Safety, Immunogenicity of RTS,S/AS02A, and RTS,S/AS01B Malaria Vaccines in Malaria-experienced Adults.

A Phase IIb Randomized, Double-blind, Controlled Study of the Safety, Immunogenicity and Proof-of-concept of RTS,S/AS02A, and RTS,S/AS01B, Two Candidate Malaria Vaccines in Malaria-experienced Adults Living in Western Kenya.

The candidate malaria vaccine RTS,S/AS02A developed by GSK Biologicals demonstrated 30% efficacy against clinical episodes of malaria and approximately 58% efficacy against severe malaria disease. As a potential improvement to RTS,S/AS02A, another candidate vaccine RTS,S/AS01B is being developed in parallel in collaboration with the Walter Reed Army Institute of Research (WRAIR). This study will be the first administration of the RTS,S/AS01B vaccine to the African adults to establish safety and immunogenicity in this population. Preliminary indication of vaccine efficacy with this adjuvant will be established by monitoring the time to the first infection with Plasmodium falciparum.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum
• Intervention / Treatment: Biological: RTS, S/AS01B; Biological: RTS, S/AS02A; Biological: Rabipur (Rabies) Vaccine

Detailed Description

The study comprises of 3 groups and the participating subjects will be randomly allocated to one of the three groups. The first group will receive RTS,S/AS01B, the second group will receive RTS,S/AS02A and the third group will receive rabies vaccine. Immunization will be given by IM injection on 0, 1, 2 month schedule. Infants will be followed up daily for 7 days for solicited symptoms and 30 days for unsolicited symptoms after each vaccine dose. Serious adverse events will be recorded throughout the study period. A week prior to Dose 3, subjects will be treated with a licenced anti-malarial drug. Starting from two weeks after Dose 3, the subjects will be monitored for a 14-week duration for detection of malaria infection.

• Study Type: Interventional
• Enrollment (Actual): 255
• Phase: Phase 2

Contacts and Locations

Study Locations

• Kenya
  • Kisumu, Kenya
    • U.S. Army Research Unit-Kenya

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Healthy male or female volunteers aged between 18 and 35 years at the time of first vaccination who have given written consent for their participation in the study were included
• If the volunteer is female, she must be of non-childbearing potential, i.e. either surgically sterilized or one year post-menopausal; or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after completion of the vaccination series

Exclusion criteria:

• If a subject plans to take vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine(s) with the exception of tetanus toxoid will be excluded
• Volunteers with any confirmed or suspected immunosuppressive or immunodeficient conditions
• Family history of congenital or hereditary immunodeficiency
• History of allergic reactions to previous immunizations
• HBsAg positive subjects
• History of splenectomy
• Pregnant or lactating females will be excluded from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VACC 1 (RTS, S/AS01B); RTS, S/AS01B: 0.5mL dose; 50ug RTS, S antigen, 50ug QS21 and liposomes in phosphate-buffered saline administered intramuscular deltoid of non-dominant arm at 0, 1 and 2 months.	Biological: RTS, S/AS01B; 0.5mL dose; 50ug RTS, S antigen, 50ug QS21 and liposomes in phosphate-buffered saline administered intramuscular deltoid of non-dominant arm at 0, 1 and 2 months.
Experimental: VACC 2 (RTS, S/AS02A); RTS, S/AS02A: 0.5mL dose; 50ug RTS, S antigen, 50ug QS21 and proprietary oil-water emulsion in phosphate-buffered saline administered intramuscular deltoid of non-dominant arm at 0, 1 and 2 months.	Biological: RTS, S/AS02A; 0.5mL dose; 50ug RTS, S antigen, 50ug QS21 and proprietary oil-water emulsion in phosphate-buffered saline administered intramuscular deltoid of non-dominant arm at 0, 1 and 2 months.
Active Comparator: Rabipur (Rabies) Vaccine; Rabipur (Rabies) Vaccine: 1.0mL dose administered intramuscular deltoid of non-dominant arm at 0, 1 and 2 months.	Biological: Rabipur (Rabies) Vaccine; 1.0mL dose administered intramuscular deltoid of non-dominant arm at 0, 1 and 2 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Proportion of Subjects With Grade 3 Solicited and Unsolicited General Reactions After Vaccination of RTS, S/AS02A and RTS, S/AS01B	Proportion of subjects with grade 3 solicited and unsolicited general reactions after vaccination of RTS, S/AS02A and RTS, S/AS01B during a 7 day follow-up period (day of vaccination + 6 days).	7 day follow-up (day of vaccination + 6 days)
Safety: Number of Administered Doses Eliciting Grade 3 Unsolicited Symptoms	Grade 3 unsolicited symptoms reported following any number of administered doses	6.5 months
Safety: Number of Doses Eliciting Solicited Local Symptoms Reported Over 7 Day Follow-up Period	Incidence overall solicited general and local reactions over 7 day follow-up period after dose 1, 2 and 3 (Total Cohort)	7 day follow-up period (day of vaccination + 6 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Occurrence of SAEs	Percentage of subjects experiencing SAEs classified by MedRA System Organ Class and Preferred Term (Month 6.5-12)	months 6.5 thru 12
Safety: Occurrence of SAEs	Percentage of subjects reporting SAEs classified by MedDRA System Organ Class and Preferred Term (Month 0-12)	months 0 thru 12
Occurrence of Hematology Parameters Below Normal Range	Occurrence of hematology parameters below normal range (Total Cohort)	Days 0, 6, 66, and 90; Months 6 and 12
Occurrence of Biochemistry Parameters Above Normal Ranges	Occurrence of parameters of biochemical monitoring above normal ranges (Total Cohort)	Days 0, 6, and 90

