Background Malaria immunity is commonly believed to wane in the absence of Plasmodium falciparum exposure, based on limited epidemiological data and short-lived antibody responses in some longitudinal studies in endemic areas. Methods A cross-sectional study was conducted among sub-Saharan African adults residing in Spain for 1 up to 38 years (immigrants) with clinical malaria (n=55) or without malaria (n=37), na？ve adults (travelers) with a first clinical malaria episode (n=20) and life-long malaria exposed adults from Mozambique (semi-immune adults) without malaria (n=27) or with clinical malaria (n=50). Blood samples were collected and IgG levels against the erythrocytic antigens AMA-1 and MSP-142 (3D7 and FVO strains), EBA-175 and DBL-α were determined by Luminex. IgG levels against antigens on the surface of infected erythrocytes (IEs) were measured by flow cytometry. Results Immigrants without malaria had lower IgG levels than healthy semi-immune adults regardless of the antigen tested (P≤0.026), but no correlation was found between IgG levels and time since migration. Upon reinfection, immigrants with malaria had higher levels of IgG against all antigens than immigrants without malaria. However, the magnitude of the response compared to semi-immune adults with malaria depended on the antigen tested. Thus, immigrants had higher IgG levels against AMA-1 and MSP-142 (P≤0.015), similar levels against EBA-175 and DBL-α, and lower levels against IEs (P≤0.016). Immigrants had higher IgG levels against all antigens tested compared to travelers (P≤0.001), both with malaria. Conclusions Upon cessation of malaria exposure, IgG responses to malaria-specific antigens were maintained to a large extent, although the conservation and the magnitude of the recall response depended on the nature of the antigen. Studies on immigrant populations can shed light on the factors that determine the duration of malaria specific antibody responses and its effect on protection, with important implications for future vaccine design and public health control measures.
Amanna IJ, Carlson NE, Slifka MK (2007) Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357: 1903–1915. doi:10.1056/NEJMoa066092. PubMed: 17989383.
Cohen S, McGregor IA, Carrington S (1961) Gamma-globulin and acquired immunity to human malaria. Nature 192: 733–737. doi:10.1038/192733a0. PubMed: 13880318.
Sabchareon A, Burnouf T, Ouattara D, Attanath P, Bouharoun-Tayoun H et al. (1991) Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria. Am J Trop Med Hyg 45: 297–308. PubMed: 1928564.
Richards JS, Stanisic DI, Fowkes FJI, Tavul L, Dabod E et al. (2010) Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia. Clin Infect Dis 51: e50–e60. doi:10.1086/656413. PubMed: 20843207.
Dodoo D, Aikins A, Kusi KA, Lamptey H, Remarque E et al. (2008) Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children. Malar J 7: 142. doi:10.1186/1475-2875-7-142. PubMed: 18664257.
Conway DJ, Cavanagh DR, Tanabe K, Roper C, Mikes ZS et al. (2000) A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med 6: 689–692. doi:10.1038/76272. PubMed: 10835687.
Polley SD, Mwangi T, Kocken CHM, Thomas AW, Dutta S et al. (2004) Human antibodies to recombinant protein constructs of Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) and their associations with protection from malaria. Vaccine 23: 718–728. doi:10.1016/j.vaccine.2004.05.031. PubMed: 15542195.
Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI et al. (1998) Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med 4: 358–360. doi:10.1038/nm0398-358. PubMed: 9500614.
Mayor A, Rovira-Vallbona E, Srivastava A, Sharma SK, Pati SS et al. (2009) Functional and immunological characterization of a Duffy binding-like alpha domain from Plasmodium falciparum erythrocyte membrane protein 1 that mediates rosetting. Infect Immun 77: 3857–3863. doi:10.1128/IAI.00049-09. PubMed: 19546191.
