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Malaria Journal
Published in: Malaria Journal 1/2014

Open Access 01-12-2014 | Research

Impact of age of first exposure to Plasmodium falciparum on antibody responses to malaria in children: a randomized, controlled trial in Mozambique

Authors: Augusto J Nhabomba, Caterina Guinovart, Alfons Jiménez, Maria N Manaca, Llorenç Quintó, Pau Cisteró, Ruth Aguilar, Arnoldo Barbosa, Mauricio H Rodríguez, Quique Bassat, John J Aponte, Alfredo Mayor, Chetan E Chitnis, Pedro L Alonso, Carlota Dobaño

Published in: Malaria Journal | Issue 1/2014

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Abstract

Background

The impact of the age of first Plasmodium falciparum infection on the rate of acquisition of immunity to malaria and on the immune correlates of protection has proven difficult to elucidate. A randomized, double-blind, placebo-controlled trial using monthly chemoprophylaxis with sulphadoxine-pyrimethamine plus artesunate was conducted to modify the age of first P. falciparum erythrocytic exposure in infancy and assess antibodies and malaria risk over two years.

Methods

Participants (n = 349) were enrolled at birth to one of three groups: late exposure, early exposure and control group, and were followed up for malaria morbidity and immunological analyses at birth, 2.5, 5.5, 10.5, 15 and 24 months of age. Total IgG, IgG subclasses and IgM responses to MSP-119, AMA-1, and EBA-175 were measured by ELISA, and IgG against variant antigens on the surface of infected erythrocytes by flow cytometry. Factors affecting antibody responses in relation to chemoprophylaxis and malaria incidence were evaluated.

Results

Generally, antibody responses did not vary significantly between exposure groups except for levels of IgM to EBA-175, and seropositivity of IgG1 and IgG3 to MSP-119. Previous and current malaria infections were strongly associated with increased IgG against MSP-119, EBA-175 and AMA-1 (p < 0.0001). After adjusting for exposure, only higher levels of anti-EBA-175 IgG were significantly associated with reduced clinical malaria incidence (IRR 0.67, p = 0.0178).

Conclusions

Overall, the age of first P. falciparum infection did not influence the magnitude and breadth of IgG responses, but previous exposure was critical for antibody acquisition. IgG responses to EBA-175 were the strongest correlate of protection against clinical malaria.

