Volume 96, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Malaria incidence is highly heterogeneous even in areas of high transmission, although no conclusive evidence exists that innate or naturally acquired resistance can prevent infection over an extended period of time. This longitudinal study examined immunoparasitological evidence for a malaria-resistant phenotype in which children do not develop malaria despite an extended period of exposure to parasites. Within a birth cohort followed from 2002 to 2006 in Muheza, Tanzania, an area of intense transmission, children ( = 687) provided blood smears biweekly during infancy and monthly thereafter. Maternal and childhood characteristics were obtained, cord-blood cytokines were measured, and antibody responses were assayed as measures of stage-specific exposure. Sixty-three (9.2%) children had no blood smear–positive slides over 2 years of follow-up (range: 1–3.5 years) and were identified as malaria resistant. Malaria-resistant children were similar to other children with respect to completeness of follow-up and all maternal and childhood characteristics except residence area. Antibody seroprevalence was similar for two sporozoite antigens, but malaria-resistant children had a lower antibody seroprevalence to merozoite antigens merozoite surface protein 1 (5.4% versus 30.2%; < 0.0001) and apical membrane antigen 1 (7.2% versus 33.3%; < 0.0001). Malaria-resistant children had higher cytokine levels in cord blood, particularly interleukin-1β. In summary, a subset of children living in an area of intense transmission was exposed to malaria parasites, but never developed patent parasitemia; this phenotype was associated with a distinct cytokine profile at birth and antibody profile during infancy. Further research with malaria-resistant children may identify mechanisms for naturally acquired immunity.


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  1. World Health Organization, 2015. World Malaria Report. Geneva, Switzerland: World Health Organization. [Google Scholar]
  2. Doolan DL, Dobano C, Baird JK, , 2009. Acquired immunity to malaria. Clin Microbiol Rev 22: 1336.[Crossref] [Google Scholar]
  3. Goncalves BP, Huang CY, Morrison R, Holte S, Kabyemela E, Prevots DR, Fried M, Duffy PE, , 2014. Parasite burden and severity of malaria in Tanzanian children. N Engl J Med 370: 17991808.[Crossref] [Google Scholar]
  4. Wilson PT, Malhotra I, Mungai P, King CL, Dent AE, , 2013. Transplacentally transferred functional antibodies against Plasmodium falciparum decrease with age. Acta Trop 128: 149153.[Crossref] [Google Scholar]
  5. Trape JF, Pison G, Spiegel A, Enel C, Rogier C, , 2002. Combating malaria in Africa. Trends Parasitol 18: 224230.[Crossref] [Google Scholar]
  6. Cairns ME, Asante KP, Owusu-Agyei S, Chandramohan D, Greenwood BM, Milligan PJ, , 2013. Analysis of partial and complete protection in malaria cohort studies. Malar J 12: 355.[Crossref] [Google Scholar]
  7. Trape JF, Rogier C, Konate L, Diagne N, Bouganali H, Canque B, Legros F, Badji A, Ndiaye G, Brahimi K, Faye O, Druilhe P, Pereira da Silva L, , 1994. The Dielmo project: a longitudinal study of natural malaria infection and the mechanisms of protective immunity in a community living in a holoendemic area of Senegal. Am J Trop Med Hyg 51: 123137. [Google Scholar]
  8. Tran TM, Li S, Doumbo S, Doumtabe D, Huang CY, Dia S, Bathily A, Sangala J, Kone Y, Traore A, Niangaly M, Dara C, Kayentao K, Ongoiba A, Duonbo OK, Traore B, Compton PD, , 2013. An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin Infect Dis 57: 4047.[Crossref] [Google Scholar]
  9. Mackinnon MJ, Mwangi TW, Snow RW, Marsh K, Williams TN, , 2005. Heritability of malaria in Africa. PLoS Med 2: e340.[Crossref] [Google Scholar]
  10. Mwangi TW, Fegan G, Williams TN, Kinyanjui SM, Snow RW, Marsh K, , 2008. Evidence for over-dispersion in the distribution of clinical malaria episodes in children. PLoS One 3: e2196.[Crossref] [Google Scholar]