Matteelli a, Colombini P, Gulletta M, Castelli F, Carosi G (1999) Epidemiological features and case management practices of imported malaria in northern Italy 1991-1995. Trop Med Int Health 4: 653–657. doi:10.1046/j.1365-3156.1999.00468.x. PubMed: 10583898.
Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP et al. (2002) Imported Falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases. Clin Infect Dis 34: 572–576. doi:10.1086/338235. PubMed: 11803507.
Mascarello M, Allegranzi B, Angheben A, Anselmi M, Concia E et al. (2008) Imported malaria in adults and children: epidemiological and clinical characteristics of 380 consecutive cases observed in Verona, Italy. J Travel Med 15: 229–236. doi:10.1111/j.1708-8305.2008.00204.x. PubMed: 18666922.
Bouchaud O, Cot M, Kony S, Durand R, Schiemann R et al. (2005) Do African immigrants living in France have long-term malarial immunity? Am J Trop Med Hyg 72: 21–25. PubMed: 15728861.
Salvadó E, Pinazo MJ, Mu？oz J, Alonso D, Naniche D et al. (2008) Clinical presentation and complications of Plasmodium falciparum malaria in two populations: travelers and immigrants. Enferm Infecc Microbiol Clin 26: 282–284. doi:10.1157/13120415. PubMed: 18479645.
Monge-Maillo B, Norman F, Pérez-Molina JA, Díaz-Menéndez M, Rubio JM et al. (2012) Plasmodium falciparum in asymptomatic immigrants from sub-Saharan Africa, Spain. Parasite Immunol 18: 356–357. PubMed: 22305463.
González A, Nicolás JM, Mu？oz J, Castro P, Mas J. et. al. (2009) Severe imported malaria in adults: retrospective study of 20 cases. Am J Trop Med Hyg 81: 595–599.
Kleinschmidt I, Sharp B (2001) Patterns in age-specific malaria incidence in a population exposed to low levels of malaria transmission intensity. Trop Med Int Health 6: 986–991. doi:10.1046/j.1365-3156.2001.00817.x. PubMed: 11737835.
Luxemburger C, Ricci F, Nosten F, Raimond D, Bathet S et al. (1997) The epidemiology of severe malaria in an area of low transmission in Thailand. Trans R Soc Trop Med Hyg 91: 256–262. doi:10.1016/S0035-9203(97)90066-3. PubMed: 9231189.
Cavanagh DR, Elhassan IM, Roper C, Robinson VJ, Giha H et al. (1998) A longitudinal study of type-specific antibody responses to Plasmodium falciparum merozoite surface protein-1 in an area of unstable malaria in Sudan. J Immunol 161: 347–359. PubMed: 9647243.
Giha HA, Staalsoe T, Dodoo D, Elhassan IM, Roper C et al. (1999) Nine-year longitudinal study of antibodies to variant antigens on the surface of Plasmodium falciparum-infected erythrocytes. Infect Immun 67: 4092–4098. PubMed: 10417178.
Früh K, Doumbo O, Müller HM, Koita O, McBride J et al. (1991) Human antibody response to the major merozoite surface antigen of Plasmodium falciparum is strain specific and short-lived. Infect Immun 59: 1319–1324. PubMed: 2004813.
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. doi:10.1186/1475-2875-6-82. PubMed: 17598897.
Ramasamy R, Nagendran K, Ramasamy MS (1994) Antibodies to epitopes on merozoite and sporozoite surface antigens as serologic markers of malaria transmission: studies at a site in the dry zone of Sri Lanka. Am J Trop Med Hyg 50: 537–547. PubMed: 7515593.
Akpogheneta OJ, Duah NO, Tetteh KK, Dunyo S, Lanar DE et al. (2008) Duration of naturally acquired antibody responses to blood-stage Plasmodium falciparum is age dependent and antigen specific. Infect Immun 76: 1748–1755. doi:10.1128/IAI.01333-07. PubMed: 18212081.
