International Centers of Excellence for Malaria Research: Background, Progress, and Ongoing Activities
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



A blood test that captures cumulative exposure over time and assesses levels of naturally acquired immunity (NAI) would provide a critical tool to monitor the impact of interventions to reduce malaria transmission and broaden our understanding of how NAI develops around the world as a function of age and exposure. This article describes a collaborative effort in multiple International Centers of Excellence in Malaria Research (ICEMRs) to develop such tests using malaria-specific antibody responses as biosignatures of transmission and immunity. The focus is on the use of and protein microarrays to identify a panel of the most informative antibody responses in diverse malaria-endemic settings representing an unparalleled spectrum of malaria transmission and malaria species mixes before and after interventions to reduce malaria transmission.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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  1. Ayieko C, Maue AC, Jura WG, Noland GS, Ayodo G, Rochford R, John CC, , 2013. Changes in B cell populations and merozoite surface protein-1-specific memory B cell responses after prolonged absence of detectable infection. PLoS One 8: e67230.[Crossref] [Google Scholar]
  2. Wipasa J, Suphavilai C, Okell LC, Cook J, Corran PH, Thaikla K, Liewsaree W, Riley EM, Hafalla JC, , 2010. Long-lived antibody and B cell memory responses to the human malaria parasites, Plasmodium falciparum and Plasmodium vivax . PLoS Pathog 6: e1000770.[Crossref] [Google Scholar]
  3. Ndungu FM, Lundblom K, Rono J, Illingworth J, Eriksson S, Farnert A, , 2013. Long-lived Plasmodium falciparum specific memory B cells in naturally exposed Swedish travelers. Eur J Immunol 43: 29192929.[Crossref] [Google Scholar]
  4. Weiss GE, Ndungu FM, McKittrick N, Li S, Kimani K, Crompton PD, Marsh K, Pierce SK, , 2012. High efficiency human memory B cell assay and its application to studying Plasmodium falciparum-specific memory B cells in natural infections. J Immunol Methods 375: 6874.[Crossref] [Google Scholar]
  5. Fowkes FJ, McGready R, Cross NJ, Hommel M, Simpson JA, Elliot SR, Richards JS, Lackovic K, Viladpai-Nguen J, Narum D, Tsuboi T, Anders RF, Nosten F, Beeson JG, , 2012. New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women. J Infect Dis 206: 16121621.[Crossref] [Google Scholar]
  6. Ndungu FM, Olotu A, Mwacharo J, Nyonda M, Apfeld J, Mramba LK, Fegan GW, Bejon P, Marsh K, , 2012. Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children. Proc Natl Acad Sci USA 109: 82478252.[Crossref] [Google Scholar]
  7. Ondigo 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 Plasmodium falciparum antigens. J Infect Dis 210: 11231132.[Crossref] [Google Scholar]
  8. Struik SS, Riley EM, , 2004. Does malaria suffer from lack of memory? Immunol Rev 201: 268290.[Crossref] [Google Scholar]
  9. Akpogheneta OJ, Duah NO, Tetteh KK, Dunoy S, Lanar DE, Pinder M, Conway DJ, , 2008. Duration of naturally acquired antibody responses to blood-stage Plasmodium falciparum is age dependent and antigen specific. Infect Immun 76: 17481755.[Crossref] [Google Scholar]
  10. Kinyanjui SM, Conway DJ, Lanar DE, Marsh K, , 2007. IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life. Malar J 6: 82.[Crossref] [Google Scholar]
