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The changes occurring in the T cell repertoire during clinical malaria infection in children remain unknown. In this study, we undertook the first detailed comparative study of the T cell repertoire in African children with and without clinical malaria to test the hypothesis that clonotypic expansions that occur during P. falciparum infection will contribute to the generation of a T cell repertoire that is unique to each disease state. We profiled the complementarity-determining region 3 (CDR3) of the TCRβ chain sequences from children with Plasmodium falciparum infections (asymptomatic, uncomplicated and severe malaria) and compared these with sequences from healthy children. Interestingly, we discovered that children with symptomatic malaria have a lower TCR diversity and frequency of shared (or “public”) TCR sequences compared to asymptomatic children. Also, TCR diversity was inversely associated with parasitemia. Furthermore, by clustering TCR sequences based on their predicted antigen specificities, we identified a specificity cluster, with a 4-mer amino acid motif, that is overrepresented in the asymptomatic group compared to the diseased groups. Further investigations into this finding may help in delineating important antigenic targets for vaccine and therapeutic development. The results show that the T cell repertoire in children is altered during malaria, suggesting that exposure to P. falciparum antigens disrupts the adaptive immune response, which is an underlying feature of the disease.

Background In malaria, clinical disease has been associated with increased levels of endothelial activation due to the sequestration of infected erythrocytes. However, the levels and impact of endothelial activation and pro-angiogenic molecules such as vascular endothelial growth factor (VEGF)–A and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) in asymptomatic malaria have not been well characterized. Methods Blood samples were obtained from community children for malaria diagnosis using microscopy and polymerase chain reaction. A multiplex immunoassay was used to determine the levels of intracellular adhesion molecule (ICAM)–1, vascular endothelial growth factor (VEGF)–A, and VEGFR2 in the plasma of children with microscopic or submicroscopic asymptomatic parasitemia and compared with levels in uninfected controls. Results Levels of ICAM-1, VEGF-A, and VEGFR2 were significantly increased in children with microscopic asymptomatic parasitemia compared with uninfected controls. Also, levels of VEGF-A were found to be inversely associated with age. Additionally, a receiver operating characteristic analysis revealed that plasma levels of ICAM-1 (area under the curve [AUC], 0.72) showed a moderate potential in discriminating between children with microscopic malaria from uninfected controls when compared with VEGF-A (AUC, 0.67) and VEGFR2 (AUC, 0.69). Conclusions These data imply that endothelial activation and pro-angiogenic growth factors could be one of the early host responders during microscopic asymptomatic malaria and may play a significant role in disease pathogenesis.

The quest for a licensed effective vaccine against malaria remains a global priority. Even though classical vaccine design strategies have been successful for some viral and bacterial pathogens, little success has been achieved for Plasmodium falciparum, which causes the deadliest form of malaria due to its diversity and ability to evade host immune responses. Nevertheless, recent advances in vaccinology through high throughput discovery of immune correlates of protection, lymphocyte repertoire sequencing and structural design of immunogens, provide a comprehensive approach to identifying and designing a highly efficacious vaccine for malaria. In this review, we discuss novel vaccine approaches that can be employed in malaria vaccine design.

Background Asymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication. Increasing levels of regulatory T cells (Tregs) in Plasmodium falciparum infections have been associated with the risk of developing clinical disease, suggesting that individuals with asymptomatic infections may have reduced Treg frequency. However, the relationship between Tregs, cellular activation and parasite control in asymptomatic malaria remains unclear. Methods In a cross-sectional study, the levels of Tregs and other T cell activation phenotypes were compared using flow cytometry in symptomatic, asymptomatic and uninfected children before and after stimulation with infected red blood cell lysates (iRBCs). In addition, the association between these T cell phenotypes and parasitaemia were investigated. Results In children with asymptomatic infections, levels of Tregs and activated T cells were comparable to those in healthy controls but significantly lower than those in symptomatic children. After iRBC stimulation, levels of Tregs remained lower for asymptomatic versus symptomatic children. In contrast, levels of activated T cells were higher for asymptomatic children. Strikingly, the pre-stimulation levels of two T cell activation phenotypes (CD8+CD69+ and CD8+CD25+CD69+) and the post-stimulation levels of two regulatory phenotypes (CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+) were significantly positively correlated with and explained 68% of the individual variation in parasitaemia. A machine-learning model based on levels of these four phenotypes accurately distinguished between asymptomatic and symptomatic children (sensitivity = 86%, specificity = 94%), suggesting that these phenotypes govern the observed variation in disease status. Conclusion Compared to symptomatic P. falciparum infections, in children asymptomatic infections are characterized by lower levels of Tregs and activated T cells, which are associated with lower parasitaemia. The results indicate that T cell regulatory and activation phenotypes govern both parasitaemia and disease status in paediatric malaria in the studied sub-Saharan African population. Electronic supplementary material The online version of this article (10.1186/s12936-018-2410-6) contains supplementary material, which is available to authorized users.