Wipasa J, Suphavilai C, Okell LC, Cook J, Corran PH et al. (2010) Long-lived antibody and B Cell memory responses to the human malaria parasites, Plasmodium falciparum and Plasmodium vivax. PLOS Pathog 6: e1000770.
Drakeley CJ, Corran PH, Coleman PG, Tongren JE, McDonald SLR et al. (2005) Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure. Proc Natl Acad Sci U S A 102: 5108–5113. doi:10.1073/pnas.0408725102. PubMed: 15792998.
Udhayakumar V, Kariuki S, Kolczack M, Girma M, Roberts JM et al. (2001) Longitudinal study of natural immune responses to the Plasmodium falciparum apical membrane antigen (AMA-1) in a holoendemic region of malaria in western Kenya: Asembo Bay Cohort Project VIII. Am J Trop Med Hyg 65: 100–107. PubMed: 11508382.
Migot F, Chougnet C, Raharimalala L, Astagneau P, Lepers JP et al. (1993) Human immune responses to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) after a decrease in malaria transmission in Madagascar. Am J Trop Med Hyg 48: 432–439. PubMed: 8470778.
Dodoo D, Theander TG, Kurtzhals JA, Koram K, Riley E et al. (1999) Levels of antibody to conserved parts of Plasmodium falciparum merozoite surface protein 1 in Ghanaian children are not associated with protection from clinical malaria. Infect Immun 67: 2131–2137. PubMed: 10225865.
Perraut R, Mercereau-Puijalon O, Diouf B, Tall A, Guillotte M et al. (2000) Seasonal fluctuation of antibody levels to Plasmodium falciparum parasitized red blood cell-associated antigens in two Senegalese villages with different transmission conditions. Am J Trop Med Hyg 62: 746–751. PubMed: 11304067.
Weiss GE, Traore B, Kayentao K, Ongoiba A, Doumbo S et al. (2010) The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLOS Pathog 6: e1000912.
Vande Waa JA, Jensen JB, Akood MA, Bayoumi R (1984) Longitudinal study on the in vitro immune response to Plasmodium falciparum in Sudan. Infect Immun 45: 505–510. PubMed: 6378799.
Chougnet C, Deloron P, Lepers JP, Tallet S, Rason MD et al. (1990) Humoral and cell-mediated immune responses to the Plasmodium falciparum antigens PF155/RESA and CS protein: seasonal variations in a population recently reexposed to endemic malaria. Am J Trop Med Hyg 43: 234–242. PubMed: 2221217.
Ndungu FM, Olotu A, Mwacharo J, Nyonda M, Apfeld J et al. (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 U S A 109.
Migot F, Chougnet C, Raharimalala L, Astagneau P, Lepers JP et al. (1993) Human immune responses to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) after a decrease in malaria transmission in Madagascar. Am J Trop Med Hyg 48: 432–439. PubMed: 8470778.
Wipasa J, Suphavilai C, Okell LC, Cook J, Corran PH et al. (2010) Long-lived antibody and B Cell memory responses to the human malaria parasites, Plasmodium falciparum and Plasmodium vivax. PLOS Pathog 6: e1000770.
Nogaro SI, Hafalla JC, Walther B, Remarque EJ, Tetteh KKa et al. (2011) The Breadth, but Not the Magnitude, of Circulating Memory B Cell Responses to P. falciparum Increases with Age/Exposure in an Area of Low Transmission. PLOS ONE 6: e25582. doi:10.1371/journal.pone.0025582. PubMed: 21991321.
Moncunill G, Mayor A, Jiménez A, Nhabomba A, Puyol L et al. (2013) Cytokine and Antibody Responses to Plasmodium falciparum in Na？ve Individuals during a First Malaria Episode: Effect of Age and Malaria Exposure. PLOS ONE 8: e55756. doi:10.1371/journal.pone.0055756. PubMed: 23437061.
