Lack of associations of α(+) - thalassemia with the risk of Plasmodium falciparum and Plasmodium vivax infection and disease in a cohort of children aged 3-21 months from Papua New Guinea

Despite consistent evidence of a protective effect of alpha(+)-thalassemia against severe Plasmodium falciparum disease, the mechanisms underlying this protection remain unknown. An increase in risk of Plasmodium vivax malaria in early childhood resulting in a cross-species protection against severe P. falciparum malaria has been proposed as a possible mechanism in Melanesian children. The association of alpha(+)-thalassemia genotypes with a risk of P. falciparum and P. vivax infection and uncomplicated illness was reassessed in a cohort of 1,112 Papua New Guinean children, followed from 3-21 months of age. Three hundred and eighty-nine (35.0%) children were homozygous for a(+)-thalassemia (-a/-a), 506 (45.5%) heterozygous (aa/-a) and 217 (19.5%) homozygous for the wild-type allele. No significant differences in the incidence of P. falciparum (Pf) or P. vivax (Pv) malaria were observed between alpha(+)-thalassemia homozygote (Pf: Incidence rate ratio (IRR) = 1.13, CI(95) (0.82,1.56), P = 0.45, Pv: IRR = 1.15, CI(95) (0.9881.56), P = 0.31), heterozygote (Pf: IRR = 0.98, CI(95) (0.71,1.34), P = 0.93, Pv: IRR = 1.14, CI(95) (0.88,1.48), P =0.33) and wild-type children. The prevalence of infection with either species did not differ between alpha(+)-thalassemia genotypes, although densities of P. vivax (but not of P. falciparum) infections were significantly higher in alpha(+)-thalassemia homozygote and heterozygote children. An excessive risk of moderate-to-severe anemia (hemoglobin (Hb) > 8 g/dl) was observed in alpha(+)-thalassemia homozygote children (IRR = 1.54, CI(95)(1.12, 2.11), P = 0.008). This study therefore failed to confirm an increased risk of P. vivax or P. falciparum malaria in very young, alpha(+)-thalassemic children without significant levels of acquired immunity. This confirms the lack of protection by alpha(+)-thalassemia against uncomplicated P. falciparum and challenges the hypothesis of immunological cross-protection between P. falciparum and P. vivax as a mechanism underlying alpha(+)-thalassemia protection against severe P. falciparum disease in Melanesian children