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- ItemRestrictedAssessing the effectiveness of extending Malaria Community Case Management (MCCM) to all ages in Malawi: a mixed methods study(Kamuzu University of Health Sciences, 2021-11-19) Phiri S, Kamija5.1 Background and rationale The burden of malaria is high in Malawi, where access to care remains a challenge. Integrated community case management (iCCM) has been shown to be effective in reducing morbidity and mortality among children less than five years of age for pneumonia, diarrhea, and malaria. Some countries, including Malawi, have expressed an interest in extending malaria community case management (mCCM). Rigorous studies to scale up mCCM for all ages are necessary prior to introducing and scaling up this strategy in high-transmission settings.5.2 Objectives 5.2.1 Broad Objective To analyse the effectiveness of extending community case management of malaria to all age groups over a 12-month period in the districts of Neno, Ntchisi and Salima, MalawiSpecific Objectives1.2.To assess analyze the effectiveness of extending mCCM to all ages on the proportion of children aged 2 months to <5 years, 5 to <15 years, and those aged 15+ years with febrile illness in the previous 2 weeks who: 1) sought care for that illness; 2) sought care within 24 hours; 3) were tested for malaria; and 4) were treated with an appropriate antimalarial if they tested positive for malaria 3.To describe the effectiveness of extending mCCM to all ages on the prevalence of malaria parasitaemia among children aged 2 months to <5 years, and among children 5 to <15 years 4.To evaluate the effectiveness of extending mCCM to all ages on the proportion of illchildren aged 2 months to <5 years seeking care for pneumonia and diarrhea. 5.To assess the acceptability, feasibility, perceptions and experiences of extending mCCM to all ages, according to community members, HSAs, and health facility in charges. 6.To estimate the implementation costs of extending mCCM to all ages from provider perspective. 7.To describe the incremental cost-effectiveness of extending mCCM to all ages for 12 months compared with standard CCM from societal perspective (provider and household). 5.3 Study Design Cluster-randomized trial with two arms (intervention and control) taking place in the catchment areas of a minimum of 24 health facilities (12 per arm) over a period of 12 months. ● Control arm: Case management of malaria by health facilities and HSAs in line with current national recommendations (iCCM for children <5 years) ● Intervention arm: Case management of malaria by health facilities and HSAs in line with current national recommendations (iCCM for children <5 years), with an extension of community case management of malaria to all ages To achieve the objectives of the study, three types of data collection will take place: 1. Cross-sectional household surveys, pre- and post-intervention (0 and 12 months, respectively) 2. Qualitative in-depth interviews and focus groups 3. Data abstraction of routine service use from HSAs and health facilities and periodic costs from project documents and reports 5.3.1 Study Interventions Screening with malaria rapid diagnostic test and treatment of malaria positive cases with firstfist line antimalarial therapy Artemether-Lumefantrine (AL). 5.3.2 Primary outcome The primary outcome is the proportion of individuals two months of age or older, reporting a fever in the previous 2 weeks who were tested with a malaria RDT by an HSA or at a health facility by a health worker. This outcome will be measured by cross-sectional household surveys. 5.3.3 Sample size 1. Enrollment in each cross-sectional household survey will be offered to 66 households in each health facility cluster (2 EAs per health facility with 33 households each EA), giving a total of 794 per arm (12 health facilities), or 1,588 households in total (24 health facilities). 2. The qualitative component will include in-depth interviews with 30-40 individuals in the intervention and control arms (HSAs + beneficiaries/care-seekers/community members + Facility in-charges) and 6 focus group discussions with care-seekers, HSA in the intervention and control arms. 3. Routine data abstraction will include the 24 study facilities and all HSAs in their catchment areas. 4. The cost data abstraction will include 2 district coordinators visited quarterly from the three study districts. 5.3.4 Data Analysis 1. Household Survey Data: A mixed effects logistic regression model will be fitted to the data to estimate the difference in odds of the outcome between the intervention and the control. Odds ratios and corresponding 95% confidence intervals will be reported. Tests of significance will be performed at a level of 𝛂 = 0.05 with corrections for multiple comparisons when needed. 