Trial registration

ClinicalTrials.gov: NCT00231452.
Appendix
Available only for authorised users
Literature
1.
WHO: World Malaria Report. 2012, Geneva: World Health Organization, 238-
2.
3.
Stanisic DI, Richards JS, McCallum FJ, Michon P, King CL, Schoepflin S, Gilson PR, Murphy VJ, Anders RF, Mueller I, Beeson JG: Immunoglobulin G subclass-specific responses against Plasmodium falciparum merozoite antigens are associated with control of parasitemia and protection from symptomatic illness. Infect Immun. 2009, 77: 1165-1174. 10.1128/IAI.01129-08.PubMedCentralCrossRefPubMed
4.
Greenhouse B, Ho B, Hubbard A, Njama-Meya D, Narum DL, Lanar DE, Dutta S, Rosenthal PJ, Dorsey G, John CC: Antibodies to Plasmodium falciparum antigens predict a higher risk of malaria but protection from symptoms once parasitemic. J Infect Dis. 2011, 204: 19-26. 10.1093/infdis/jir223.PubMedCentralCrossRefPubMed
5.
Ofori MF, Dodoo D, Staalsoe T, Kurtzhals JAL, Koram K, Theander TG, Akanmori BD, Hviid L: Malaria-induced acquisition of antibodies to Plasmodium falciparum variant surface antigens. Infect Immun. 2002, 70: 2982-2988. 10.1128/IAI.70.6.2982-2988.2002.PubMedCentralCrossRefPubMed
6.
Nielsen MA, Staalsoe T, Kurtzhals JAL, Goka BQ, Dodoo D, Alifrangis M, Theander TG, Akanmori BD, Hviid L: Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity. J Immunol. 2002, 168: 3444-3450.CrossRefPubMed
7.
Richards JS, Beeson JG: The future for blood-stage vaccines against malaria. Immunol Cell Biol. 2009, 87: 377-390. 10.1038/icb.2009.27.CrossRefPubMed
8.
Chen Q, Schlichtherle M, Wahlgren M: Molecular aspects of severe malaria. Clin Microbiol Rewiews. 2000, 13: 439-450. 10.1128/CMR.13.3.439-450.2000.CrossRef
9.
Osier FHA, Fegan G, Polley SD, Murungi L, Verra F, Tetteh KKA, Lowe B, Mwangi T, Bull PC, Thomas AW, Cavanagh DR, McBride JS, Lanar DE, Mackinnon MJ, Conway DJ, Marsh K: Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria. Infect Immun. 2008, 76: 2240-2248. 10.1128/IAI.01585-07.PubMedCentralCrossRefPubMed
10.
Oeuvray C, Bouharoun-Tayoun H, Gras-Masse H, Bottius E, Kaidoh T, Aikawa M, Filgueira MC, Tartar A, Druilhe P: Merozoite surface protein-3: a malaria protein inducing antibodies that promote Plasmodium falciparum killing by cooperation with blood monocytes. Blood. 1994, 84: 1594-1602.PubMed
11.
Roussilhon C, Oeuvray C, Müller-Graf C, Tall A, Rogier C, Trape J-F, Theisen M, Balde A, Pérignon J-L, Druilhe P: Long-term clinical protection from falciparum malaria is strongly associated with IgG3 antibodies to merozoite surface protein 3. PLoS Med. 2007, 4: e320-10.1371/journal.pmed.0040320.PubMedCentralCrossRefPubMed
12.
Spring MD, Cummings JF, Ockenhouse CF, Dutta S, Reidler R, Cohen J, Heppner DG: Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1) administered in adjuvant system AS01B or AS02A. PLoS One. 2009, 4: e5254-10.1371/journal.pone.0005254.PubMedCentralCrossRefPubMed
13.
McCallum FJ, Persson KEM, Mugyenyi CK, Fowkes FJI, Simpson JA, Richards JS, Williams TN, Marsh K, Beeson JG: Acquisition of growth-inhibitory antibodies against blood-stage Plasmodium falciparum. PLoS One. 2008, 3: e3571-10.1371/journal.pone.0003571.PubMedCentralCrossRefPubMed
14.
Cowman AF, Crabb BS: Invasion of red blood cells by malaria parasites. Cell. 2006, 124: 755-766. 10.1016/j.cell.2006.02.006.CrossRefPubMed
15.
Verra F, Chokejindachai W, Weedall GD, Polley SD, Mwangi TW, Marsh K, Conway DJ: Contrasting signatures of selection on the Plasmodium falciparum erythrocyte binding antigen gene family. Mol Biochem Parasitol. 2006, 149: 182-90. 10.1016/j.molbiopara.2006.05.010.CrossRefPubMed
16.
Fowkes FJI, Richards JS, Simpson JA, Beeson JG: The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: A systematic review and meta-analysis. PLoS Med. 2010, 7: e1000218-10.1371/journal.pmed.1000218.PubMedCentralCrossRefPubMed
17.
Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K: Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med. 1998, 4: 358-360. 10.1038/nm0398-358.PubMedCentralCrossRefPubMed
18.
Marsh K, Howard RJ: Antigens induced on erythrocytes by Plasmodium falciparum: expression of diverse and conserved determinants. Science. 1986, 231: 150-153. 10.1126/science.2417315.CrossRefPubMed