  11. White MT, Griffin JT, Akpogheneta O, Conway DJ, Koram KA, Riley EM, Ghani AC, , 2014. Dynamics of the antibody response to Plasmodium falciparum infection in African children. J Infect Dis 210: 11151122.[Crossref] [Google Scholar]
  12. Baum E, Sattabongkot J, Sirichaisinthop J, Kiattibutr K, Davies DH, Jain A, Lo E, Lee MC, Randall AZ, Molina DM, Liang X, Cui L, Felgner PL, Yan G, , 2015. Submicroscopic and asymptomatic and infections are common in western Thailand—molecular and serological evidence. Malar J 14: 95.[Crossref] [Google Scholar]
  13. Crompton PD, Kayala MA, Traore B, Kayentao K, Ongoiba A, Weiss GE, Molina DM, Burk CR, Waisberg M, Jasinskas A, Tan X, Doumbo S, Doumtabe D, Kone Y, Narum DL, Liang X, Doumbo OK, Miller LH, Doolan DL, Baldi P, Felgner PL, Pierce SK, , 2010. A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray. Proc Natl Acad Sci USA 107: 69586963.[Crossref] [Google Scholar]
  14. Doolan DL, Mu Y, Unal B, Sundaresh S, Hirst S, Valdez C, Randall A, Molina D, Liang X, Freilich DA, Oloo JA, Blair PL, Aguiar JC, Baldi P, Davies DH, Felgner PL, , 2008. Profiling humoral immune responses to P. falciparum infection with protein microarrays. Proteomics 8: 46804694.[Crossref] [Google Scholar]
  15. Sundaresh S, Doolan DL, Hirst S, Mu Y, Unal B, Davies DH, Felgner PL, Baldi P, , 2006. Identification of humoral immune responses in protein microarrays using DNA microarray data analysis techniques. Bioinformatics 22: 17601766.[Crossref] [Google Scholar]
  16. Trieu A, Kayala MA, Burk C, Molina DM, Frelich DA, Richie TL, Baldi P, Felgner DA, Doolan DL, , 2011. Sterile protective immunity to malaria is associated with a panel of novel P. falciparum antigens. Mol Cell Proteomics 10: M111.007948.[Crossref] [Google Scholar]
  17. Molina DM, Finney OC, Arevalo-Herrera M, Herrera S, Felgner PL, Gardner MJ, Liang X, Wang R, , 2012. Plasmodium vivax pre-erythrocytic-stage antigen discovery: exploiting naturally acquired humoral responses. Am J Trop Med Hyg 87: 460469.[Crossref] [Google Scholar]
  18. Bailey JA, Pablo J, Niangaly A, Travassos MA, Ouattara A, Coulibaly D, Laurens MB, Takala-Harrison SL, Lyke KE, Skinner J, Berry AA, Jasisnkas A, Nakajima-Sasaki R, Kouriba B, Thera MA, Felgner PL, Doumbo OK, Plowe CV, , 2015. Seroreactivity to a large panel of field-derived Plasmodium falciparum apical membrane antigen 1 and merozoite surface protein 1 variants reflects seasonal and lifetime acquired responses to malaria. Am J Trop Med Hyg 92: 912.[Crossref] [Google Scholar]
  19. Davies DH, Liang X, Hernandez JE, Randall A, Hirst S, Mu Y, Romero KM, Nguyen TT, Kalantari-Dehaghi M, Crotty S, Baldi P, Villarreal LP, Felgner PL, , 2005. Profiling the humoral immune response to infection by using proteome microarrays: high-throughput vaccine and diagnostic antigen discovery. Proc Natl Acad Sci USA 102: 547552.[Crossref] [Google Scholar]
  20. Finney OC, Danziger SA, Molina DM, Vignali M, Takagi A, Ji M, Stanisic DI, Siba PM, Liang X, Aitchison JD, Mueller I, Gardner MJ, Wang R, , 2014. Predicting antidisease immunity using proteome arrays and sera from children naturally exposed to malaria. Mol Cell Proteomics 13: 26462660.[Crossref] [Google Scholar]
  21. Culleton R, Carter R, , 2012. African Plasmodium vivax: distribution and origins. Int J Parasitol 42: 10911097.[Crossref] [Google Scholar]
  22. Ryan JR, Stoute JA, Amon J, Dunton RF, Mtalib R, Koros J, Owour B, Luckhart S, Wirtz RA, Barnwell JW, Rosenberg R, , 2006. Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in western Kenya. Am J Trop Med Hyg 75: 575581. [Google Scholar]
