SEARCHRCTinfectious disease, immunology

RCT·infectious disease, immunology, clinical trial, hematology, epidemiology·PMC10264070

The Dantu blood group prevents parasite growth in vivo : Evidence from a controlled human malaria infection study

eLife · 10 authors, 11 centres

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TL;DR

A controlled human malaria infection study in Kenyan adults found that individuals with the Dantu blood group were completely protected from developing a pre-defined blood-stage parasitaemia threshold, while over 20% of Dantu-negative individuals reached this endpoint.

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This was a controlled human malaria infection study in 141 Kenyan adults, who were genotyped for the Dantu blood group and other malaria-protective polymorphisms. The primary outcome was reaching a parasitaemia threshold of ≥500/μl within 21 days post-inoculation. No other genetic variants showed a significant impact. The results provide the first direct in vivo evidence that the Dantu blood group protects against early-phase P. falciparum infection, consistent with in vitro mechanisms involving red blood cell invasion.

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RCT

SPECIALTY

infectious disease

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AI pipeline

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100% · A

ORIGINAL PAPER

PMC10264070

The Dantu blood group prevents parasite growth in vivo : Evidence from a controlled human malaria infection study

eLife

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ABSTRACT

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 × 10 3 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. Funding: The Kenya CHMI study was supported by an award from Wellcome (grant number 107499). SK was supported by a Training Fellowship (216444/Z/19/Z), TNW by a Senior Research Fellowship (202800/Z/16/Z), JCR by an Investigator Award (220266/Z/20/Z), and core support to the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya (203077), all from Wellcome. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Clinical trial number: NCT02739763

CITATION EXPORT

Silvia N Kariuki, Alexander W Macharia, Johnstone Makale et al.. The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study. eLife. (2023). https://doi.org/10.7554/eLife.83874

AUTHORS

10 · 11 CENTRES

Silvia N Kariuki, Alexander W Macharia, Johnstone Makale, Wilfred Nyamu, Stephen L Hoffman, Melissa C Kapulu, Philip Bejon, Julian C Rayner, Thomas N Williams, Amy Wesolowski

1 https://ror.org/04r1cxt79Centre for Geographic Medicine Research (Coast), KEMRI-Wellcome Trust Research Programme Kilifi Kenya
2 Sanaria Incorporate Rockville United States
3 https://ror.org/052gg0110Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford Oxford United Kingdom
4 https://ror.org/013meh722Cambridge Institute for Medical Research, University of Cambridge Cambridge United Kingdom
5 https://ror.org/041kmwe10Institute for Global Health Innovation, Department of Surgery and Cancer, Imperial College London London United Kingdom
Johns Hopkins Bloomberg School of Public Health United States
https://ror.org/05wg1m734Radboud University Medical Centre Netherlands
Johns Hopkins Bloomberg School of Public Health United States
Johns Hopkins Bloomberg School of Public Health United States
https://ror.org/01nrxwf90University of Edinburgh United Kingdom
https://ror.org/01znkr924Mahidol University Thailand

EDITOR / REVIEWER

Amy Wesolowski, Jos W van der Meer, Amy Wesolowski, Wiebke Nahrendorf, Nicholas J White