  11. Loucoubar C, Grange L, Paul R, Huret A, Tall A, Telle O, Roussilhon C, Faye J, Diene-Sarr F, Trape JF, Mercereau-Puijalon O, Sakuntabhai A, Bureau JF, , 2013. High number of previous Plasmodium falciparum clinical episodes increases risk of future episodes in a sub-group of individuals. PLoS One 8: e55666.[Crossref] [Google Scholar]
  12. Creasey A, Giha H, Hamad AA, El Hassan IM, Theander TG, Arnot DE, , 2004. Eleven years of malaria surveillance in a Sudanese village highlights unexpected variation in individual disease susceptibility and outbreak severity. Parasitology 129: 263271.[Crossref] [Google Scholar]
  13. Mutabingwa TK, Bolla MC, Li JL, Domingo GJ, Li X, Fried M, Duffy PE, , 2005. Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med 2: e407.[Crossref] [Google Scholar]
  14. Ellman R, Maxwell C, Finch R, Shayo D, , 1998. Malaria and anaemia at different altitudes in the Muheza district of Tanzania: childhood morbidity in relation to level of exposure to infection. Ann Trop Med Parasitol 92: 741753.[Crossref] [Google Scholar]
  15. Gwamaka M, Kurtis JD, Sorensen BE, Holte S, Morrison R, Mutabingwa TK, Fried M, Duffy PE, , 2012. Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin Infect Dis 54: 11371144.[Crossref] [Google Scholar]
  16. Kabyemela E, Goncalves BP, Prevots DR, Morrison R, Jarrington W, Gwamaka M, Kurtis JD, Fried M, Duffy PE, , 2013. Cytokine profiles at birth predict malaria severity during infancy. PLoS One 8: e77214.[Crossref] [Google Scholar]
  17. Cham GK, Kurtis J, Lusingu J, Theander TG, Jensen AT, Turner L, , 2008. A semi-automated multiplex high-throughput assay for measuring IgG antibodies against Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) domains in small volumes of plasma. Malar J 7: 108.[Crossref] [Google Scholar]
  18. Harrington WE, Mutabingwa TK, Kabyemela E, Fried M, Duffy PE, , 2011. Intermittent treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistance. Clin Infect Dis 53: 224230.[Crossref] [Google Scholar]
  19. Woolhouse ME, Dye C, Etard JF, Charlwood JD, Garnett GP, Hagan P, Hu JLK, Ndhlovu PD, Quinnell RJ, Watts CH, Chandiwana SK, Anderson RM, , 1997. Heterogeneities in the transmission of infectious agents: implications for the design of control programs. Proc Natl Acad Sci USA 94: 338342.[Crossref] [Google Scholar]
  20. Taylor SM, Parobek CM, Fairhurst RM, , 2012. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis 12: 457468.[Crossref] [Google Scholar]
  21. Modiano D, Petrarca V, Sirima BS, Nebie I, Diallo D, Esposito F, Coluzzi M, , 1996. Different response to Plasmodium falciparum malaria in west African sympatric ethnic groups. Proc Natl Acad Sci USA 93: 1320613211.[Crossref] [Google Scholar]
  22. Okulicz JF, Lambotte O, , 2011. Epidemiology and clinical characteristics of elite controllers. Curr Opin HIV AIDS 6: 163168.[Crossref] [Google Scholar]
  23. Pereyra F, Jia X, McLaren PJ, The International HIV Controllers Study; , 2010. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330: 15511557.[Crossref] [Google Scholar]
  24. Vaughan AM, Aly AS, Kappe SH, , 2008. Malaria parasite pre-erythrocytic stage infection: gliding and hiding. Cell Host Microbe 4: 209218.[Crossref] [Google Scholar]
  25. Silvie O, Goetz K, Matuschewski K, , 2008. A sporozoite asparagine-rich protein controls initiation of Plasmodium liver stage development. PLoS Pathog 4: e1000086.[Crossref] [Google Scholar]
  26. Badu K, Afrane YA, Larbi J, Stewart VA, Waitumbi J, Angov E, Ong'echa JM, Perkins DJ, Zhou G, Githeko A, Yan G, , 2012. Marked variation in MSP-119 antibody responses to malaria in western Kenyan highlands. BMC Infect Dis 12: 50.[Crossref] [Google Scholar]
  27. Corran P, Coleman P, Riley E, Drakeley C, , 2007. Serology: a robust indicator of malaria transmission intensity? Trends Parasitol 23: 575582.[Crossref] [Google Scholar]
  28. Drakeley CJ, Corran PH, Coleman PG, Tongren JE, McDonald SLR, Malima R, Lusingu J, Manjurano A, Nkya WMM, Lemnge MM, Reyburn H, Riley EM, , 2005. Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure. Proc Natl Acad Sci USA 102: 51085113.[Crossref] [Google Scholar]
