Evaluation of RTS,S/AS02A and RTS,S/AS01B in Adults in a High Malaria Transmission Area

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 Aug 4

PMID 19649245

Citations 72

Authors

Mark E Polhemus

Shon A Remich

Bernhards R Ogutu

John N Waitumbi

Lucas Otieno

Stella Apollo

James F Cummings

Kent E Kester

Christian F Ockenhouse

Ann Stewart

Opokua Ofori-Anyinam

Isabelle Ramboer

Conor P Cahill

Marc Lievens

Marie-Claude Dubois

Marie-Ange Demoitie

Amanda Leach

Joe Cohen

W Ripley Ballou

D Gray Heppner Jr

Affiliations

Soon will be listed here.

Abstract

Background: This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine.

Methodology: A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1ratio1ratio1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (Rabipur; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination.

Principal Findings: Both candidate vaccines had a good safety profile and were well tolerated. One grade 3 systemic AE occurred within 7 days of vaccination (RTS,S/AS01B group). No unsolicited AEs or SAEs were related to vaccine. A marked increase in anti-CS antibody GMTs was observed post Dose 2 of both RTS,S/AS01B (31.6 EU/mL [95% CI: 23.9 to 41.6]) and RTS,S/AS02A (16.7 EU/mL [95% CI: 12.9 to 21.7]). A further increase was observed post Dose 3 in both the RTS,S/AS01B (41.4 EU/mL [95% CI: 31.7 to 54.2]) and RTS,S/AS02A (21.4 EU/mL [95% CI: 16.0 to 28.7]) groups. Anti-CS antibody GMTs were significantly greater with RTS,S/AS01B compared to RTS,S/AS02A at all time points post Dose 2 and Dose 3. Both candidate vaccines produced strong anti-HBs responses. Vaccine efficacy in the RTS,S/AS01B group was 29.5% (95% CI: -15.4 to 56.9, p = 0.164) and in the RTS,S/AS02A group 31.7% (95% CI: -11.6 to 58.2, p = 0.128).

Conclusions: Both candidate malaria vaccines were well tolerated over a 12 month surveillance period. A more favorable immunogenicity profile was observed with RTS,S/AS01B than with RTS,S/AS02A.

Trial Registration: Clinicaltrials.gov NCT00197054.

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References

Doherty J, Pinder M, Tornieporth N, Carton C, Vigneron L, Milligan P . A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia. Am J Trop Med Hyg. 2000; 61(6):865-8. DOI: 10.4269/ajtmh.1999.61.865. View

Greenwood B, Bojang K, Whitty C, Targett G . Malaria. Lancet. 2005; 365(9469):1487-98. DOI: 10.1016/S0140-6736(05)66420-3. View

Stoute J, Heppner Jr D, Mason C, Siangla J, Opollo M, Kester K . Phase 1 safety and immunogenicity trial of malaria vaccine RTS,S/AS02A in adults in a hyperendemic region of western Kenya. Am J Trop Med Hyg. 2006; 75(1):166-70. View

Kester K, Cummings J, Ockenhouse C, Nielsen R, Hall B, Gordon D . Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research. Vaccine. 2008; 26(18):2191-202. DOI: 10.1016/j.vaccine.2008.02.048. View

Kensil C . Saponins as vaccine adjuvants. Crit Rev Ther Drug Carrier Syst. 1996; 13(1-2):1-55. View

Kester K, Cummings J, Ofori-Anyinam O, Ockenhouse C, Krzych U, Moris P . Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis. 2009; 200(3):337-46. DOI: 10.1086/600120. View

Stewart V, Mcgrath S, Walsh D, Davis S, Hess A, Ware L . Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS,S/AS02A. Vaccine. 2006; 24(42-43):6483-92. DOI: 10.1016/j.vaccine.2006.06.033. View

Lalvani A, Moris P, Voss G, Pathan A, Kester K, Brookes R . Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine. J Infect Dis. 1999; 180(5):1656-64. DOI: 10.1086/315074. View

Kester K, McKinney D, Tornieporth N, Ockenhouse C, Heppner Jr D, Hall T . A phase I/IIa safety, immunogenicity, and efficacy bridging randomized study of a two-dose regimen of liquid and lyophilized formulations of the candidate malaria vaccine RTS,S/AS02A in malaria-naïve adults. Vaccine. 2007; 25(29):5359-66. DOI: 10.1016/j.vaccine.2007.05.005. View

10.

Ulrich J, Myers K . Monophosphoryl lipid A as an adjuvant. Past experiences and new directions. Pharm Biotechnol. 1995; 6:495-524. View

11.

Abdulla S, Oberholzer R, Juma O, Kubhoja S, Machera F, Membi C . Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med. 2008; 359(24):2533-44. DOI: 10.1056/NEJMoa0807773. View

12.

Garcon N, Heppner D, Cohen J . Development of RTS,S/AS02: a purified subunit-based malaria vaccine candidate formulated with a novel adjuvant. Expert Rev Vaccines. 2003; 2(2):231-8. DOI: 10.1586/14760584.2.2.231. View

13.

Breman J . The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. Am J Trop Med Hyg. 2001; 64(1-2 Suppl):1-11. DOI: 10.4269/ajtmh.2001.64.1. View

14.

Malaney P, Spielman A, Sachs J . The malaria gap. Am J Trop Med Hyg. 2004; 71(2 Suppl):141-6. View

15.

Bojang K, Olodude F, Pinder M, Ofori-Anyinam O, Vigneron L, Fitzpatrick S . Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children. Vaccine. 2005; 23(32):4148-57. DOI: 10.1016/j.vaccine.2005.03.019. View

16.

Pinder M, Reece W, Plebanski M, Akinwunmi P, Flanagan K, Lee E . Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia. Clin Exp Immunol. 2004; 135(2):286-93. PMC: 1808944. DOI: 10.1111/j.1365-2249.2004.02371.x. View

17.

Stoute J, Slaoui M, Heppner D, Momin P, Kester K, Desmons P . A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N Engl J Med. 1997; 336(2):86-91. DOI: 10.1056/NEJM199701093360202. View

18.

Aponte J, Aide P, Renom M, Mandomando I, Bassat Q, Sacarlal J . Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet. 2007; 370(9598):1543-51. DOI: 10.1016/S0140-6736(07)61542-6. View

19.

Macete E, Aponte J, Guinovart C, Sacarlal J, Ofori-Anyinam O, Mandomando I . Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique. Trop Med Int Health. 2007; 12(1):37-46. DOI: 10.1111/j.1365-3156.2006.01754.x. View

20.

Sun P, Schwenk R, White K, Stoute J, Cohen J, Ballou W . Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ T cells producing IFN-gamma. J Immunol. 2003; 171(12):6961-7. DOI: 10.4049/jimmunol.171.12.6961. View