Skip to main content
SpringerLink
Log in

Development of the RTS,S/AS Vaccine Candidate from Concept to Phase III

  • Chapter
  • First Online:
Progress in Parasitology

Part of the book series: Parasitology Research Monographs ((Parasitology Res. Monogr.,volume 2))

Abstract

This review describes the developmental history of the RTS,S/AS vaccine. Selection of the circumsporozoite protein (CSP) as the target antigen was key to the successful development of the vaccine so far, from concept to the initiation of Phase III testing. CSP, a pre-erythrocytic protective antigen against Plasmodium falciparum, has been demonstrated to be immunodominant and protective in pre-clinical studies both in animals and humans. The vaccine antigen was designated “RTS,S”; RTS being a hybrid polypeptide consisting of a portion of the CSP antigen and S the surface antigen of Hepatitis B virus (HBsAg). The RTS,S/AS candidate vaccine has been evaluated in multiple Phase I/II studies and shown to have a favourable safety profile and to be well tolerated in both adults and children. Consistent and significant efficacy against Plasmodium falciparum infection and disease was observed in the target population of infants and children in a range of age groups and in different malaria transmission settings. The RTS,S/AS01E malaria vaccine candidate has recently entered Phase III testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline, their partners and collaborators. If the Phase III results confirm the observations made during Phase II testing, the RTS,S/AS01E vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, could have a major public-health impact in sub-Saharan Africa.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    Engerix-B is a trademark of the GlaxoSmithKline group of companies.

References

  • Abdulla S, Oberholzer R, Juma O, Kubhoja S, Machera F, Membi C et al (2008) Safety and immunogenicity of RTS, S/AS02D malaria vaccine in infants. N Engl J Med 359:2533–2544

    Article  Google Scholar 

  • Alloueche A, Milligan P, Conway DJ (2003) Protective efficacy of the RTS, S/AS02A Plasmodium falciparum malaria vaccine is not strain specific. Am J Trop Med Hyg 68:97–101

    PubMed  Google Scholar 

  • Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J et al (2004) Efficacy of the RTS, S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 364:1411–1420

    Article  PubMed  CAS  Google Scholar 

  • Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P et al (2005) Duration of protection with RTS, S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366:2012–2018

    Article  PubMed  CAS  Google Scholar 

  • Aponte JJ, Aide P, Renom M, Mandomando I, Bassat Q, Sacarlal J et al (2007) Safety of the RTS, S/AS02D vaccine against Plasmodium falciparum infection in infants. A phase I/IIb trial in a highly endemic area in Mozambique. Lancet 370:1543–1551

    Article  PubMed  CAS  Google Scholar 

  • Ballou R, Cahill C (2007) Two decades of commitment to malaria vaccine development: GlaxoSmithKline Biologicals. Am J Trop Med Hyg 77(6 Suppl):289–295

    PubMed  Google Scholar 

  • Ballou WR, Rothbard J, Wirtz RA, Gordon DM, Williams JS, Gore RW et al (1985) Immunogenicity of synthetic peptides from the circumsporozoite protein of Plasmodium falciparum. Science 228:996–999

    Article  PubMed  CAS  Google Scholar 

  • Ballou WR, Hoffman SL, Sherwood JA, Hollingdale MR, Neva FA, Hockmeyer WT et al (1987) Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet 1:1277–1281

    Article  PubMed  CAS  Google Scholar 

  • Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J et al (2008) Efficacy of RTS, S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med 359:2521–2532

    Article  PubMed  CAS  Google Scholar 

  • Bojang KA, Milligan PJ, Pinder M, Vigneron L, Alloueche A, Kester KE et al (2001) Efficacy of RTS, S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomized trial. Lancet 358:1927–1934

    Article  PubMed  CAS  Google Scholar 

  • Bojang K, Olodude F, Pinder M, Ofori-Anyinam O, Vigneron L, Fitzpatrick S et al (2005) Phase I safety and immunogenicity of RTS, S/AS02A candidate malaria vaccine in Gambian children. Vaccine 23:4148–4157

