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.

BackgroundAbout 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients.MethodsWe searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square.ResultsSix qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total, seven different interventions (Chloroquine, Mefloquine, Mefloquine artesunate, Proguanil, Pyrimethamine, Sulfadoxine-pyrimethamine, Sulfadoxine-pyrimethamine amodiaquine) were evaluated in 912 children with SCD. Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR = 0.72, 95% CI = 0.267–1.959; I2 = 0.0%), blood transfusion (OR = 0.83, 95% CI = 0.542–1.280; I2 = 29.733%), vaso-occlusive crisis (OR = 19, 95% CI = 1.713–2.792; I2 = 93.637%), and mortality (OR = 0.511, 95% CI = 0.189–1.384; I2 = 0.0%) did not differ between the intervention and placebo groups.ConclusionThe data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients.Systematic review registrationPROSPERO (CRD42016052514).Electronic supplementary materialThe online version of this article (10.1186/s12879-018-3556-0) contains supplementary material, which is available to authorized users.

BackgroundAsymptomatic 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.MethodsIn 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.ResultsIn 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.ConclusionCompared 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 materialThe online version of this article (10.1186/s12936-018-2410-6) contains supplementary material, which is available to authorized users.

Background Pro- and anti-inflammatory cytokines are important mediators of immunity and are associated with malaria disease outcomes. However, their role in the establishment of asymptomatic infections, which may precede the development of clinical symptoms, is not as well-understood. Methods We determined the association of pro and anti-inflammatory cytokines and other immune effector molecules with the development of asymptomatic malaria. We measured and compared the plasma levels of pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin (IL)-6, IL-12p70, IL-17A, and granzyme B, the anti-inflammatory cytokine IL-4 and the regulatory cytokine IL-10 from children with asymptomatic malaria infections (either microscopic or submicroscopic) and uninfected controls using Luminex. Results We show that individuals with microscopic asymptomatic malaria had significantly increased levels of TNF-α and IL-6 compared to uninfected controls. Children with either microscopic or submicroscopic asymptomatic malaria exhibited higher levels of IFN-γ, IL-17A, and IL-4 compared to uninfected controls. The levels of most of the pro and anti-inflammatory cytokines were comparable between children with microscopic and submicroscopic infections. The ratio of IFN-γ/IL-10, TNF-α/IL-10, IL-6/IL-10 as well as IFN-γ/IL-4 and IL-6/IL-4 did not differ significantly between the groups. Additionally, using a principal component analysis, the cytokines measured could not distinguish amongst the three study populations. This may imply that neither microscopic nor submicroscopic asymptomatic infections were polarized toward a pro-inflammatory or anti-inflammatory response. Conclusion The data show that asymptomatic malaria infections result in increased plasma levels of both pro and anti-inflammatory cytokines relative to uninfected persons. The balance between pro- and anti-inflammatory cytokines are, however, largely maintained and this may in part, explain the lack of clinical symptoms. This is consistent with the generally accepted observation that clinical symptoms develop as a result of immunopathology involving dysregulation of inflammatory mediator balance in favor of pro-inflammatory mediators.

T cells play significant roles during Plasmodium falciparum infections. Their regulation of the immune response in symptomatic children with malaria has been deemed necessary to prevent immune associated pathology. In this study, we phenotypically characterized the expression of T cell inhibitory(PD-1, CTLA-4) and senescent markers (CD28(-), CD57) from children with symptomatic malaria, asymptomatic malaria and healthy controls using flow cytometry. We observed increased expression of T cell exhaustion and senescence markers in the symptomatic children compared to the asymptomatic and healthy controls. T cell senescence markers were more highly expressed on CD8 T cells than on CD4 T cells. Asymptomatically infected children had comparable levels of these markers with healthy controls except for CD8+ PD-1+ T cells which were significantly elevated in the asymptomatic children. Also, using multivariate regression analysis, CTLA-4 was the only marker that could predict parasitaemia level. The results suggest that the upregulation of immune exhaustion and senescence markers during symptomatic malaria may affect the effector function of T cells leading to inefficient clearance of parasites, hence the inability to develop sterile immunity to malaria.

Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled “cytokine storm” manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in terms of number of cases and deaths in Africa and also Asia in comparison to Europe and North America. Also, persons of colour residing in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare. Interestingly, this has not been the case in sub-Saharan Africa where majority of the population are even more deprived of the aforementioned factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. Whilst it can be argued that these lower number of cases in Africa may be due to challenges associated with the diagnosis of the disease such as lack of trained personnel and infrastructure, the number of persons who get infected and develop symptoms is proportionally lower than those who are asymptomatic, including asymptomatic cases that are never diagnosed. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.

Sepsis defined as a dysregulated immune response is a major cause of morbidity in children. In sub-Saharan Africa, the clinical features of sepsis overlap with other frequent infections such as malaria, thus sepsis is usually misdiagnosed in the absence of confirmatory tests. Therefore, it becomes necessary to identify biomarkers that can be used to distinguish sepsis from other infectious diseases. We measured and compared the plasma levels of 18 cytokines (Th1 [GM-CSF, IFN-γ, TNF-α, IL-1β, 1L-2, IL-6, IL-8, IL-12/IL-23p40, IL-15], Th2[IL-4, IL-5, IL-13), Th17 [IL17A], Regulatory cytokine (IL-10) and 7 chemokines (MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, Eotaxin/CCL11, MIG/CXCL9 and IP-10/CXCL10 using the Human Cytokine Magnetic 25-Plex Panel in plasma samples obtained from children with sepsis, clinical malaria and other febrile conditions. Children with sepsis had significantly higher levels of IL-1β, IL-12 and IL-17A compared to febrile controls but lower levels of MIP1-β/CCL4, RANTES/CCL5 and IP10/CXCL10 when compared to children with malaria and febrile controls. Even though levels of most inflammatory responses were higher in malaria compared to sepsis, children with sepsis had a higher pro-inflammatory to anti-inflammatory ratio which seemed to be mediated by mostly monocytes. A principal component analysis and a receiver operator characteristic curve analysis, identified seven potential biomarkers; IL-1β, IL-7, IL-12, IL-1RA, RANTES/CCL5, MIP1β/CCL4 and IP10/CXCL10 that could discriminate children with sepsis from clinical malaria and other febrile conditions. The data suggests that sepsis is associated with a higher pro-inflammatory environment. These pro-inflammatory cytokines/chemokines could further be evaluated for their diagnostic potential to differentiate sepsis from malaria and other febrile conditions in areas burdened with infectious diseases.

Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled “cytokine storm” manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in terms of number of cases and deaths in Africa and also Asia in comparison to Europe and North America. Also, persons of colour residing in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare. Interestingly, this has not been the case in sub-Saharan Africa where majority of the population are even more deprived of the aforementioned factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. Whilst it can be argued that these lower number of cases in Africa may be due to challenges associated with the diagnosis of the disease such as lack of trained personnel and infrastructure, the number of persons who get infected and develop symptoms is proportionally lower than those who are asymptomatic, including asymptomatic cases that are never diagnosed. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.