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Transmission heterogeneity has consequences on malaria vaccine researches


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Transmission heterogeneity has consequences on malaria vaccine researches - Conférence du 5e édition du Cours international « Atelier Paludisme » - Vincent ROBERT - Institut de Recherche pour le Developpement, Paris -

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Transmission heterogeneity has consequences on malaria vaccine researches

  1. 1. Atelier Paludisme 2007Institut Pasteur de Madagascar19 Février - 30 MarsVincent ROBERTInstitut de recherche pour le développement (IRD) UR 077 Paludologie afro-tropicaleMuséum national d’histoire naturelle (MNHN) USM-504 Biologie fonctionnelle des protozoairesL’hétérogénéité de la transmissiondoit être prise en comptedans les recherches vaccinales contre le paludisme
  2. 2. TransmissionvectorielleTransmission des PlasmodiumAnophelesAedesphlébotomesBio-écologieGamétocytesSanté publiqueAntipaludiquesRésistancePrévention del’impaludationLutteantivectorielleInsecticidesRésistanceSahara SahelSavane ForêtMadagascarVillesGuyaneTransmission des arbovirusEnseignementprofessionnelsupérieurenfantsEpidémiologieEvolutionGénétiqueImmunologieVaccinsMoustiquairesRépulsifsPlasmodiumanimauxApicomplexa Piégeage Diagnose LaboratoireSporogonieMesure de la transmission
  3. 3. Atelier PaludismeInstitut Pasteur de MadagascarFebruary 29, 2007Transmission heterogeneity hasconsequences on malaria vaccine researches1 /18
  4. 4. Three modes of transmission :Transmission • vectorial• transfusion• placental2 /18
  5. 5. MOSQUITO-HUMANTRANSMISSIONMOSQUITOHUMANThe transmissionHUMAN-MOSQUITOTRANSMISSSION? or the two transmissions ?VaccinesInhibition of sporozoite invasionInhibition of merozoite invasionInhibition of infected red blood cells cyto-adherenceImmunity regulationInhibition of sporogonic developmentTransmissionblocking vaccines3 /18
  6. 6. transmission morbidity mortalitythe malaria in one slideHumanuninfectedHumaninfectedHumansickHumandeadnatural immunity- --vector controlprevention ofinfectiondrug treatment--- - -and / or vaccines4 /18
  7. 7. Transmission and natural immunity are highly linkedIf the vaccine would have nothing to deal with the stimulation of natural immunity and only induces newimmunological mechanism of protection (fully different from natural situations), one may speculate :- the induction of protective immunity by a vaccine is not linked to transmission intensity,- but the duration of protection might be.Transmission intensity has important consequences for theartificial induction of protective immunity by a vaccineTransmission may act positively, as additional boostersNew infections may act negatively, overwhelming the protective immunityThe development of the vaccine must document transmission intensity,(except during phases testing safety), as soon as the first phasestesting immunogenicity and efficacy in endemic zonesInfants do not constitute a special issue5 /18
  8. 8. The measure ofThe measure of PlasmodiumPlasmodium transmissiontransmission≠≠ number of inoculation ofnumber of inoculation of PlasmodiumPlasmodiumper person : ordinary, an adultper person : ordinary, an adultper unit of time : night, month, year, lifeper unit of time : night, month, year, lifeDefinitionE I R : Entomological Inoculation RateEIR = ma x sma = biting rates = sporozoite indexUnit : Nb of bites of infected anopheline per human and per unit of time6 /18
  9. 9. Does EIR measure transmission ?• Mean on a sample of persons : what about individual variationsfor an adult human ?in a mean environment ?• Mean on a period time : what about the temporal variations ?==> specify if transmission is seasonal or permanent,(duration of season without transmission)• Measure established from awaked voluntaries• Give the Nb of bites of infected anophelines(about double of the Nb of bites that induce blood parasite infection )EIR is a proxy of malaria transmission7 /18
  10. 10. 8 /18
  11. 11. Incidence ofIncidence of P. falciparumP. falciparum simple malaria attackssimple malaria attacksin relation to age and intensity of transmissionin relation to age and intensity of transmissionAnnualAnnualNbNbofmalariaattacksofmalariaattacks0011223344556600 55 1010 1515 2020 2525 3030 3535 4040 4545 5050Age (years)Age (years)DananéDanané, Côte dIvoire:, Côte dIvoire: ≥≥≥≥≥≥≥≥ 300300 b.i.ab.i.a./human/year./human/yearDielmoDielmo,, SénégalSénégal: 100: 100--300300 b.i.ab.i.a./human/year./human/yearNdiopNdiop,, SénégalSénégal: 10: 10--3030 b.i.ab.i.a./human/year./human/yearPikinePikine,, SénégalSénégal:: ≤≤≤≤≤≤≤≤11 b.i.ab.i.a./human/year./human/yearTotalTotal NbNb of attacksof attacksat 60 years oldat 60 years old2525434362622525% within% withinadultsadults10%10%23%23%41%41%50%50%9 /18
  12. 12. NonNon--entomological methods to measure transmissionentomological methods to measure transmissionParasitological (Parasitological (presence of parasites)presence of parasites)Longitudinal or transversal surveysLongitudinal or transversal surveysIncidence of the disease (Detection of new clinical cases;Detection of new clinical cases;with parasiwith parasitological confirmation)tological confirmation)Serological (Serological (AbAb :: indirect markers of the presence of parasiteindirect markers of the presence of parasite))10 /18