    Article  PubMed  CAS  Google Scholar 

  • Bojang K, Milligan P, Pinder M, Doherty T, Leach A, Ofori-Anyinam O et al (2009) Five year safety and immunogenicity of GlaxoSmithKline’s candidate malaria vaccine RTS, S/AS02 following administration to semi-immune adult men living in a malaria-endemic region of The Gambia. Hum Vaccin 5(4):242–247

    Article  PubMed  CAS  Google Scholar 

  • Brown AE, Singharaj P, Webster HK, Pipithkul J, Gordon DM, Boslego JW et al (1994) Safety, immunogenicity and limited efficacy study of a recombinant Plasmodium falciparum circumsporozoite vaccine in Thai soldiers. Vaccine 12:102

    Article  PubMed  CAS  Google Scholar 

  • ClinicalTrials.gov (2009) http://www.clinicaltrials.gov/ct2/show/NCT00866619?term=malaria+efficacy&rank=2.

  • Doherty JF, Pinder M, Tornieporth N, Carton C, Vigneron L, Milligan P et al (1999) A phase I safety and immunogenicity trial with the candidate malaria vaccine, RTS, S/SABAS2, in semi-immune adults in the Gambia. Am J Trop Med Hyg 61:865–868

    PubMed  CAS  Google Scholar 

  • Doolan DL, Marinez-Alier N (2006) Immune response to pre-erythrocytic stages of malaria parasites. Curr Mol Med 6:69–85

    Article  Google Scholar 

  • Enosse S, Dobaño C, Quelhas D, Aponte JJ, Lievens M, Leach A et al (2006) RTS, S/AS02A malaria vaccine reduces the genotypic multiplicity of Plasmodium falciparum infections without inducing selection on polymorphic CSP T-cell epitopes. PLoS Clin Trials 1:e5. doi:10.1371/journal.pctr.0010005

    Article  PubMed  Google Scholar 

  • Ferreira A, Schofield L, Enea V, Schellekens H, van der Meide P, Collins WE, Nussenzweig RS, Nussenzweig V (1986) Inhibition of development of exoerythrocytic forms of malaria parasites by γ interferon. Science 232:881–884

    Article  PubMed  CAS  Google Scholar 

  • Frevert U, Nardin E (2008) Cellular effector mechanisms against liver stages. Cell Microbiol 10:1956–1967

    Article  PubMed  CAS  Google Scholar 

  • Fries LF, Gordon DM, Richards RL, Egan JE, Hollingdale MR, Gross M et al (1992) Liposomal malaria vaccine in humans: a safe and potent adjuvant strategy. Proc Natl Acad Sci USA 89:358–362

    Article  PubMed  CAS  Google Scholar 

  • Garçon N, Heppener DG, Cohen J (2003) Development of RTS, S/AS02: a purified subunit-based malaria vaccine candidate formulated with a novel adjuvant. Expert Rev Vaccines 2:231–238

    Article  PubMed  Google Scholar 

  • Good M, Pombo D, Quakyi I, Riley EM, Houghten RA, Menon A et al (1988) Human T-cell recognition of the circumsporozoite protein of Plasmodium falciparum: immunodominant T-cell domains map to the polymorphic regions of the molecule. Proc Natl Acad Sci USA 85:1199–1203

    Article  PubMed  CAS  Google Scholar 

  • Gordon DM, McGovern TW, Krzych U, Cohen JC, Schneider I, LaChance R et al (1995) Safety, immunogenicity and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein / HBsAg subunit vaccine. J Infect Dis 171:1576–1585

    Article  PubMed  CAS  Google Scholar 

  • Hockmeyer WT, Ballou WR, Young JF (1986) Recent efforts in the development of a sporozoite vaccine against Plasmodium falciparum. In: Lerner RA, Chanoc RM, Brown F (eds) Vaccine 86: molecular and chemical basis of resistance to parasitic, bacterial, and viral diseases. Cold Spring Laboratory, Cold Spring Harbor

    Google Scholar 

  • Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, Doolan DL et al (2002) Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J Infect Dis 185:1155–1164