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seropositivity Rates for Anti-HBs Antibodies by Infection Status PRE	Seropositivity rates and GMTs for Anti-HBs antibodies by infection status (Total Cohort) Seropositive >3.3 mlU/mL; Seroprotected >10 mIU/mL Infection defined as P. falciparum asexual parasitemia >0 PRE= Prevaccination	Prevaccination
Seropositivity Rates for Anti-HBs Antibodies by Infection Status PIII(D90)	Seropositivity rates and GMTs for Anti-HBs antibodies by infection status (Total Cohort) Seropositive >3.3 mlU/mL; Seroprotected: >10 mlU/mL Infection defined as P. falciparum asexual parasitemia >0 PIII(D90)= post dose 3 (day 90)	Day 90
Seropositivity Rates for Anti-HBs Antibodies by Infection Status PIII(M12)	Seropositivity rates and GMTs for Anti-HBs antibodies by infection status (Total Cohort) Seropositive >3.3 mlU/mL; Seroprotected: >10 mlU/mL Infection defined as P. falciparum asexual parasitemia >0 PIII(M12)= post dose 3 (month 12)	Month 12
Seropositivity Rates for Anti-HBs Antibodies by Vaccine Group PRE	Seropositivity rates for Anti-HBs antibodies by vaccine group (ATP Cohort for Immunogenicity). Seropositive >3.3 mlU/ML PRE=Prevaccination	Prevaccination
Seropositivity Rates for Anti-HBs Antibodies by Vaccine Group PIII(D90)	Seropositivity rates for Anti-HBs antibodies by vaccine group (ATP Cohort for Immunogenicity). Seropositive >3.3 mlU/ML PIII(D90)= post dose 3 (Day 90)	Day 90
Seropositivity Rates for Anti-HBs Antibodies by Vaccine Group PIII(M12)	Seropositivity rates for Anti-HBs antibodies by vaccine group (ATP Cohort for Immunogenicity). Seropositive >3.3 mlU/ML PIII(M12)= post dose 3 (Month 12)	Month 12
Seroprotection Rates for Anti-HBs Antibodies by Vaccine Group PRE	Seroprotection rates for Anti-HBs antibodies by vaccine group (ATP Cohort for Immunogenicity). Seroprotected >10 mlU/mL PRE=Prevaccination	Prevaccination
Seroprotection Rates for Anti-HBs Antibodies by Vaccine Group PIII (D90)	Seroprotection rates for Anti-HBs antibodies by vaccine group (ATP Cohort for Immunogenicity). Seroprotected >10 mlU/mL PIII(D90)= post dose 3 (Day 90)	Day 90
Seroprotection Rates for Anti-HBs Antibodies by Vaccine Group PIII (M12)	Seroprotection rates for Anti-HBs antibodies by vaccine group (ATP Cohort for Immunogenicity). Seroprotected >10 mlU/mL PIII(M12)= post dose 3 (Month 12)	Month 12
Geometric Mean Antibody Titers (GMTs) for Anti-HBs Antibodies by Vaccine Group PRE	Geometric mean antibody titers (GMTs) for Anti-HBs antibodies by vaccine group (According to protocol (ATP) Cohort for Immunogenicity) PRE=Prevaccination	Prevaccination
Geometric Mean Titers (GMTs) for Anti-HBs Antibodies by Vaccine Group PIII (D90)	Geometric mean titers (GMTs) for Anti-HBs antibodies by vaccine group (According to protocol (ATP) Cohort for Immunogenicity) PIII(D90)= post dose 3 (Day 90)	Day 90
Geometric Mean Titers (GMTs) for Anti-HBs Antibodies by Vaccine Group PIII (M12)	Geometric mean titers (GMTs) for Anti-HBs antibodies by vaccine group (According to protocol (ATP) Cohort for Immunogenicity) PIII(M12)= post dose 3 (Month 12)	Month 12
Geometric Mean Titers (GMTs) for Anti-HBs Antibodies by Infection Status PRE	Geometric mean titers (GMTs) for Anti-HBs antibodies by infection status (Total Cohort) Infection defined as P. falciparum asexual parasitemia >0 PRE= Prevaccination	Prevaccination
