title: Impact of age of first exposure to Plasmodium falciparum on antibody responses to malaria in children: a randomized, controlled trial in Mozambique.
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-1(19), 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-1(19). Previous and current malaria infections were strongly associated with increased IgG against MSP-1(19), 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.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00231452.
authors.affiliation: Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique. augusto.nhabomba@gmail.com.
authors.forename: Augusto J
authors.initials: AJ
authors.lastname: Nhabomba
authors.forename: Caterina
authors.initials: C
authors.lastname: Guinovart
authors.forename: Alfons
authors.initials: A
authors.lastname: Jiménez
authors.forename: Maria N
authors.initials: MN
authors.lastname: Manaca
authors.forename: Llorenç
authors.initials: L
authors.lastname: Quintó
authors.forename: Pau
authors.initials: P
authors.lastname: Cisteró
authors.forename: Ruth
authors.initials: R
authors.lastname: Aguilar
authors.forename: Arnoldo
authors.initials: A
authors.lastname: Barbosa
authors.forename: Mauricio H
authors.initials: MH
authors.lastname: Rodríguez
authors.forename: Quique
authors.initials: Q
authors.lastname: Bassat
authors.forename: John J
authors.initials: JJ
authors.lastname: Aponte
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mayor
authors.forename: Chetan E
authors.initials: CE
authors.lastname: Chitnis
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Alonso
authors.forename: Carlota
authors.initials: C
authors.lastname: Dobaño
mesh_terms: D056704:Adaptive Immunity; D000367:Age Factors; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology*; D000953:Antigens, Protozoan / Q000097:blood / Q000276:immunology*; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D018890:Chemoprevention; D002675:Child, Preschool; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D008297:Male; D009073:Mozambique / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000276:immunology; D015995:Prevalence; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D000962:Antimalarials; D037621:Artemisinins; C578917:sulfadoxine-pyrimethamine-artesunate; D013413:Sulfadoxine; D011739:Pyrimethamine