
Number of Participants with Unsolicited adverse events in all participants
Occurrence of unsolicited adverse events
Time frame: Up to 28 days following each vaccination
Number of Participants with Serious adverse events in all participants
Occurrence of serious adverse events
Time frame: Through the whole study duration, 24 months post dose 3 or 12 months post dose 4
Number of Participants with Abnormal Laboratory Values post-vaccination in laboratory safety group
Laboratory adverse events
Time frame: at 7 days following each vaccination
Anti-NANP IgG antibodies
Antibody responses to NANP IgG antibodies
Time frame: at 4 weeks post dose 3
Anti-Pfs230D1 IgG antibodies
Antibody responses to Pfs230D1 IgG antibodies
Time frame: at 4 weeks post dose 3
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Sterile, purified inactivated rabies vaccine prepared on vero cells, indicated for the prevention of rabies in children and adults.
Recombinant Pfs230D1M drug substance lots/batches cGMP manufactured using Pichia pastoris manufactured at the Pilot Bioproduction Facility, Walter Reed Army Institute of Research (Silver Spring, Maryland), and at SIIPL respectively. Recombinant CRM197 is a recombinant protein and its drug substance lots/batches cGMP manufactured using Pseudomonas fluorescens production strain at SIIPL, India.
R21 is a fusion protein of hepatitis B surface antigen (HBsAg) to the C-terminus and central repeats of the circumsporozoite (CS) protein of Plasmodium falciparum. R21 VLP, recombinant HBsAg spontaneously self-assembled \& formed a virus-like particle, wherein circumsporozoite protein (CSP) from Plasmodium falciparum is presented on the VLP of recombinant HBsAg particles. R21 Malaria antigen expressed in recombinant high expressing Hansenula polymorpha production strain. The R21 Malaria drug substance lots/batches were cGMP manufactured at SIIPL, India.
active ingredient in Matrix-M1 are saponin-based fractions. Matrix-M1 has a ratio of Matrix-A and Matrix-C of 85:15 (by weight). Both Matrix-A and Matrix-C are individual fractions (separated by chromatography) derived from extracts from the Quillaja saponaria tree. Matrix-M1 (Adjuvanted) is cGMP manufactured by Serum Institute of India, PVD, LTD (SIIPL), Pune.
To assess vaccine functional activity against transmission by DSF
Proportion reduction in proportion of infected mosquitoes (among those dissected)
Time frame: from 2 weeks to 24 weeks after completion of the primary vaccine course +/- booster
To assess vaccine functional activity against transmission by DSF
Proportion reduction in DSFs with at least one infected mosquito
Time frame: from 2 weeks to 24 weeks after completion of the primary vaccine course +/- booster
humoral immunogenicity time trends and durability
Antibody responses to Pfs230D1
Time frame: at baseline, 28 days after each dose and through study completion, at an average of 1 month
humoral immunogenicity time trends and durability
Antibody responses to NANP
Time frame: at baseline, 28 days after each dose and through study completion, at an average of 1 month
To assess the protective efficacy against clinical malaria caused by Pf
Efficacy against clinical malaria as defined by: presence of asexual P. falciparum parasitemia \>0 parasites/µL and/or RDT positive with either an axillary temperature of ≥37.5 °C or one or more of the following symptoms: history of fever within the last 48 hours, headache, myalgia, arthralgia, malaise, nausea, dizziness, or abdominal pain
Time frame: At 24 and 52 weeks after completion of the primary and booster vaccine course