    Article  PubMed  Google Scholar 

  • Hollingdale MR, Ballou WR, Aley SB, Young JF, Pancake S, Miller LH, Hockmeyer WT (1987) Plasmodium falciparum: elicitation by peptides and recombinant circumsporozoite proteins of circulating mouse antibodies inhibiting sporozoite invasion of hepatoma cells. Exp Parasitol 63:345–351

    Article  PubMed  CAS  Google Scholar 

  • Kester KE, McKinney DA, Ockenhouse CF, Heppner DG, Wellde BT, Stoute JA et al (2001) Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J Infect Dis 183:640–647

    Article  PubMed  CAS  Google Scholar 

  • Kester KE, McKinney DA, Tornieporth N, Ockenhouse CF, Heppner DG, Hall T et al (2007) A phase 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 25:3559–3566

    Article  Google Scholar 

  • Kester KE, Cummings JF, Ockenhouse CF, Nielsen R, Hall BT, Gordon DM et al (2008) 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 26:2191–2202

    Article  PubMed  CAS  Google Scholar 

  • Kester KK, Cummings JF, Ofori-Anyinam O, Ockenhouse CF, Krzych U, Moris P et al (2009) Randomized, double-blind, phase 2a trial of Falciparum malaria vaccines RTS, S/AS01B and RTS, S/AS02A in malaria-naïve adults; safety, efficacy, and immunologic associates of protection. J Infect Dis 200:337–346

    Article  PubMed  CAS  Google Scholar 

  • Kumar KA, Sano G, Boscardin S, Nussenzweig RS, Nussenzweig MC, Zavala F, Nussenzweig V (2006) The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature 444:937–940

    Article  PubMed  CAS  Google Scholar 

  • Kumar KA, Baxter P, Tarun AS, Kappe SH, Nussenzweig V (2009) Conserved protective mechanisms in radiation and genetically attenuated uis3 and uis4 Plasmodium sporozoites. PLoS One 4:e4480

    Article  PubMed  Google Scholar 

  • Lell B, Agnandji S, Von Glasenapp I et al (2009) A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS, S malaria vaccine candidates in children in Gabon. PLoS One 4(10):e7611

    Article  PubMed  Google Scholar 

  • Macete E, Aponte JJ, Guinovart C, Sacarlal J, Ofori-Anyinam O, Mandomando I et al (2007a) Safety and immunogenicity of the RTS, S/AS02A candidate malaria vaccine in children aged 1–4 in Mozambique. Trop Med Int Health 12:37–46

    PubMed  CAS  Google Scholar 

  • Macete EV, Sacarlal J, Aponte JJ, Leach A, Navia MM, Milman J et al (2007b) Evaluation of two formulations of adjuvanted RTS, S malaria vaccine in children aged 3 to 5 years living in a malaria-endemic region of Mozambique: a phase I/IIb randomized double-blind bridging trial. Trials 8:11

    Article  PubMed  Google Scholar 

  • Malaria Vaccine Technology Roadmap (2006) www.malariavaccineroadmap.net/pdfs/Malaria_Vaccine_TRM_Final.pdf

  • Mettens P, Dubois P, Demoitié MA, Bayat B, Donner MN, Bourguignon P et al (2008) Improved T cell responses to Plasmodium falciparum circumsporozoite protein in mice and monkeys induced by a novel formulation of RTS, S vaccine Antigen. Vaccine 26:1072–1082

    Article  PubMed  CAS  Google Scholar 

  • Mueller AK, Labaied M, Kappe SG, Matuschewski K (2005) Genetically modified Plasmodium parasites as a protective experimental malaria vaccine. Nature 433:113–114

    Article  Google Scholar 

  • Nussenzweig V, Nussenzweig RS (1989) Rationale for the development of an engineered sporozoite malaria vaccine. Adv Immunol 45:283–331

    Article  PubMed  CAS  Google Scholar 

  • Owusu-Agyei S, Ansong D, Asante KP et al (2009) Evaluation of RTS, S/AS02D and RTS, S/AS01E malaria candidate vaccines when given according to different vaccination schedules in Ghanaian children. PLoS One 4(10):e7302

