title: Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria.
abstract: BACKGROUND
  Elucidating the mechanisms of naturally acquired immunity to Plasmodium falciparum infections would be highly valuable for malaria vaccine development. Asymptomatic multiclonal infections have been shown to predict protection from clinical malaria in a transmission-dependent manner, but the mechanisms underlying this are unclear. We assessed the breadth of antibody responses to several vaccine candidate merozoite antigens in relation to the infecting parasite population and clinical immunity.
  
  
  METHODS
  In a cohort study in Tanzania, 320 children aged 1-16 years who were asymptomatic at baseline were included. We genotyped P. falciparum infections by targeting the msp2 gene using polymerase chain reaction and capillary electrophoresis and measured antibodies to 7 merozoite antigens using a multiplex assay. We assessed the correlation between the number of clones and the breadth of the antibody response, and examined their effects on the risk of malaria during 40 weeks of follow-up using age-adjusted multivariate regression models.
  
  
  RESULTS
  The antibody breadth was positively correlated with the number of clones (RR [risk ratio], 1.63; 95% confidence interval [CI], 1.32-2.02). Multiclonal infections were associated with a nonsignificant reduction in the risk of malaria in the absence of antibodies (RR, 0.83; 95% CI, .29-2.34). The breadth of the antibody response was significantly associated with a reduced risk of malaria in the absence of infections (RR, 0.25; 95% CI, .09-.66). In combination, these factors were associated with a lower risk of malaria than they were individually (RR, 0.14; 95% CI, .04-.48).
  
  
  CONCLUSIONS
  These data suggest that malaria vaccines mimicking naturally acquired immunity should ideally induce antibody responses that can be boosted by natural infections.
authors: Infectious Diseases Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Josea
authors: J
authors: Rono
authors: Faith H A
authors: FH
authors: Osier
authors: Daniel
authors: D
authors: Olsson
authors: Scott
authors: S
authors: Montgomery
authors: Leah
authors: L
authors: Mhoja
authors: Ingegerd
authors: I
authors: Rooth
authors: Kevin
authors: K
authors: Marsh
authors: Anna
authors: A
authors: Färnert
mesh_terms: D000293:Adolescent; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000276:immunology*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D058345:Asymptomatic Infections; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology*; D052940:Merozoites / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D012306:Risk; D013636:Tanzania
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C065974:merozoite surface protein 2, Plasmodium
keywords: antibodies; immunity; malaria; merozoite surface antigens; multiclonal infections
references: PLoS Med. 2005 Dec;2(12):e340
references: 16259530
references: Mol Biochem Parasitol. 1994 Mar;64(1):165-9
references: 8078519
references: Parasite Immunol. 2003 Nov-Dec;25(11-12):531-43
references: 15053774
references: Stat Methods Med Res. 2001 Jun;10(3):195-216
references: 11446148
references: Clin Infect Dis. 2010 Oct 15;51(8):e50-60
references: 20843207
references: Vaccine. 2006 May 8;24(19):4233-46
references: 16111789
references: J Infect Dis. 2011 Jul 1;204(1):19-26
references: 21628654
references: Trans R Soc Trop Med Hyg. 1999 Feb;93 Suppl 1:15-20
references: 10450421
references: Infect Immun. 1995 Nov;63(11):4382-8
references: 7591074
references: Trans R Soc Trop Med Hyg. 1999 Feb;93 Suppl 1:29-34
references: 10450423
references: Microbes Infect. 2007 Jan;9(1):103-10
references: 17194613
references: Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):10030-5
references: 22665809
references: Malar J. 2009 Apr 23;8:78
references: 19386138
references: Vaccine. 2013 Aug 20;31(37):3936-42
references: 23800539
references: Parasitology. 1993 Jul;107 ( Pt 1):11-8
references: 8355994
references: Trans R Soc Trop Med Hyg. 1999 Feb;93 Suppl 1:59-64
references: 10450428
references: J Infect Dis. 2007 Jan 15;195(2):279-87
references: 17191173
references: Am J Trop Med Hyg. 1995 Jan;52(1):81-8
references: 7856831
references: Trop Med Int Health. 2003 Jan;8(1):3-11
references: 12535242
references: PLoS One. 2010 Oct 27;5(10):e13649
references: 21048970
references: Infect Immun. 2009 Mar;77(3):1165-74
references: 19139189
references: Infect Immun. 2008 May;76(5):2240-8
references: 18316390
references: Parasitol Today. 1998 Nov;14(11):462-7
references: 17040849
references: J Infect Dis. 2009 Oct 1;200(7):1166-75
references: 19702508
references: Trans R Soc Trop Med Hyg. 1997 Sep-Oct;91(5):602-5
references: 9463681
references: Malar J. 2007 Jun 28;6:82
references: 17598897
references: Am J Epidemiol. 2004 Apr 1;159(7):702-6
references: 15033648
references: J Infect Dis. 1999 Apr;179(4):989-95
references: 10068596
references: Clin Exp Immunol. 1992 Dec;90(3):357-62
references: 1458672
references: Am J Trop Med Hyg. 1996 Jun;54(6):613-9
references: 8686780
references: Vaccine. 2004 Dec 16;23(5):718-28
references: 15542195
references: Parasite Immunol. 2007 Aug;29(8):387-94
references: 17650180
references: Trans R Soc Trop Med Hyg. 1999 Feb;93 Suppl 1:3-9
references: 10450419
references: Nature. 1961 Nov 25;192:733-7
references: 13880318
references: Am J Trop Med Hyg. 1994 Nov;51(5):593-602
references: 7985752
references: Infect Immun. 2001 Dec;69(12):7783-92
references: 11705960
references: Clin Exp Immunol. 2002 Aug;129(2):326-31
references: 12165090