  23. Pullan RL, Bukirwa H, Staedke SG, Snow RW, Brooker S, , 2010. Plasmodium infection and its risk factors in eastern Uganda. Malar J 9: 2.[Crossref] [Google Scholar]
  24. Tobian AA, Mehlotra RK, Malhotra I, Wamachi A, Mungai P, Koech D, Ouma J, Zimmerman P, King CL, , 2000. Frequent umbilical cord-blood and maternal-blood infections with Plasmodium falciparum, P. malariae, and P. ovale in Kenya. J Infect Dis 182: 558563.[Crossref] [Google Scholar]
  25. White NJ, Imwong M, , 2012. Relapse. Adv Parasitol 80: 113150.[Crossref] [Google Scholar]
  26. Dent AE, Nakajima R, Liang L, Baum E, Moormann AM, Sumba PO, Vulule J, Babineau D, Randall A, Davies DH, Felgner PL, Kazura JW, , 2015. Plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in Kenya. J Infect Dis. Apr 15. pii: jiv224 [Epub ahead of print]. [Google Scholar]
  27. Barbosa S, Gozze AB, Lima NF, Bastista CL, Bastos M da S, Nicolete VC, Fontoura PS, Goncalves RM, Viana SA, Menezes MJ, Scopel KK, Cavasini CE, Malafronte R dos S, da Silva-Nunes M, Vinetz JM, Castro MC, Ferreira MU, , 2014. Epidemiology of disappearing Plasmodium vivax malaria: a case study in rural Amazonia. PLoS Negl Trop Dis 8: e3109.[Crossref] [Google Scholar]
  28. Torres KJ, Castrillon CE, Moss EL, Saito M, Tenorio R, Molina DM, Davies H, Neafsey DE, Felgner P, Vinetz JM, Gamboa D, , 2015. Genome-level determination of Plasmodium falciparum blood-stage targets of malarial clinical immunity in the Peruvian Amazon. J Infect Dis 211: 13421351. [Google Scholar]
  29. Smith DL, Drakeley CJ, Chiyaka C, Hay SI, , 2010. A quantitative analysis of transmission efficiency versus intensity for malaria. Nat Commun 1: 108.[Crossref] [Google Scholar]
  30. Corran P, Coleman P, Riley E, Drakeley C, , 2007. Serology: a robust indicator of malaria transmission intensity? Trends Parasitol 23: 575582.[Crossref] [Google Scholar]
  31. Bosomprah S, , 2014. A mathematical model of seropositivity to malaria antigen, allowing seropositivity to be prolonged by exposure. Malar J 13: 12.[Crossref] [Google Scholar]
  32. Cook J, Kleinschmidt I, Schwabe C, Nseng G, Bousema T, Corrah PH, Riley EM, Drakeley CJ, , 2011. Serological markers suggest heterogeneity of effectiveness of malaria control interventions on Bioko Island, Equatorial Guinea. PLoS One 6: e25137.[Crossref] [Google Scholar]
  33. Stewart L, Gosling R, Griffin J, Gesase S, Campo J, Hashim R, Masika P, Mosha J, Bousema T, Shekalaghe S, Cook J, Corran P, Ghani A, Riley EM, Drakeley C, , 2009. Rapid assessment of malaria transmission using age-specific sero-conversion rates. PLoS One 4: e6083.[Crossref] [Google Scholar]
  34. Yeka A, Nankabirwa J, Mpimbaza A, Kigozi R, Arinaitwe E, Drakeley C, Greenhouse B, Kamaya MR, Dorsey G, Steadke SG, , 2015. Factors associated with malaria parasitemia, anemia and serological responses in a spectrum of epidemiological settings in Uganda. PLoS One 10: e0118901.[Crossref] [Google Scholar]
  35. Doolan DL, Dobano C, Baird JK, , 2009. Acquired immunity to malaria. Clin Microbiol Rev 22: 1336.[Crossref] [Google Scholar]
  36. Langhorne J, Ndungu FM, Sponaas AM, Marsh K, , 2008. Immunity to malaria: more questions than answers. Nat Immunol 9: 725732.[Crossref] [Google Scholar]
  37. Luxemburger C, Nosten F, White NJ, , 1999. Naturally acquired immunity to vivax malaria. Lancet 354: 162.[Crossref] [Google Scholar]
  38. Mueller I, Galinski MR, Tsuboi T, Arevalo-Herrera M, Collins WE, King CL, , 2013. Natural acquisition of immunity to Plasmodium vivax: epidemiological observations and potential targets. Adv Parasitol 81: 77131.[Crossref] [Google Scholar]