19.
Abdel-Latif MS, Khattab A, Lindenthal C, Kremsner PG, Klinkert M-Q: Recognition of variant rifin antigens by human antibodies induced during natural Plasmodium falciparum infections. Infect Immun. 2002, 70: 7013-7021. 10.1128/IAI.70.12.7013-7021.2002.PubMedCentralCrossRefPubMed
20.
Baruch DI, Gormely JA, Ma C, Howard RJ, Pasloske BL: Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1996, 93: 3497-3502. 10.1073/pnas.93.8.3497.PubMedCentralCrossRefPubMed
21.
Egan AF, Burghaus P, Druilhe P, Holder AA, Riley EM: Human antibodies to the 19 kDa C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 inhibit parasite growth in vitro. Parasite Immunol. 1999, 21: 133-139. 10.1046/j.1365-3024.1999.00209.x.CrossRefPubMed
22.
Vestergaard LS, Lusingu JP, Nielsen MA, Mmbando BP, Dodoo D, Akanmori BD, Alifrangis M, Bygbjerg IC, Lemnge MM, Staalsoe T, Hviid L, Theander TG: Differences in human antibody reactivity to Plasmodium falciparum variant surface antigens are dependent on age and malaria transmission intensity in northeastern Tanzania. Infect Immun. 2008, 76: 2706-2714. 10.1128/IAI.01401-06.PubMedCentralCrossRefPubMed
23.
Baird JK: Age-dependent characteristics of protection v. susceptibility to Plasmodium falciparum. Ann Trop Med Parasitol. 1998, 92: 367-390. 10.1080/00034989859366.CrossRefPubMed
24.
Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, Mshinda H, Alonso P: Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet. 2001, 357: 1471-1477. 10.1016/S0140-6736(00)04643-2.CrossRefPubMed
25.
Alonso PL, Smith T, Schellenberg JR, Masanja H, Mwankusye S, Urassa H: Bastos de Azevedo I, Chongela J, Kobero S, Menendez C: Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania. Lancet. 1994, 344: 1175-1181. 10.1016/S0140-6736(94)90505-3.CrossRefPubMed
26.
Guinovart C, Dobaño C, Bassat Q, Nhabomba A, Quintó L, Manaca MN, Aguilar R, Rodríguez MH, Barbosa A, Aponte JJ, Mayor AG, Renom M, Moraleda C, Roberts DJ, Schwarzer E, Le Souëf PN, Schofield L, Chitnis CE, Doolan DL, Alonso PL: The role of age and exposure to Plasmodium falciparum in the rate of acquisition of naturally acquired immunity: a randomized controlled trial. PLoS One. 2012, 7: e32362-10.1371/journal.pone.0032362.PubMedCentralCrossRefPubMed
27.
Alonso P, Aponte J, Gomez-Olive X, Nhacolo A, Thomson R, Macete E, Abacassamo F, Ventura PJ, Dgedge M: Manhiça demographic surveillance system. Indepth Monogr. Volume 1. 2002, Maputo: Centro de Investigação em Saúde de Manhiça, 1-15.
28.
Sacarlal J, Aponte JJ, Aide P, Mandomando I, Bassat Q, Guinovart C, Leach A, Milman J, Macete E, Espasa M, Ofori-Anyinam O, Thonnard J, Corachan S, Dubois M-C, Lievens M, Dubovsky F, Ballou WR, Cohen J, Alonso PL: Safety of the RTS, S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial. Vaccine. 2008, 26: 174-84. 10.1016/j.vaccine.2007.11.003.CrossRefPubMed
29.
Quelhas D, Jiménez A, Quintó L, Serra-Casas E, Mayor A, Cisteró P, Puyol L, Wilson DW, Richards JS, Nhampossa T, Macete E, Aide P, Mandomando I, Sanz S, Aponte JJ, Alonso PL, Beeson JG, Menéndez C, Dobaño C: IgG against Plasmodium falciparum variant surface antigens and growth inhibitory antibodies in Mozambican children receiving intermittent preventive treatment with sulfadoxine-pyrimethamine. Immunobiology. 2011, 216: 793-802. 10.1016/j.imbio.2010.12.010.CrossRefPubMed
30.
Mayor A, Rovira-Vallbona E, Machevo S, Bassat Q, Aguilar R, Quintó L, Jiménez A, Sigauque B, Dobaño C, Kumar S, Singh B, Gupta P, Chauhan VS, Chitnis CE, Alonso PL, Menéndez C: Parity and placental infection affect antibody responses against Plasmodium falciparum during pregnancy. Infect Immun. 2011, 79: 1654-1659. 10.1128/IAI.01000-10.PubMedCentralCrossRefPubMed
31.
Trager W, Jensen JB: Human malaria parasites in continuous culture. Science. 1976, 193: 673-675. 10.1126/science.781840.CrossRefPubMed
32.
Quelhas D, Puyol L, Quintó L, Serra-Casas E, Nhampossa T, Macete E, Aide P, Mayor A, Mandomando I, Sanz S, Aponte JJ, Chauhan VS, Chitnis CE, Alonso PL, Menéndez C, Dobaño C: Impact of intermittent preventive treatment with sulfadoxine-pyrimethamine on antibody responses to erythrocytic-stage Plasmodium falciparum antigens in infants in Mozambique. Clin Vaccine Immunol. 2008, 15: 1282-1291. 10.1128/CVI.00044-08.PubMedCentralCrossRefPubMed
