Volume 75, Issue 2_suppl
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


A double-blind, phase IIb, randomized controlled trial of the malaria vaccine RTS,S/AS02A showed an efficacy of 45.0% in reducing the force of infection for and of 29.9% in reducing incidence of clinical malaria in children 1–4 years of age in Manhiça, Mozambique. We simulate this trial using a stochastic model of epidemiology, and the setting-specific seasonal pattern of entomologic inoculations as input. The simulated incidence curve for the control group was comparable with that observed in the trial. To reproduce the observed efficacy in extending time to first infection, the model needed to assume an efficacy of 52% in reducing the force of infection. This bias arises as a result of acquired partial immunity against blood stages, thus suggesting an explanation for the lower efficacy observed in a previous trial in semi-immune adult men in The Gambia. The shape of the incidence of infection curve for the vaccine cohort in Manhiça indicates that the vaccine provides incomplete protection to a large proportion of the vaccinees, rather than offering complete protection to some recipients and none to others. This behavior is compatible with a model of no decay in efficacy over the six-month surveillance period of the trial. The model accurately reproduced the lower efficacy against clinical disease than against infection. In the simulations this finding resulted from loss of acquired clinical immunity as a result of a reduction in the force of infection in the vaccinated cohort. The model also predicted greater efficacy against severe diseases than against clinical disease. The success of the simulation model in reproducing the results of the Manhiça trial encourages us to apply the same model to predict the potential public health and economic impact if RTS,S/AS02A were to be introduced into the existing expanded program on immunization.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Alonso PL, Sacarlal J, Aponte J, Leach A, Macete E, Milman J, Mandomando I, Spiessens B, Guinovart C, Espasa M, Bassat Q, Aide P, Ofori-Anyinam O, Navia MM, Corachan S, Ceuppens M, Dubois MC, Demoitie MA, Dubovsky F, Menendez C, Tornieporth N, Ballou WR, Thompson R, Cohen J, 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. [Google Scholar]
  2. Bojang K, Milligan PJM, Pinder M, Vigneron L, Alloueche A, Kester KE, Ballou WR, Conway D, Reece WHH, Gothard P, Yamuah L, Delchambre M, Voss G, Greenwood BM, Hill A, McAdam KP, Tornieporth N, Cohen JD, Doherty T, 2001. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 358 : 1927–1934. [Google Scholar]
  3. Halloran ME, Haber M, Longini IM Jr, 1992. Interpretation and estimation of vaccine efficacy under heterogeneity. Am J Epidemiol 136 : 328–343. [Google Scholar]
  4. Halloran ME, Longini IM Jr, Struchiner CJ, 1996. Estimability and interpretation of vaccine efficacy using frailty mixing models. Am J Epidemiol 144 : 83–97. [Google Scholar]
  5. Alonso PL, Molyneux ME, Smith T, 1995. Design and methodology of field-based intervention trials of malaria vaccines. Parasitol Today 11 : 197–200. [Google Scholar]
  6. Smith T, Schellenberg JA, Hayes R, 1994. Attributable fraction estimates and case definitions for malaria in endemic areas. Stat Med 13 : 2345–2358. [Google Scholar]
  7. Schellenberg JR, Smith T, Alonso PL, Hayes R, 1994. What is clinical malaria? Finding case definitions for field research in highly endemic areas. Parasitol Today 10 : 439–442. [Google Scholar]
