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A key focus of MORU is building scientific research capacity in Thailand and SE and South Asia. One way we do this is by hosting students in a world-class research environment. In this video, you’ll hear from some of our current students about why living and studying in SE Asia and at MORU is such a great experience.
Kinetics of naturally induced binding and neutralising anti-SARS-CoV-2 antibody levels and potencies among SARS-CoV-2 infected Kenyans with diverse grades of COVID-19 severity: an observational study
Background Given the low levels of coronavirus disease 2019 (COVID-19) vaccine coverage in sub-Saharan Africa (sSA), despite high levels of natural severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) exposures, strategies for extending the breadth and longevity of naturally acquired immunity are warranted. Designing such strategies will require a good understanding of naturally acquired immunity. Methods We measured whole-spike immunoglobulin G (IgG) and spike-receptor binding domain (RBD) total immunoglobulins (Igs) on 585 plasma samples collected longitudinally over five successive time points within six months of COVID-19 diagnosis in 309 COVID-19 patients. We measured antibody-neutralising potency against the wild-type (Wuhan) SARS-CoV-2 pseudovirus in a subset of 51 patients over three successive time points. Binding and neutralising antibody levels and potencies were then tested for correlations with COVID-19 severities. Results Rates of seroconversion increased from day 0 (day of PCR testing) to day 180 (six months) (63.6% to 100 %) and (69.3 % to 97%) for anti-spike-IgG and anti-spike-RBD binding Igs, respectively. Levels of these binding antibodies peaked at day 28 (p<0.01) and were subsequently maintained for six months without significant decay (p>0.99). Similarly, antibody-neutralising potencies peaked at day 28 (p<0.01) but declined by three-fold, six months after COVID-19 diagnosis (p<0.01). Binding antibody levels were highly correlated with neutralising antibody potencies at all the time points analysed (r>0.60, p<0.01). Levels and potencies of binding and neutralising antibodies increased with disease severity. Conclusions Most COVID-19 patients generated SARS-CoV-2 specific binding antibodies that remained stable in the first six months of infection. However, the respective neutralising antibodies decayed three-fold by month-six of COVID-19 diagnosis suggesting that they are short-lived, consistent with what has been observed elsewhere in the world. Thus, regular vaccination boosters are required to sustain the high levels of anti-SARS-CoV-2 naturally acquired neutralising antibody potencies in our population.
Maintenance of high temporal Plasmodium falciparum genetic diversity and complexity of infection in asymptomatic and symptomatic infections in Kilifi, Kenya from 2007 to 2018
Abstract Background High levels of genetic diversity are common characteristics of Plasmodium falciparum parasite populations in high malaria transmission regions. There has been a decline in malaria transmission intensity over 12 years of surveillance in the community in Kilifi, Kenya. This study sought to investigate whether there was a corresponding reduction in P. falciparum genetic diversity, using msp2 as a genetic marker. Methods Blood samples were obtained from children (< 15 years) enrolled into a cohort with active weekly surveillance between 2007 and 2018 in Kilifi, Kenya. Asymptomatic infections were defined during the annual cross-sectional blood survey and the first-febrile malaria episode was detected during the weekly follow-up. Parasite DNA was extracted and successfully genotyped using allele-specific nested polymerase chain reactions for msp2 and capillary electrophoresis fragment analysis. Results Based on cross-sectional surveys conducted in 2007–2018, there was a significant reduction in malaria prevalence (16.2–5.5%: P-value < 0.001), however msp2 genetic diversity remained high. A high heterozygosity index (He) (> 0.95) was observed in both asymptomatic infections and febrile malaria over time. About 281 (68.5%) asymptomatic infections were polyclonal (> 2 variants per infection) compared to 46 (56%) polyclonal first-febrile infections. There was significant difference in complexity of infection (COI) between asymptomatic 2.3 [95% confidence interval (CI) 2.2–2.5] and febrile infections 2.0 (95% CI 1.7–2.3) (P = 0.016). Majority of asymptomatic infections (44.2%) carried mixed alleles (i.e., both FC27 and IC/3D7), while FC27 alleles were more frequent (53.3%) among the first-febrile infections. Conclusions Plasmodium falciparum infections in Kilifi are still highly diverse and polyclonal, despite the reduction in malaria transmission in the community.
The mRNA content of plasma extracellular vesicles provides a window into molecular processes in the brain during cerebral malaria
The impact of cerebral malaria on the transcriptional profiles of cerebral tissues is difficult to study using noninvasive approaches. We isolated plasma extracellular vesicles (EVs) from patients with cerebral malaria and community controls and sequenced their mRNA content. Deconvolution analysis revealed that EVs from cerebral malaria are enriched in transcripts of brain origin. We ordered the patients with cerebral malaria based on their EV-transcriptional profiles from cross-sectionally collected samples and inferred disease trajectory while using healthy community controls as a starting point. We found that neuronal transcripts in plasma EVs decreased with disease trajectory, whereas transcripts from glial, endothelial, and immune cells increased. Disease trajectory correlated positively with severity indicators like death and was associated with increased VEGFA-VEGFR and glutamatergic signaling, as well as platelet and neutrophil activation. These data suggest that brain tissue responses in cerebral malaria can be studied noninvasively using EVs circulating in peripheral blood.