  39. Schofield L, Mueller I, , 2006. Clinical immunity to malaria. Curr Mol Med 6: 205221.[Crossref] [Google Scholar]
  40. Riley EM, Wahl S, Perkins DJ, Schofield L, , 2006. Regulating immunity to malaria. Parasite Immunol 28: 3549.[Crossref] [Google Scholar]
  41. Freitas do Rosario AP, Langhorne J, , 2012. T cell-derived IL-10 and its impact on the regulation of host responses during malaria. Int J Parasitol 42: 549555.[Crossref] [Google Scholar]
  42. Couper KN, Blount DG, Riley EM, , 2008. IL-10: the master regulator of immunity to infection. J Immunol 180: 57715777.[Crossref] [Google Scholar]
  43. Jagannathan P, Eccles-James I, Bowen K, Nankya F, Auma A, Wamala S, Ebusu C, Muhindo MK, Arinaitwe E, Briggs J, Greenhouse B, Tappero JW, Kamaya MR, Dorsey G, Feeney ME, , 2014. IFNγ/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children. PLoS Pathog 10: e1003864.[Crossref] [Google Scholar]
  44. Illingworth J, Butler NS, Roetynck S, Mwacharo J, Pierce SK, Bejon P, Crompton PD, Marsh K, Ndungu FM, , 2013. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J Immunol 190: 10381047.[Crossref] [Google Scholar]
  45. Cohen S, Mc GI, Carrington S, , 1961. Gamma-globulin and acquired immunity to human malaria. Nature 192: 733737.[Crossref] [Google Scholar]
  46. Richards JS, Arumugam TU, Reiling L, Healer J, Hodder AN, Fowkes FJ, Cross N, Langer C, Takeo S, Uboldi AD, Thompson JK, Gilson PR, Coppel RL, Siba PM, King CL, Torii M, Chitnis CE, Narum DL, Mueller I, Crabb BS, Cowman AF, Tsuboi T, Beeson J, , 2013. Identification and prioritization of merozoite antigens as targets of protective human immunity to Plasmodium falciparum malaria for vaccine and biomarker development. J Immunol 191: 795809.[Crossref] [Google Scholar]
  47. Bull PC, Pain A, Ndungu FM, Kinyanjui SM, Roberts DJ, Newbold CI, Marsh K, , 2005. Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity. J Infect Dis 192: 11191126.[Crossref] [Google Scholar]
  48. Bull PC, Marsh K, , 2001. The role of antibodies to Plasmodium falciparum-infected-erythrocyte surface antigens in naturally acquired immunity to malaria. Trends Microbiol 10: 5558.[Crossref] [Google Scholar]
  49. Stanisic DI, Fowkes FJ, Koinari M, Javati S, Lin E, Kiniboro B, Richards JS, Robinson LJ, Schofield L, Kazura JW, King CL, Zimmerman P, Felger I, Siba PM, Mueller I, Beeson JG, , 2014. Acquisition of antibodies against Plasmodium falciparum merozoites and malaria immunity in young children: influence of age, force of infection, and magnitude of response. Infect Immun 83: 646660.[Crossref] [Google Scholar]
  50. Hill DL, Eriksson EM, Li Wai Suen CS, Chiu CY, Ryg-Cornejo V, Robinson LJ, Siba PM, Mueller I, Hansen DS, Schofield L, , 2013. Opsonising antibodies to P. falciparum merozoites associated with immunity to clinical malaria. PLoS One 8: e74627. [Google Scholar]
  51. Raj DK, Nixon CP, Nixon CE, Dvorin JD, DiPetrillo CG, Pond-Tor S, Wu HW, Jolly G, Pischel L, Lu A, Michelow IC, Cheng L, Conteh S, McDonald EA, Absalon S, Holte S, Friedman JF, Fried M, Duffy PE, Kurtis JD, , 2014. Antibodies to PfSEA-1 block parasite egress from RBCs and protect against malaria infection. Science 344: 871877.[Crossref] [Google Scholar]

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  • Received : 15 Jan 2015
  • Accepted : 05 Jun 2015
  • Published online : 02 Sep 2015

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