Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases.

Malaria has had a major effect on the human genome, many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemic regions 1 , 2 . Recently, it was shown that the blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals 3 – 5 . This is a similar degree of protection to sickle cell trait and considerably greater than the best malaria vaccine, but until now the protective mechanism has been unknown. Here, we demonstrate a significant impact of Dantu on Plasmodium falciparum-merozoite RBC invasion. Dantu was associated with extensive changes to the RBC surface protein repertoire, but unexpectedly, inhibition did not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we found a strong link between RBC tension and merozoite invasion and identified a tension threshold above which invasion rarely occurred, even in non-Dantu RBCs. Dantu RBCs had higher average tension, meaning that a greater proportion resisted invasion. These findings provide both an explanation for the malaria-protective effect of Dantu, and fresh insights into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs both within and between individuals.

Background Sickle cell disease is the most common severe monogenic disorder in humans. In Africa, 50-90% of children born with sickle cell disease die before they reach their fifth birthday. In this study, we aimed to describe the comparative incidence of specific clinical outcomes among children aged between birth and 5 years with and without sickle cell disease, who were resident within the Kilifi area of Kenya. Methods This prospective cohort study was done on members of the Kilifi Genetic Birth Cohort Study (KGBCS) on the Indian Ocean coast of Kenya. Recruitment to the study was facilitated through the Kilifi Health and Demographic Surveillance System (KHDSS), which covers a resident population of 260 000 people, and was undertaken between Jan 1, 2006, and April 30, 2011. All children who were born within the KHDSS area and who were aged 3-12 months during the recruitment period were eligible for inclusion. Participants were tested for sickle cell disease and followed up for survival status and disease-specific admission to Kilifi County Hospital by passive surveillance until their fifth birthday. Children with sickle cell disease were offered confirmatory testing and care at a dedicated outpatient clinic. Findings 15 737 infants were recruited successfully to the KGBCS, and 128 (0•8%) of these infants had sickle cell disease, of whom 70 (54•7%) enrolled at the outpatient clinic within 12 months of recruitment. Mortality was higher in children with sickle cell disease (58 per 1000 person-years of observation, 95% CI 40-86) than in those without sickle cell disease (2•4 per 1000 person-years of observation, 2•0-2•8; adjusted incidence rate ratio [IRR] 23•1, 95% CI 15•1-35•3). Among children with sickle cell disease, mortality was lower in those who enrolled at the clinic (adjusted IRR 0•26, 95% CI 0•11-0•62) and in those with higher levels of haemoglobin F (HbF; adjusted IRR 0•40, 0•17-0•94). The incidence of admission to hospital was also higher in children with sickle cell disease than in children without sickle cell disease (210 per 1000 person-years of observation, 95% CI 174-253, vs 43 per 1000 person-years of observation, 42-45; adjusted IRR 4•80, 95% CI 3•84-6•15). The most common reason for admission to hospital among those with sickle cell disease was severe anaemia (incidence 48 per 1000 person-years of observation, 95% CI 32-71). Admission to hospital was lower in those with a recruitment HbF level above the median (IRR 0•43, 95% CI 0•24-0•78; p=0•005) and those who were homozygous for α-thalassaemia (0•07, 0•01-0•83; p=0•035). Interpretation Although morbidity and mortality were high in young children with sickle cell disease in this Kenyan cohort, both were reduced by early diagnosis and supportive care. The emphasis must now move towards early detection and prevention of long-term complications of sickle cell disease. Funding Wellcome Trust.

Sickle cell anemia (SCA) is the commonest severe monogenic disorders of humans. The disease has been highly characterized in high‐income countries but not in sub‐Saharan Africa where SCA is most prevalent. We conducted a retrospective cohort study of all children 0–13 years admitted from within a defined study area to Kilifi County Hospital in Kenya over a five‐year period. Children were genotyped for SCA retrospectively and incidence rates calculated with reference to population data. Overall, 576 of 18,873 (3.1%) admissions had SCA of whom the majority (399; 69.3%) were previously undiagnosed. The incidence of all‐cause hospital admission was 57.2/100 person years of observation (PYO; 95%CI 52.6–62.1) in children with SCA and 3.7/100 PYO (95%CI 3.7–3.8) in those without SCA (IRR 15.3; 95%CI 14.1–16.6). Rates were higher for the majority of syndromic diagnoses at all ages beyond the neonatal period, being especially high for severe anemia (hemoglobin <50 g/L; IRR 58.8; 95%CI 50.3–68.7), stroke (IRR 486; 95%CI 68.4–3,450), bacteremia (IRR 23.4; 95%CI 17.4–31.4), and for bone (IRR 607; 95%CI 284–1,300), and joint (IRR 80.9; 95%CI 18.1–362) infections. The use of an algorithm based on just five clinical features would have identified approximately half of all SCA cases among hospital‐admitted children with a number needed to test to identify each affected patient of only fourteen. Our study illustrates the clinical epidemiology of SCA in a malaria‐endemic environment without specific interventions. The targeted testing of hospital‐admitted children using the Kilifi Algorithm provides a pragmatic approach to early diagnosis in high‐prevalence countries where newborn screening is unavailable.

Background Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy. Methods Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives. Findings Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers’ families, study staff and the research institution’s reputation more widely. Conclusion Developing ethically and scientifically strong HIS relies on grounded accounts of volunteers, study staff and the wider community, understood in the socioeconomic, political and cultural context where studies are implemented. Recognition of the diverse, and sometimes perverse, nature of potential benefits and burdens in a given context, and who this might implicate, is critical to this process. Prior and ongoing stakeholder engagement is core to developing these insights.