Background: The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the
selection of numerous human genetic variants that confer an advantage against severe malaria and
death. One such variant is the Dantu blood group antigen, which is associated with 74% protection
against severe and complicated P. falciparum malaria infections in homozygous individuals, similar
to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu
exerts this protection by increasing the surface tension of red blood cells, thereby impeding the
ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no
studies have yet explored this hypothesis in vivo.
Methods: We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a
controlled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculated
with 3.2 × 103
aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored
for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis
of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum
parasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in
the presence of parasitaemia of any density. On study completion, all participants were genotyped
both for Dantu and for four other polymorphisms that are associated with protection against severe
falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in
the red cell calcium transporter ATP2B4.
Results: The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparison
to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111
(44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and
0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on
either outcome were seen for any of the other genetic variants under study.
Conclusions: This study reveals, for the first time, that the Dantu blood group is associated with
high-level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning
more about the mechanisms involved could potentially lead to new approaches to the prevention or
treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly
testing the protective impact of genotypes previously identified using other methods.