  29. Noland GS, Hendel-Paterson B, Min XM, Moormann AM, Vulule JM, Narum D, Lanar DE, Kazura JW, John CC, , 2008. Low prevalence of antibodies to preerythrocytic but not blood-stage Plasmodium falciparum antigens in an area of unstable malaria transmission compared to prevalence in an area of stable malaria transmission. Infect Immun 76: 57215728.[Crossref] [Google Scholar]
  30. Ondingo BN, Hodges JS, Ireland KF, Magak NG, Lanar DE, Dutta S, Narum DL, Park GS, Ofulla AV, John CC, , 2014. Estimation of recent and long-term malaria transmission in a population by antibody testing to multiple Plasmodum falciparum antigens. J Infect Dis (Auckl) 210: 11231132.[Crossref] [Google Scholar]
  31. Ishino T, Boisson B, Orito Y, Lacroix C, Bishoff E, Loussert C, Janse C, Menard R, Yuda M, Baldacci P, , 2009. LISP1 is important for the egress of Plasmodium berghei parasites from liver cells. Cell Microbiol 11: 13291339.[Crossref] [Google Scholar]
  32. Krzych U, Lyon JA, Jareed T, Schneider I, Hollingdale MR, Gordon DM, Ballou WR, , 1995. T lymphocytes from volunteers immunized with irradiated Plasmodium falciparum sporozoites recognize liver and blood stage malaria antigens. J Immunol 155: 40724077. [Google Scholar]
  33. Fowkes FJ, Richards JS, Simpson JA, Beeson JG, , 2010. The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: a systematic review and meta-analysis. PLoS Med 7: e1000218.[Crossref] [Google Scholar]
  34. Offeddu V, Thathy V, Marsh K, Matuschewski K, , 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection. Int J Parasitol 42: 535548.[Crossref] [Google Scholar]
  35. Mordmuller BG, Metzger WG, Juillard P, Brinkman BMN, Verweij CL, Grau GE, Kremsner PG, , 1997. Tumor necrosis factor in Plasmodium falciparum malaria: high plasma level is associated with fever, but high production capacity is associated with rapid fever clearance. Eur Cytokine Netw 8: 2935. [Google Scholar]
  36. Pied S, Civas A, Berlot-Picard F, Renia L, Miltgen F, Gentilini M, Doly J, Mazier D, , 1992. IL-6 induced by IL-1 inhibits malaria pre-erythrocytic stages but its secretion is down-regulated by the parasite. J Immunol 148: 197201. [Google Scholar]
  37. Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P, Hommel M, Lambert PH, , 1989. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 320: 15861591.[Crossref] [Google Scholar]
  38. Malhotra I, Dent A, Mungai P, Wamachi A, Ouma JH, Narum DL, Muchiri E, Tisch DJ, King CL, , 2009. Can prenatal malaria exposure produce an immune tolerant phenotype? A prospective birth cohort study in Kenya. PLoS Med 6: e1000116.[Crossref] [Google Scholar]
  39. Adegnika AA, Kohler C, Agnandji ST, Chai AK, Lubuda L, Breitling LP, Schonkeren D, Weerdenburg E, Issifou S, Luty AJF, Kremsner PG, Yazdanbakhsh M, , 2008. Pregnancy-associated malaria affects toll-like receptor ligand-induced cytokine responses in cord blood. J Infect Dis 198: 928936.[Crossref] [Google Scholar]
  40. Bottius E, Guanzirolli A, Trape JF, Rogier C, Konate L, Druilhe P, , 1996. Malaria: even more chronic in nature than previously thought; evidence for subpatent parasitaemia detectable by the polymerase chain reaction. Trans R Soc Trop Med Hyg 90: 1519.[Crossref] [Google Scholar]
  41. Nsobya SL, Parikh S, Kironde F, Lubega G, Kamya MR, Ronsenthal PJ, Dorsey G, , 2004. Molecular evaluation of the natural history of asymptomatic parasitemia in Ugandan children. J Infect Dis 189: 22202226.[Crossref] [Google Scholar]
  42. Wagner G, Koram K, McGuinness D, Bennett S, Nkrumah F, Riley E, , 1998. High incidence of asymptomatic malara infections in a birth cohort of children less than one year of age in Ghana, detected by multicopy gene polymerase chain reaction. Am J Trop Med Hyg 59: 115123. [Google Scholar]

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  • Received : 05 Jul 2016
  • Accepted : 14 Dec 2016
  • Published online : 27 Feb 2017

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