    Article  PubMed  Google Scholar 

  • Polhemus ME, Remich SA, Ogutu BR, Waitumbi JN, Otieno L, Apollo S et al (2009) Evaluation of RTS, S/AS02A and RTS, S/AS01B in adults in a high malaria transmission area. PLoS One 4(7):e6465

    Article  PubMed  Google Scholar 

  • Potocnjak P, Yoshida N, Nussenzweig RS, Nussenzweig V (1980) Monovalent fragments (Fab) of monoclonal antibodies against a sporozoite surface antigen (pb44) protect mice against malaria infection. J Exp Med 151:1504–1513

    Article  PubMed  CAS  Google Scholar 

  • Reece WH, Pinder M, Gothard PK, Milligan P, Bojang K, Doherty T et al (2004) A CD4(+)T cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease. Nat Med 10:406–410

    Article  PubMed  CAS  Google Scholar 

  • Rutgers T, Cabezon T, Harford N, Vanderbrugge D, Descurieux M, Van Opstal O et al (1987) Expression of different forms of HBV envelope proteins in yeast. J Med Virol 21:53A

    Google Scholar 

  • Sacarlal J, Aide P, Aponte JJ, Renom M, Leach A, Mandomando I et al (2009) Long-term safety and efficacy of the RTS, S/AS02A malaria vaccine in Mozambican children. J Infect Dis 200:329–336

    Article  PubMed  Google Scholar 

  • Sherwood JA, Copeland RS, Taylor KA, Abok K, Oloo AJ, Were JB et al (1996) Plasmodium falciparum circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya. Vaccine 14:817–827

    Article  PubMed  CAS  Google Scholar 

  • Singh AP, Buscaglia CA, Wang Q, Levay A, Nussenzweig DR, Walker JR et al (2007) Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite. Cell 131:492–504

    Article  PubMed  CAS  Google Scholar 

  • Sinnis P, Nussenzweig V (1996) Preventing sporozoite invasion of hepatocytes. In: Hoffman SL (ed) Malaria vaccine development: a multi-immune response approach. American Society for Microbiology, Washington DC, pp 15–33, Chapter 2

    Google Scholar 

  • Stewart VA, McGrath SM, Walsh DS, Davis S, Hess AS, Ware LA et al (2006a) Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS, S/AS02A. Vaccine 24:6483–6492

    Article  PubMed  CAS  Google Scholar 

  • Stewart VA, Walsh DS, McGrath SM, Kester KE, Cummings JF, Voss G et al (2006b) Cutaneous delayed-type hypersensitivity (DTH) in a multi-formulation comparator. Vaccine 24:6493–6502

    Article  PubMed  CAS  Google Scholar 

  • Stoute JA, Slaoui M, Heppner DG, Garçon N, Kester KE, Desmons P, Schwenk R et al (1997) A preliminary evaluation of a recombinant circumsporozoite protein malaria vaccine against Plasmodium falciparum. N Engl J Med 36:86–91

    Article  Google Scholar 

  • Vekemans J, Ballou R (2008) Plasmodium falciparum malaria vaccines in development. Expert Rev Vaccines 7(2):223–240

    Article  PubMed  CAS  Google Scholar 

  • Wirtz RA, Ballou WR, Schneider I, Chedid L, Young JF, Hollingdale M et al (1987) Plasmodium falciparum: immunogenicity of circumsporozoite protein constructs produced in Escherichia coli. Exp Parasitol 63:166–172

    Article  PubMed  CAS  Google Scholar 

  • Young JF, Hockmeyer WT, Gross M, Ballou WR, Wirtz RA, Trosper JH et al (1985) Expression of Plasmodium falciparum circumsporozoite protein in Escherichia coli for potential use in a human malaria vaccine. Science 228:958–962

    Article  PubMed  CAS  Google Scholar 

  • Young JF, Gross M, Ballou WR, Hockmeyer WT (1987) Expression of Plasmodium falciparum antigens. In: Kohler H, LoVerde PT (eds) Escherichia coli for the development of a human malaria vaccine. Vaccines: new concepts and developments. Proceedings of the 10th international convocation on immunology. Longman Scientific and Technical, Essex, 1987, pp 251–260