  8. Smith T, Maire N, Dietz K, Killeen GF, Vounatsou P, Molineaux L, Tanner M, 2006. Relationships between the entomologic inoculation rate and the force of infection for Plasmodium falciparum malaria. Am J Trop Med Hyg 75 (Suppl 2): 11–18. [Google Scholar]
  9. Maire N, Smith T, Ross A, Owusu-Agyei S, Dietz K, Molineaux L, 2006. A model for natural immunity to asexual blood stages of Plasmodium falciparum in endemic areas. Am J Trop Med Hyg 75 (Suppl 2): 19–31. [Google Scholar]
  10. Ross A, Maire N, Molineaux L, Smith T, 2006. An epidemiologic model of severe morbidity and mortality caused by Plasmodium falciparum. Am J Trop Med Hyg 75 (Suppl 2): 63–73. [Google Scholar]
  11. Smith T, Ross A, Maire N, Rogier C, Trape JF, Molineaux L, 2006. An epidemiologic model of the incidence of acute illness in Plasmodium falciparum malaria. Am J Trop Med Hyg 75 (Suppl 2): 56–62. [Google Scholar]
  12. Alonso PL, Saute F, Aponte J, Gomez-Olivé FX, Nhacalo A, Thompson R, Macete E, Abacassamo F, Ventura PJ, Bosch X, Mendendez C, Dgedge M, 2002. Manhiça DSS, Mozambique. INDEPTH Network, ed. Population, Health and Survival at INDEPTH Sites. Ottawa, Ontario, Canada: International Development Research Centre.
  13. Aranda C, Aponte JJ, Saute F, Casimiro S, Pinto J, Sousa C, do Rosario V, Petrarca V, Dgedge M, Alonso P, 2005. Entomological characteristics of malaria transmission in Manhiça, a rural area in southern Mozambique. J Med Entomol 42 : 180–186. [Google Scholar]
  14. Smith T, Killeen G, Maire N, Ross A, Molineaux L, Tediosi F, Hutton G, Utzinger J, Dietz K, Tanner M, 2006. Mathematical modeling of the impact of malaria vaccines on the clinical epidemiology and natural history of Plasmodium falciparum malaria: overview. Am J Trop Med Hyg 75 (Suppl 2): 1–10. [Google Scholar]
  15. Saute F, Aponte J, Almeda J, Ascasco C, Vaz N, Dgedge M, Alonso P, 2003. Malaria in southern Mozambique: incidence of clinical malaria in children living in a rural community in Manhiça district. Trans R Soc Trop Med Hyg 97 : 665–660. [Google Scholar]
  16. Goodman CA, Coleman PG, Mills A, 2000. Economic Analysis of Malaria Control in sub-Saharan Africa. Geneva: Global Forum for Health Research.
  17. McCombie SC, 1996. Treatment seeking for malaria: a review of recent research. Soc Sci Med 43 : 933–945. [Google Scholar]
  18. Hudgens MG, Gilbert PB, Self SG, 2004. Endpoints in vaccine trials. Stat Methods Med Res 13 : 89–114. [Google Scholar]
  19. Rogier C, Trape JF, 1995. Study of premunition development in holo- and mesoendemic malaria areas in Dielmo and Ndiop (Senegal): preliminary results, 1990–1994. Med Trop (Mars) 55 : 71–76. [Google Scholar]
  20. Trape JF, Rogier C, 1996. Combating malaria morbidity and mortality by reducing transmission. Parasitol Today 12 : 236–240. [Google Scholar]
  21. McKenzie FE, Samba EM, 2004. The role of mathematical modeling in evidence-based malaria control. Am J Trop Med Hyg 71 (Suppl 2): 94–96. [Google Scholar]
  22. Glynn JR, Bradley DJ, 1995. Inoculum size, incubation period and severity of malaria. Analysis of data from malaria therapy records. Parasitology 110 : 7–19. [Google Scholar]
  23. Kester KE, McKinney DA, Tornieporth N, Ockenhouse CF, Heppner DG, Hall T, Krzych U, Delchambre M, Voss G, Dowler MG, Palensky J, Wittes J, Cohen J, Ballou WR; RTS,S Malaria Vaccine Evaluation Group, 2001. Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J Infect Dis 183: 640–647. [Google Scholar]

Data & Media loading...

  • Received : 18 Sep 2005
  • Accepted : 07 Feb 2006

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error