2. Qualitative data: Translation from Chichewa to English will occur during transcription into Word and will be kept secure until the analysis is complete. Translation and transcription will be verified by the research assistant and the scientific lead (social science) for quality assurance. Data will be coded and entered into NVivo 12 for the extraction themes will be identified using a content analysis approach. The analysis will be carried out according to the thematic analysis method, which consists of dividing the text into basic units for assessment. Each interview and focus group participant will be assigned a code or participant ID number, which will be used in presenting quotes. 3. Cost-effectiveness data: Cost and cost-effectiveness analyses will be undertaken to assess the financial and economic impacts of mCCM for all ages compared to the standard iCCM strategy (without extension of malaria treatment). The budget impact analysis will help determine if the expanded strategy is feasible given existing amounts in the national budget for malaria. 5.4 Expected findings and dissemination of results 5.4.1 Expected findings We hypothesize that the expansion of mCCM to all ages will lead to an increase in a) care seeking by patients with fever, b) the proportion of subjects with fever who received a malaria RDT, and c) the proportion of cases of malaria confirmed by RDT who received adequate antimalarial treatment. More specifically, we hypothesize that the proportion of individuals with recent fever for whom a malaria RDT was performed (main indicator) at the beginning of the study will be 40% in both arms, and will increase to 62% in the intervention arm by the end of the study. We assume that this proportion will remain constant at 40% in the control arm (see sample size section). 5.4.2 Dissemination of results A mid-term report will be submitted to the MoH NMCP and other study partners (WHO, PMI, USAID) in 2022. The report will include results of the baseline survey, and details on challenges and successes during study implementation. The mid-term report will also highlight key elements for planning the extension of mCCM to all ages for the country.
- ItemRestrictedAssessing the effectiveness of the anti-drug theft interventions on the availability of Malaria drugs at Ntcheu District Hospital(Kamuzu University of Health Sciences, 2021-03-21) Kachala Nkhoma, PriscillaType of study: This will be a longitudinal and cross sectional type of study where both quantitative and qualitative methods will be used. It will be longitudinal because observations will be made for a specific period of time, that is, one year before and after the drug audit was conducted. We will conduct structured in-depth interviews of health care workers eligible for the study and community members. Problem statement: Drug theft has been a concern especially in public health facilities in Malawi. Essential drugs such as malaria have been stolen by the health workers and other members of the community. Several measures or interventions have been put in place starting from the MoHP and every health facility has their own in order to reduce or eliminate drug theft. The anti-drug theft interventions range from expensive to cheaper ones. Since the implementation of these interventions in the health facilities as well as the DTIU intervention from 2016, at Ntcheu District Hospital, seven people were convicted of drug theft and these included health workers and some chiefs [1]. Although antidrug theft interventions are implemented and some individuals have been convicted, drug theft still occurs in the health facilities despite the implementation of anti-drug theft interventions. Assessment on these interventions to determine their effectiveness have not been carried out hence the need to conduct this study. This study will also assess the availability of malaria drugs since the implementation of these interventions at the hospital. Study objectives: The purpose of study is to assess the effectiveness of anti-drug theft interventions on the availability of medicines and medical supplies at Ntcheu District Hospital. The specific objectives are: To determine the availability of anti-malarial drugs before and after the anti-drug theft interventions at the hospital. To explore factors that influence theft of malaria drugs at the hospital To explore the impact of malaria drug theft to the health workers and the community surrounding the hospital. Methodology This study will employ mixed method where quantitative and qualitative methods will be used. Quantitative method will be used to determine the availability of anti-malarial drugs before and after the DTIU drug audit and the implementation of the anti-drug theft interventions. Quantitative data will come from the Logistical Management Information System (LMIS), District Health Information System (DHIS2), and audit reports from the DTIU in the Ministry of Health and Population (MoHP). The qualitative method will be used to explore factors that influence drug theft and anything to be done to improve availability of malaria drugs as well as the impact of malaria drug theft at the hospital as well in the community. The participants will be 20 in