33.
Mayor A, Serra-Casas E, Bardají A, Sanz S, Puyol L, Cisteró P, Sigauque B, Mandomando I, Aponte JJ, Alonso PL, Menéndez C: Sub-microscopic infections and long-term recrudescence of Plasmodium falciparum in Mozambican pregnant women. Malar J. 2009, 8: 9-10.1186/1475-2875-8-9.PubMedCentralCrossRefPubMed
34.
Quelhas D, Puyol L, Quintó L, Nhampossa T, Serra-Casas E, Macete E, Aide P, Sanz S, Aponte JJ, Doolan DL, Alonso PL, Menéndez C, Dobaño C: Intermittent preventive treatment with sulfadoxine-pyrimethamine does not modify plasma cytokines and chemokines or intracellular cytokine responses to Plasmodium falciparum in Mozambican children. BMC Immunol. 2012, 13: 5-10.1186/1471-2172-13-5.PubMedCentralCrossRefPubMed
35.
Dobaño C, Quelhas D, Quintó L, Puyol L, Serra-Casas E, Mayor A, Nhampossa T, Macete E, Aide P, Mandomando I, Sanz S, Puniya SK, Singh B, Gupta P, Bhattacharya A, Chauhan VS, Aponte JJ, Chitnis CE, Alonso PL, Menéndez C: Age-dependent IgG subclass responses to Plasmodium falciparum EBA-175 are differentially associated with incidence of malaria in Mozambican children. Clin Vaccine Immunol. 2012, 19: 157-66. 10.1128/CVI.05523-11.PubMedCentralCrossRefPubMed
36.
Serra-Casas E, Menéndez C, Bardají A, Quintó L, Dobaño C, Sigauque B, Jiménez A, Mandomando I, Chauhan VS, Chitnis CE, Alonso PL, Mayor A: 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. 2010, 201: 123-31. 10.1086/648595.CrossRefPubMed
37.
Gray JC, Corran PH, Mangia E, Gaunt MW, Li Q, Tetteh KKA, Polley SD, Conway DJ, Holder AA, Bacarese-Hamilton T, Riley EM, Crisanti A: Profiling the antibody immune response against blood stage malaria vaccine candidates. Clin Chem. 2007, 53: 1244-1253. 10.1373/clinchem.2006.081695.CrossRefPubMed
38.
Polley SD, Mwangi T, Kocken CHM, Thomas AW, Dutta S, Lanar DE, Remarque E, Ross A, Williams TN, Mwambingu G, Lowe B, Conway DJ, Marsh K: Human antibodies to recombinant protein constructs of Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) and their associations with protection from malaria. Vaccine. 2004, 23: 718-728. 10.1016/j.vaccine.2004.05.031.CrossRefPubMed
39.
Ngoundou-Landji J, Nwuba RI, Anumudu CI, Odaibo AB, Matondo Maya WD, Awobode HO, Okafor CM, Morenikeji OA, Asinobi A, Nwagwu M, Holder AA, Ntoumi F: Fine specificity of anti-MSP119 antibodies and multiplicity of Plasmodium falciparum merozoite surface protein 1 types in individuals in Nigeria with sub-microscopic infection. Malar J. 2010, 9: 287-10.1186/1475-2875-9-287.PubMedCentralCrossRefPubMed
40.
McCarra MB, Ayodo G, Sumba PO, Kazura JW, Moormann AM, Narum DL, John CC: Antibodies to Plasmodium falciparum erythrocyte-binding antigen-175 are associated with protection from clinical malaria. Pediatr Infect Dis J. 2011, 30 (12): 1037-1042. 10.1097/INF.0b013e31822d1451.PubMedCentralCrossRefPubMed
41.
Dodoo D, Aikins A, Kusi KA, Lamptey H, Remarque E, Milligan P, Bosomprah S, Chilengi R, Osei YD, Akanmori BD, Theisen M: Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children. Malar J. 2008, 7: 142-10.1186/1475-2875-7-142.PubMedCentralCrossRefPubMed
42.
Campo JJ, Dobaño C, Sacarlal J, Guinovart C, Mayor A, Angov E, Dutta S, Chitnis C, Macete E, Aponte JJ, Alonso PL: Impact of the RTS S malaria vaccine candidate on naturally acquired antibody responses to multiple asexual blood stage antigens. PLoS One. 2011, 6: e25779-10.1371/journal.pone.0025779.PubMedCentralCrossRefPubMed
Metadata
Title
Impact of age of first exposure to Plasmodium falciparum on antibody responses to malaria in children: a randomized, controlled trial in Mozambique
Authors
Augusto J Nhabomba
Caterina Guinovart
Alfons Jiménez
Maria N Manaca
Llorenç Quintó
Pau Cisteró
Ruth Aguilar
Arnoldo Barbosa
Mauricio H Rodríguez
Quique Bassat
John J Aponte
Alfredo Mayor
Chetan E Chitnis
Pedro L Alonso
Carlota Dobaño
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2014
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-13-121

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