Kocken CHM, Withers-Martinez C, Dubbeld MA, van der Wel A, Hackett F et al. (2002) High-level expression of the malaria blood-stage vaccine candidate Plasmodium falciparum apical membrane antigen 1 and induction of antibodies that inhibit erythrocyte invasion. Infect Immun 70: 4471–4476. doi:10.1128/IAI.70.8.4471-4476.2002. PubMed: 12117958.
Angov E (2003) Development and pre-clinical analysis of a Plasmodium falciparum Merozoite Surface Protein-142 malaria vaccine. Mol Biochem Parasitol 128: 195–204. doi:10.1016/S0166-6851(03)00077-X. PubMed: 12742586.
Angov E, Hillier CJ, Kincaid RL, Lyon JA (2008) Heterologous protein expression is enhanced by harmonizing the codon usage frequencies of the target gene with those of the expression host. PLOS ONE 3: e2189. doi:10.1371/journal.pone.0002189. PubMed: 18478103.
Campo JJ, Doba？o C, Sacarlal J, Guinovart C, Mayor A et al. (2011) Impact of the RTS,S Malaria Vaccine Candidate on Naturally Acquired Antibody Responses to Multiple Asexual Blood Stage Antigens. PLOS ONE 6: e25779. doi:10.1371/journal.pone.0025779. PubMed: 22022448.
Tanabe K, Mackay M, Goman M, Scaife JG (1987) Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum. J Mol Biol 195: 273–287. doi:10.1016/0022-2836(87)90649-8. PubMed: 3079521.
Campo JJ, Doba？o C, Sacarlal J, Guinovart C, Mayor A et al. (2011) Impact of the RTS,S Malaria Vaccine Candidate on Naturally Acquired Antibody Responses to Multiple Asexual Blood Stage Antigens. PLOS ONE 6: e25779. doi:10.1371/journal.pone.0025779. PubMed: 22022448.
Quelhas D, Puyol L, Quintó L, Serra-Casas E, Nhampossa T et al. (2008) Impact of intermittent preventive treatment with sulfadoxine-pyrimethamine on antibody responses to erythrocytic-stage Plasmodium falciparum antigens in infants in Mozambique. Clin Vaccine Immunol 15: 1282–1291. doi:10.1128/CVI.00044-08. PubMed: 18495848.
Serra-Casas E, Menéndez C, Bardají A, Quintó L, Doba？o C et al. (2010) The effect of intermittent preventive treatment during pregnancy on malarial antibodies depends on HIV status and is not associated with poor delivery outcomes. J Infect Dis 201: 123–131. doi:10.1086/648595. PubMed: 19954383.
Rovira-Vallbona E, Moncunill G, Bassat Q, Aguilar R, Machevo S et al. (2012) Low antibodies against Plasmodium falciparum and imbalanced pro-inflammatory cytokines are associated with severe malaria in Mozambican children: a case-control study. Malar J 11: 181. doi:10.1186/1475-2875-11-181. PubMed: 22646809.
Quelhas D, Jiménez A, Quintó L, Serra-Casas E, Mayor A et al. (2011) IgG against Plasmodium falciparum variant surface antigens and growth inhibitory antibodies in Mozambican children receiving intermittent preventive treatment with sulfadoxine-pyrimethamine. Immunobiology 216: 793–802. doi:10.1016/j.imbio.2010.12.010. PubMed: 21257227.
Ahuja A, Anderson SM, Khalil A, Shlomchik MJ (2008) Maintenance of the plasma cell pool is independent of memory B cells. Proc Natl Acad Sci U S A 105: 4802–4807. doi:10.1073/pnas.0800555105. PubMed: 18339801.
Moncunill G, Mayor A, Bardají A, Puyol L, Nhabomba A et al. (2013) Cytokine profiling in immigrants with clinical malaria after extended periods of interrupted exposure to Plasmodium falciparum. PLOS ONE 8: e73360.