Breadth of Antibodies to Plasmodium falciparum Variant Surface Antigens Is Associated With Immunity in a Controlled Human Malaria Infection Study
BackgroundPlasmodium falciparum variant surface antigens (VSAs) contribute to malaria pathogenesis by mediating cytoadhesion of infected red blood cells to the microvasculature endothelium. In this study, we investigated the association between anti-VSA antibodies and clinical outcome in a controlled human malaria infection (CHMI) study.MethodWe used flow cytometry and ELISA to measure levels of IgG antibodies to VSAs of five heterologous and one homologous P. falciparum parasite isolates, and to two PfEMP1 DBLβ domains in blood samples collected a day before the challenge and 14 days after infection. We also measured the ability of an individual’s plasma to inhibit the interaction between PfEMP1 and ICAM1 using competition ELISA. We then assessed the association between the antibody levels, function, and CHMI defined clinical outcome during a 21-day follow-up period post infection using Cox proportional hazards regression.ResultsAntibody levels to the individual isolate VSAs, or to two ICAM1-binding DBLβ domains of PfEMP1, were not associated with a significantly reduced risk of developing parasitemia or of meeting treatment criteria after the challenge after adjusting for exposure. However, anti-VSA antibody breadth (i.e., cumulative response to all the isolates) was a significant predictor of reduced risk of requiring treatment [HR 0.23 (0.10-0.50) p= 0.0002].ConclusionThe breadth of IgG antibodies to VSAs, but not to individual isolate VSAs, is associated with protection in CHMI.
Proteomic analysis of extracellular vesicles from a Plasmodium falciparum Kenyan clinical isolate defines a core parasite secretome
Background: Many pathogens secrete effector molecules to subvert host immune responses, to acquire nutrients, and/or to prepare host cells for invasion. One of the ways that effector molecules are secreted is through extracellular vesicles (EVs) such as exosomes. Recently, the malaria parasite P. falciparum has been shown to produce EVs that can mediate transfer of genetic material between parasites and induce sexual commitment. Characterizing the content of these vesicles may improve our understanding of P. falciparum pathogenesis and virulence. Methods: Previous studies of P. falciparum EVs have been limited to long-term adapted laboratory isolates. In this study, we isolated EVs from a Kenyan P. falciparum clinical isolate adapted to in vitro culture for a short period and characterized their protein content by mass spectrometry (data are available via ProteomeXchange, with identifier PXD006925). Results: We show that P. falciparum extracellular vesicles (PfEVs) are enriched in proteins found within the exomembrane compartments of infected erythrocytes such as Maurer’s clefts (MCs), as well as the secretory endomembrane compartments in the apical end of the merozoites, suggesting that these proteins play a role in parasite-host interactions. Comparison of this novel clinically relevant dataset with previously published datasets helps to define a core secretome present in Plasmodium EVs. Conclusions: P. falciparum extracellular vesicles contain virulence-associated parasite proteins. Therefore, analysis of PfEVs contents from a range of clinical isolates, and their functional validation may improve our understanding of the virulence mechanisms of the parasite, and potentially identify targets for interventions or diagnostics.
Controlled human malaria infection (CHMI) outcomes in Kenyan adults is associated with prior history of malaria exposure and anti-schizont antibody response
Abstract Background Individuals living in endemic areas acquire immunity to malaria following repeated parasite exposure. We sought to assess the controlled human malaria infection (CHMI) model as a means of studying naturally acquired immunity in Kenyan adults with varying malaria exposure. Methods We analysed data from 142 Kenyan adults from three locations representing distinct areas of malaria endemicity (Ahero, Kilifi North and Kilifi South) enrolled in a CHMI study with Plasmodium falciparum sporozoites NF54 strain (Sanaria® PfSPZ Challenge). To identify the in vivo outcomes that most closely reflected naturally acquired immunity, parameters based on qPCR measurements were compared with anti-schizont antibody levels and residence as proxy markers of naturally acquired immunity. Results Time to endpoint correlated more closely with anti-schizont antibodies and location of residence than other parasite parameters such as growth rate or mean parasite density. Compared to observational field-based studies in children where 0.8% of the variability in malaria outcome was observed to be explained by anti-schizont antibodies, in the CHMI model the dichotomized anti-schizont antibodies explained 17% of the variability. Conclusions The CHMI model is highly effective in studying markers of naturally acquired immunity to malaria. Trial registration Clinicaltrials.gov number NCT02739763. Registered 15 April 2016
Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity
Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.
Understanding the benefits and burdens associated with a malaria human infection study in Kenya: experiences of study volunteers and other stakeholders
Abstract 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.
Phagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria
AbstractRing-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/μl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and −140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria.
Efficacy of artemisinin-based combination therapy (ACT) in people living with HIV (PLHIV) diagnosed with uncomplicated Plasmodium falciparum malaria in Africa: a WWARN systematic review.