Geometric Mean Titers (GMTs) for Anti-HBs Antibodies by Infection Status PIII (D90)	Geometric mean titers (GMTs) for Anti-HBs antibodies by infection status (Total Cohort) Infection defined as P. falciparum asexual parasitemia >0 PIII(D90)= post dose 3 (day 90)	Day 90
Geometric Mean Titers (GMTs) for Anti-HBs Antibodies by Infection Status PIII (M12)	Geometric mean titers (GMTs) for Anti-HBs antibodies by infection status (Total Cohort) Infection defined as P. falciparum asexual parasitemia >0 PIII(M12)= post dose 3 (month 12)	Month 12
Geometric Mean Titers (GMTs) for Anti-CS Antibodies up to Month 12 by Vaccine Group PRE	Geometric mean titers (GMTs) for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PRE= prevaccination	Prevaccination
Geometric Mean Titers (GMTs) for Anti-CS Antibodies up to Month 12 by Vaccine Group PII (D60)	Geometric mean titers (GMTs) for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PII(D60)= post dose 2 (day 60)	1 month post dose 2
Geometric Mean Titers (GMTs) for Anti-CS Antibodies up to Month 12 by Vaccine Group PIII (D90)	Geometric mean titers (GMTs) for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PIII(D90)= post dose 3 (day 90)	1 month post dose 3
Geometric Mean Titers (GMTs) for Anti-CS Antibodies up to Month 12 by Vaccine Group PIII (M6.5)	Geometric mean titers (GMTs) for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PIII(M6.5)= post dose 3 (month 6.5)	4 months post dose 3
Geometric Mean Titers (GMTs) for Anti-CS Antibodies up to Month 12 by Vaccine Group PIII (M12)	Geometric mean titers (GMTs) for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PIII(M12)= post dose 3 (month 12)	10 months post dose 3
Geometric Mean Antibody Titers (GMTs) for Anti-CS Antibodies by Infection Status PRE	Geometric mean antibody titers (GMTs) for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Infection defined as P. falciparum asexual parasitemia >0 PRE= Pre-vaccination	PRE
Geometric Mean Antibody Titers (GMTs) for Anti-CS Antibodies by Infection Status PII (D60)	Geometric mean antibody titers (GMTs) for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Infection defined as P. falciparum asexual parasitemia >0 PII(D60)= post dose 2 (day 60)	post dose 2 (day 60)
Geometric Mean Antibody Titers (GMTs) for Anti-CS Antibodies by Infection Status PIII (D90)	Geometric mean antibody titers (GMTs) for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Infection defined as P. falciparum asexual parasitemia >0 PIII(D90)= post dose 3 (day 90)	post dose 3 (day 90)
Geometric Mean Antibody Titers (GMTs) for Anti-CS Antibodies by Infection Status PIII (M6.5)	Geometric mean antibody titers (GMTs) for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Infection defined as P. falciparum asexual parasitemia >0 PIII(M6.5)= post dose 3 (month 6.5)	post dose 3 (month 6.5)
Seropositivity Rates for Anti-CS Antibodies by Vaccine Group PRE	Seropositivity rates for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PRE= prevaccination	Prevaccination
Seropositivity Rates for Anti-CS Antibodies by Vaccine Group PII (D60)	Seropositivity rates for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3. PII(D60)= post dose 2 (day 60)	1 month post dose 2
Seropositivity Rates for Anti-CS Antibodies by Vaccine Group PIII (D90)	Seropositivity rates for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PIII(D90)= post dose 3 (day 90)	1 month post dose 3