    Google Scholar 

  • Zavala F, Tam JP, Hollingdale MR, Cochrane AH, Quakyi I, Nussenzweig RS, Nussenzweig V (1985) Rationale for the development of a synthetic vaccine against P. falciparum malaria. Science 228:1436–1440

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The results reported in this review are the fruit of many years of very hard work by literally hundreds of highly dedicated individuals in research institutions and in organisations involved in the development of the RTS,S/AS malaria vaccine, in Europe, the USA, and Africa.

The authors wish in particular to acknowledge the many partner organisations that contributed to this work, including the Southern collaborating institutions: the Institut de Recherche en Science de la Santé, Nanoro, Burkina, the Kumasi Centre for Collaborative Research, Ghana, the School of Medical Sciences Kumasi, Ghana, the Kintampo Health Research Centre, Ghana, the Albert Schweitzer Hospital, Gabon, the Kenya Medical Research Institute, Kilifi, Kenya, the Wellcome Collaborative Research Programme, Kilifi, Kenya, the Kenya Medical Research Institute, Kisumu, Kenya, the University of North Carolina Project, Lilongwe, Malawi, the Centro de Investigação em Saude de Manhiça, Mozambique, the Ifakara Health Institute, Tanzania and the National Institute of Medical Research, Tanzania; and the Northern collaborating institutions: the Prince Leopold Institute of Tropical Medicine, Belgium, the University of Copenhagen, Denmark, the University of Tuebingen, Germany, the Bernhard Nocht Institute, Germany, the University of Barcelona, Spain, the Swiss Tropical Institute, Switzerland, the London School of Hygiene & Tropical Medicine, UK, the University of North Carolina at Chapel Hill, USA, the Walter Reed Army Institute of Research, USA, and the Center for Disease Control and Prevention, USA; the PATH Malaria Vaccine Initiative (PATH-MVI), the Malaria Clinical Trial Alliance (MCTA), and the Clinical Trial Partnership Committee (CTPC) which is a network of African-based research centres and Northern partners, PATH-MVI and GSK. The CTPC oversees the implementation of the RTS,S/AS clinical development plan. Most of all, the authors want to thank the thousands of volunteers who participated in the RTS,S/AS clinical trials, as well as their families and communities, for their trust and cooperation.

The authors would also like to acknowledge the significant contribution of Dr. Julia Donnelly for expert editorial assistance and Dr. Julie Harriague (4Clinics) for writing assistance.

Conflicts of Interest: J. Cohen, J. Vekemans, A. Leach and L. Schuerman are employees of GlaxoSmithKline Biologicals. A. Leach, J. Vekemans, J. Cohen, L. Schuerman and S. Benns hold shares in GlaxoSmithKline. J. Cohen is listed as an inventor of patented malaria vaccines, including RTS,S.

Comment of editor: In the mean time the clinical trial was successfully finished!

Author information

Authors and Affiliations

  1. GlaxoSmithKline (GSK) Biologicals, Rue de l’Institut 89, B-1330, Rixensart, Belgium

    Joe Cohen, Sarah Benns, Johan Vekemans, Amanda Leach & Lode Schuerman

Authors
  1. Joe Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Benns
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johan Vekemans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amanda Leach
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lode Schuerman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joe Cohen .

Editor information

Editors and Affiliations

  1. Department of Zoomorphology, Cell Biology and Parasitology,, Heinrich Heine University, Universitätsstr. 1, Düsseldorf, 40225, Germany

    Heinz Mehlhorn

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Cohen, J., Benns, S., Vekemans, J., Leach, A., Schuerman, L. (2011). Development of the RTS,S/AS Vaccine Candidate from Concept to Phase III. In: Mehlhorn, H. (eds) Progress in Parasitology. Parasitology Research Monographs, vol 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-21396-0_7

Download citation

Publish with us

Policies and ethics

Search

Navigation