BackgroundAfrica bears the highest double burden of HIV and malaria worldwide. In 2023, an estimated 25.9 million people were living with HIV (PLHIV), and 246 million malaria cases were diagnosed in Africa. Malaria patients co-infected with HIV are considered at a higher risk of failing malaria treatment, according to the World Health Organization (WHO) guidelines. This systematic literature review aims to assess the treatment outcomes following artemisinin-based combination therapy (ACT) in PLHIV.MethodsThe literature search was conducted up to April 2022 in the following databases: MEDLINE, EMBASE, Web of Science, Cochrane Central, WHO Global Index Medicus, Clinicaltrials.gov, and the WorldWide Antimalarial Resistance Network (WWARN) Clinical Trial Library. Studies describing any malaria treatment outcomes or anti-malarial drug exposure in PLHIV treated for uncomplicated Plasmodium falciparum malaria infection were eligible for inclusion.ResultsA total of 26 articles describing 19 studies conducted between 2003 and 2017 in six countries were included in this review; it represented 2850 malaria episodes in PLHIV across various transmission settings. The most studied artemisinin-based combination was artemether-lumefantrine (in 16 studies). PLHIV were treated with various antiretroviral therapy (ART) regimens, namely efavirenz (EFV), nevirapine (NVP), atazanavir-ritonavir (ATVr), lopinavir-ritonavir (LPV/r), and/or on prophylaxis with trimethoprim-sulfamethoxazole (TS), or were untreated (in 3 studies). There was no evidence of an increased risk of recrudescence in PLHIV compared to those without HIV. When treated with artemether-lumefantrine, PLHIV receiving LPV/r had a lower risk of malaria recurrence compared to PLHIV on NVP-based or EFV-based ART, or those without HIV. LPV/r increased lumefantrine exposure and EFV-treated patients had a reduced exposure to both artemether and lumefantrine; NVP reduced artemether exposure only.ConclusionsLimited data on ACT outcomes or drug exposure in PLHIV in Africa remains a reality to date, and the effect of antivirals appears inconsistent in the literature. Considering the heterogeneity in study designs, these review's findings support conducting an individual patient data meta-analysis to explore the impact of antiretroviral therapy on anti-malarial treatment.Trial registrationThe protocol for the original search was published on PROSPERO with registration number CRD42018089860.
A pragmatic randomized controlled trial of standard care versus corticosteroids plus standard care for treatment of pneumonia in adults admitted to Kenyan hospitals (SONIA)
Background Mortality among adults admitted to hospital with community acquired pneumonia in resource-limited settings is high. Recent studies conducted in high-income settings have demonstrated beneficial effects of low-dose corticosteroids in reducing mortality in patients with severe community acquired pneumonia. It is unknown whether these findings apply to low-income settings such as sub-Saharan Africa. This pragmatic randomized-controlled open-label trial will determine the effect of adjunctive low-dose corticosteroids in the management of adults admitted to hospital with community acquired pneumonia on mortality 30-days post-randomization. Methods We will enroll and randomize 2180 patients admitted with a diagnosis of community acquired pneumonia into two arms: the control and intervention arm. Those in the control arm will receive standard care for the treatment of community acquired pneumonia i.e., combination therapy with a beta-lactam and macrolide antibiotic. Those in the intervention arm will receive up to 10-days treatment with low-dose oral corticosteroids in addition to standard care. All participants will be followed up to 30- days post randomization and their final status recorded (alive or dead). Discussion If adjunctive low-dose oral corticosteroids are found to be beneficial, this easily scalable intervention would significantly reduce the currently high mortality associated with community acquired pneumonia. Pan-African Clinical Trials Registry: PACTR202111481740832; ISRCTRN registry: ISRCTN36138594
Knowledge and practice of healthy behaviors for dementia and stroke prevention in a United States cohort
Abstract At least 45% of dementia and 60% of stroke cases are due to modifiable risk factors and could in part be prevented through healthy behavior. This cross-sectional study clustered and characterized a U.S. cohort’s knowledge and practice of healthy behavior associated with dementia and stroke. A total of 1,478 participants (mean age: 45.5 years, 51.8% female) were included. A hierarchical cluster analysis was performed to identify clusters based on the level of knowledge and practice of healthy behavior. We defined knowledge as recognizing eight modifiable risk factors (alcohol, diet, smoking, physical activity, sleep, stress, social relationships, and purpose in life) as important. We defined practice as complying with validated recommendations for each healthy behavior. Three clusters emerged: (I) high knowledge and poor practice (II) high knowledge and good practice, and (III) lower knowledge and poor practice. Participants in the high knowledge and good practice cluster were statistically significantly older, more educated, perceived fewer barriers (financial and time limitations), and more facilitators (motivation or knowing someone with dementia or stroke) compared to the other clusters. Our findings could assist in tailoring preventative strategies to enhance knowledge, translating knowledge into practice, and addressing particular facilitators and barriers per identified cluster.