  13. 13. Efficacy of bites of infected anophelineRickman et al., 1990No appropriate animal modelIn humanAn. stephensi with P. falciparum sporozoitesin their salivary glands3 / 5 volunteersParasitaemiain Americanvolunteers10 / 10 volunteers2 / 5 volunteers1 bite2 simultaneous bites5 simultaneous bitesWhat is the fraction of bite of infected anophelines that develop parasitaemia ?About half bites of infected anophelines induces blood parasite infectionChallenges after vaccination are made usualy using 5 simultaneous bitesReminder : these voluntaries were non immune11 /18
  14. 14. Sporozoites injected per bite of infected anophelinesWhere and when ?How many ?Into the avascular skin tissue (of mice), during the probingSprozoites injected during the feeding, in the blood vessel,are re-injested with the bloodmeal. They can be numbered inthe midgut of a fed mosquito.Sidjanski & Vanderberg, 1997Kebaier & Vanderberg, 2006by the way of the stream of mosquito salivaSporozoites delivered represent only a tiny %age of the sporozoiteswithin the salivary glands of the mosquito (±1%)Range : 0 - 1000Beier et al, 1992Ponnudurai et al, 1991Rosenberg et al, 1990Mean : 10 to 2012 /18
  15. 15. 0Nb of bites ofinfected anophelinesBoundary min Boundary max1 10 100 103 104 105Evidence of heterogeneity in malaria transmission= 10 bites of infected anophelines= 1 bite of infected anophelinesper human, per year, during 100 yearsThis heterogeneity in transmission results in a variation :in the acquisition of immunity (efficient against the disease)Impossible <100Need ± 10 years if103Need ± 2 years if 104in the challenge to the immune system ; but natural infections followingvaccination may either reinforce the immunity or overwhelm it13 /18
  16. 16. Source 2002Population Reference BureauAfricaSub-saharan Africa, except southern AfricaNorth AmericaCentral + The West indiesSouthAmazonia s.l. + HaïtiAsiaEuropaOceaniaPopulation(millions)Population who get malariaat least one / life840630319140354376672832WORLD 6200 17406003010410005Malaria transmission depends mainly onAltitudeClimateUrbanisationWater surface (eg: rice field)Personal protection and vector controlJourney (eg: tourism)128%14 /18
  17. 17. Human population (millions)01 0002 0003 0004 0005 000Human population and the number of bites of infected anophelines0Nb of bitesof infectedanophelinesBoundary min Boundary max1 10 100 103 104 1057003001 740Total world populationinfected at least once15 /18
  18. 18. % of the world populationas potential targetfor malaria vaccine60%23%17%TransmissionintensitylowmediumhightRisk ofoverwhelmingvaccinal efficacy—++++AnnualEIR≤ 11 -10> 10Tropical Africa + Papua-New-GuineaBecause high number of new infections may overwhelm any protectiveimmunity (natural or vaccinal), it is conceivable that some malaria vaccines mayhave various efficacy at the different transmission levels.Human population and the number of bites of infected anophelines (2)If it is right, world population mainlyneeds vaccine efficient at low transmission level16 /18
  19. 19. Transmission intensity :CONCLUSIONSThis heterogeneity :That must be taken into account in any malaria vaccine research(except in phase 1)- ranges from 0 to 105 bites of infected anophelines per man and per life- varies by a factor of 100 000 fold across tropical Africa(some downtowns vs. some humid rural savannahs)- has huge consequences for acquisition of natural immunity- may have important consequences for the success and longevityof artificial induction of protective immunity by a vaccine124It is conceivable that some malaria vaccines may have variousefficacy at the different transmission levels317 /18
  20. 20. BibliographyFontenille D, Lochouarn L, Diatta M, Sokhna C, Dia I, Diagne N, Lemasson JJ, Ba K, Tall A, Rogier C, Trape JFFour years entomological study of the transmission of seasonal malaria in Senegal and the bionomics ofAnopheles gambiae and A. arabiensis.Trans R Soc Trop Med Hyg. 1997 Nov-Dec;91(6):647-652.Filion GJP, Paul REL & Robert Vtransmission and immunity : the importance of heterogeneity in the fight agaisnt malaria.Trends Parasitol 2006 Aug;22(8):345-348.Kebaier C & Vanderberg JPRe-ingestion of Plasmodium berghei sporozoites after delivery into the host by mosquitoes.Am J Trop Med Hyg. 2006 Dec, 75(6):1200-1204.Robert V, Macintyre K, Keating J, Trape JF, Duchemin JB, Warren M, Beier JCMalaria transmission in urban sub-Saharan Africa.Am J Trop Med Hyg. 2003 Feb;68(2):169-176.Snow RW, Guerra CA, Noor AM, Myint HY, Hay SIThe global distribution of clinical episodes of Plasmodium falciparum malaria.Nature. 2005 Mar 10;434(7030):214-217.Sidjanski S & Vanderberg JPDeleyed migration of Plasmodium sporozoites from the mosquito bite site to the blood.Am J Trop Med Hyg. 1997; 57:426-429.Trape JF, Rogier CCombating malaria morbidity and mortality by reducing transmission.Parasitol Today. 1996 Jun;12(6):236-240.Trape JF, Rogier C, Konate L, Diagne N, Bouganali H, Canque B, Legros F, Badji A, Ndiaye G, Ndiaye P, et al.The Dielmo project: a longitudinal study of natural malaria infection and the mechanisms of protectiveimmunity in a community living in a holoendemic area of Senegal.Am J Trop Med Hyg. 1994 Aug;51(2):123-37.18 /18