Seropositivity Rates for Anti-CS Antibodies by Vaccine Group PIII (M6.5)	Seropositivity rates for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PIII(M6.5)= post dose 3 (month 6.5)	4 months post dose 3
Seropositivity Rates for Anti-CS Antibodies by Vaccine Group PIII (M12)	Seropositivity rates for Anti-CS antibodies accessed prevaccination, 1 month post dose 2, 1 month post dose 3, 4 months post dose 3 and 10 months post dose 3 PIII(M12)= post dose 3 (month 12)	10 months post dose 3
Seropositivity Rates for Anti-CS Antibodies by Infection Status PRE	Seropositivity rates for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Seropositive: >0.5EU/mL Infection defined as P. falciparum asexual parasitemia >0 PRE= Pre-vaccination	Prevaccination
Seropositivity Rates for Anti-CS Antibodies by Infection Status PII (D60)	Seropositivity rates for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Seropositive: >0.5EU/mL Infection defined as P. falciparum asexual parasitemia >0 PII(D60)= post dose 2 (day 60)	post dose 2 (day 60)
Seropositivity Rates for Anti-CS Antibodies by Infection Status PIII (D90)	Seropositivity rates for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Seropositive: >0.5EU/mL Infection defined as P. falciparum asexual parasitemia >0 PIII(D90)= post dose 3 (day 90)	post dose 3 (day 90)
Seropositivity Rates for Anti-CS Antibodies by Infection Status PIII (M6.5)	Seropositivity rates for Anti-CS antibodies by infection status on RTS,S/AS01B and RTS,S/AS02A recipients only Seropositive: >0.5EU/mL Infection defined as P. falciparum asexual parasitemia >0 PIII(M6.5)= post dose 3 (month 6.5)	post dose 3 (month 6.5)
Efficacy: Vaccine Efficacy Against P. Falciparum Infection	Number of subjects with an episode of parasitemia (first recording of infection of asexual stage falciparum parasites >0 detected by active detection of infection (ADI) or passive case detection)	14 days after dose 3 and extending for 14 weeks
Percentage of Participants With Positive and Negative Parasite Density	Percentage of participants with positive and negative parasite density at month 6.5	at month 6.5
Geometric Mean Antibody Titers (GMTs) of Asexual P. Falciparum Parasitemia	Geometric Mean Antibody Titers (GMTs) of Asexual P. falciparum parasitemia at Month 6.5	Month 6.5

Collaborators and Investigators

• Sponsor: U.S. Army Medical Research and Development Command
• Collaborators: GlaxoSmithKline; Walter Reed Army Institute of Research (WRAIR)

Publications and helpful links

General Publications

• Polhemus ME, Remich SA, Ogutu BR, Waitumbi JN, Otieno L, Apollo S, Cummings JF, Kester KE, Ockenhouse CF, Stewart A, Ofori-Anyinam O, Ramboer I, Cahill CP, Lievens M, Dubois MC, Demoitie MA, Leach A, Cohen J, Ballou WR, Heppner DG Jr. Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLoS One. 2009 Jul 31;4(7):e6465. doi: 10.1371/journal.pone.0006465.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2005
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (Estimate): September 20, 2005

Study Record Updates

• Last Update Posted (Actual): February 12, 2021
• Last Update Submitted That Met QC Criteria: February 10, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: A-12227; IND 11220 (Other Identifier: FDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: GSK and WRAIR
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No