title: What should vaccine developers ask? Simulation of the effectiveness of malaria vaccines.
abstract: BACKGROUND
  A number of different malaria vaccine candidates are currently in pre-clinical or clinical development. Even though they vary greatly in their characteristics, it is unlikely that any of them will provide long-lasting sterilizing immunity against the malaria parasite. There is great uncertainty about what the minimal vaccine profile should be before registration is worthwhile; how to allocate resources between different candidates with different profiles; which candidates to consider combining; and what deployment strategies to consider.
  
  
  RESULTS
  We use previously published stochastic simulation models, calibrated against extensive epidemiological data, to make quantitative predictions of the population effects of malaria vaccines on malaria transmission, morbidity and mortality. The models are fitted and simulations obtained via volunteer computing. We consider a range of endemic malaria settings with deployment of vaccines via the Expanded program on immunization (EPI), with and without additional booster doses, and also via 5-yearly mass campaigns for a range of coverages. The simulation scenarios account for the dynamic effects of natural and vaccine induced immunity, for treatment of clinical episodes, and for births, ageing and deaths in the cohort. Simulated pre-erythrocytic vaccines have greatest benefits in low endemic settings (<EIR of 10.5) where between 12% and 14% of all deaths are averted when initial efficacy is 50%. In some high transmission scenarios (>EIR of 84) PEV may lead to increased incidence of severe disease in the long term, if efficacy is moderate to low (<70%). Blood stage vaccines (BSV) are most useful in high transmission settings, and are comparable to PEV for low transmission settings. Combinations of PEV and BSV generally perform little better than the best of the contributing components. A minimum half-life of protection of 2-3 years appears to be a precondition for substantial epidemiological effects. Herd immunity effects can be achieved with even moderately effective (>20%) malaria vaccines (either PEV or BSV) when deployed through mass campaigns targeting all age-groups as well as EPI, and especially if combined with highly efficacious transmission-blocking components.
  
  
  CONCLUSIONS
  We present for the first time a stochastic simulation approach to compare likely effects on morbidity, mortality and transmission of a range of malaria vaccines and vaccine combinations in realistic epidemiological and health systems settings. The results raise several issues for vaccine clinical development, in particular appropriateness of vaccine types for different transmission settings; the need to assess transmission to the vector and duration of protection; and the importance of deployment additional to the EPI, which again may make the issue of number of doses required more critical. To test the validity and robustness of our conclusions there is a need for further modeling (and, of course, field research) using alternative formulations for both natural and vaccine induced immunity. Evaluation of alternative deployment strategies outside EPI needs to consider the operational implications of different approaches to mass vaccination.
authors.affiliation: Swiss Tropical Institute, Basel, Switzerland.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Penny
authors.forename: Nicolas
authors.initials: N
authors.lastname: Maire
authors.forename: Alain
authors.initials: A
authors.lastname: Studer
authors.forename: Allan
authors.initials: A
authors.lastname: Schapira
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Smith
mesh_terms: D000818:Animals; D002138:Calibration; D003198:Computer Simulation; D016503:Drug Delivery Systems; D015195:Drug Design; D004345:Drug Industry / Q000639:trends; D006801:Humans; D008288:Malaria / Q000453:epidemiology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control; D008962:Models, Theoretical; D018512:Parasitemia / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000378:metabolism; D013269:Stochastic Processes; D014611:Vaccination
chemical_list: D017780:Malaria Vaccines
references.citation: J Infect Dis. 1996 Aug;174(2):367-72
references.pmid: 8699068
references.citation: Parasitology. 2008 Nov;135(13):1507-16
references.pmid: 18694530
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):111-8
references.pmid: 16931822
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):90-103
references.pmid: 16931820
references.citation: Nature. 2005 Mar 10;434(7030):214-7
references.pmid: 15759000
references.citation: Int J Parasitol. 2002 Dec 4;32(13):1617-24
references.pmid: 12435446
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):1-10
references.pmid: 16931810
references.citation: J Infect Dis. 2002 Mar 15;185(6):820-7
references.pmid: 11920300
references.citation: Lancet. 2005 Apr 23-29;365(9469):1487-98
references.pmid: 15850634
references.citation: Parasitology. 1989;99 Suppl:S59-79
references.pmid: 2682486
references.citation: Trans R Soc Trop Med Hyg. 1988;82(4):548-53
references.pmid: 3076711
references.citation: Vaccine. 2007 Jul 9;25(28):5115-23
references.pmid: 17577487
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):32-7
references.pmid: 16931813
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):11-8
references.pmid: 16931811
references.citation: Acta Trop. 1991 Apr;49(1):1-25
references.pmid: 1678572
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):19-31
references.pmid: 16931812
references.citation: Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):338-42
references.pmid: 8990210
references.citation: Math Biosci. 1989 May;94(1):87-113
references.pmid: 2520167
references.citation: Curr Opin Infect Dis. 2007 Oct;20(5):476-81
references.pmid: 17762780
references.citation: Lancet. 2005 Dec 10;366(9502):2012-8
references.pmid: 16338450
references.citation: Am J Epidemiol. 1996 Jul 1;144(1):83-97
references.pmid: 8659489
references.citation: PLoS Biol. 2007 Mar;5(3):e42
references.pmid: 17311470
references.citation: Lancet. 2004 Oct 16-22;364(9443):1411-20
references.pmid: 15488216
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):131-43
references.pmid: 16931824
references.citation: Lancet. 2001 Dec 8;358(9297):1927-34
references.pmid: 11747915
references.citation: Vaccine. 2007 Feb 19;25(9):1567-80
references.pmid: 17045367
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2 Suppl):104-10
references.pmid: 16931821