total, 12 Health Care Workers (HCW) and 8 community members from the catchment area of the hospital. Data will be collected by conducting In-Depth interviews and will be securely stored in a computer and a password will be used. Thematic content analysis for the interviews and time analysis for the quantitative data will be used. Quantitative data will be entered in Excel and analysed using STATA and will be presented in graphs. Consent form will be sought verbally from the study participants and ethical approval from the College of Medicine Research and Ethics Committee (COMREC). Expected Findings and Dissemination of Results In this study, we expect to determine the effectiveness of the anti-drug theft interventions in the availability of malaria drugs. Bound copies of the dissertation will be submitted for examination to College of Medicine, the Health Systems and Policy Department, School of Public Health and Family Medicine. Furthermore, the findings will be disseminated in writing as a report to the DHMT for Ntcheu District Hospital as well as the DTIU. Manuscripts of the results will be submitted to peer reviewed journals for publication. The final dissertation document will be submitted to: College of Medicine’s Office of the Dean of Postgraduate Studies and Research, College of Medicine Library, and the College of Medicine Research and Ethics Committee (COMREC).
- ItemRestrictedAn assessment of gender and intersectionality in disease exposure, care seeking behaviour and treatment pathways in malaria prevention and control in Kenya and Malawi: a case of Migori county and Chikwawa district(2022-04-13) Kumwenda, MosesType of study This project will adopt a longitudinal study design with embedded mixed methods to allow for translational research and long-term in-depth exploration. This study design will be a multidisciplinary integration among basic, clinical, practice, population, and policy-based research enabled by a multidisciplinary team of clinical and social scientists. Problem The burden of malaria persists despite the ongoing prevention and control interventions over the last two decades with the different malaria endemic and epidemic zones being strategically targeted with a view to eradicate this infectious disease. In Kenya and Malawi, malaria remains a major cause of morbidity and mortality with more than 70 percent of the population at risk of the disease. Kenya has four main malaria epidemiological zones with diversity in risk and intervention determined largely by altitude, rainfall patterns, and temperature, as well as the prevalence of malaria. Further, access to and uptake of health services for prevention and treatment knowledge of malaria and health outcomes experienced throughout the life course are influenced by the foregoing life stratifiers often overlooked in intervention programmes and policies. Objectives Main objective The aim of the study is to assess the gender and intersectionality of exposure to mosquito bites, care seeking and treatment pathways for Malaria in Migori County, Kenya when compared to Chikwawa district in southern Malawi Specific objectives 1. To assess the intersection between the risk of exposure to mosquito bites with gender and other social determinants (sex, age, occupation, level of education/class, place of residence (urban/rural), and religion) of Malaria. 2. To describe how gender power relations, the prevailing gendered social inequalities, and the culturally dominant constructions of masculinity and femininity intersect with each other in shaping people’s understanding of ill-health and influence Malaria health seeking behaviours. 3. To audit Malaria programme delivery and Malaria control interventions including research and access to Malaria and disease management services using the intersectional gender lens. 4. To identify the gender dimensions in Malaria programme delivery and control interventions in the emerging COVID-19 pandemic context. 13-The study will be conducted in Migori County, Kenya and Chikwawa district in Malawi to target health facilities and community members to explore gender and intersectionality of malaria etiology, health and health seeking and treatment pathways and inform the specific study objectives. The research will employ participatory , qualitative and quantitative methods to explore gender and intersectionality of malaria etiology, health seeking and treatment pathways. This study will be carried out in two phases: Phase one - the formative phase and will entail mainly the document reviews and piloting of the study tools and; Phase Two - mixed methods studies, the longitudinal comparative approach will include quantitative and qualitative studies to assess malaria etiology, health and health seeking and treatment pathways through a gender and intersectionality lens. Expected findings and dissemination The research protocol will be published after all ethical approvals have been received. Findings from the study will be presented through community engagement mechanisms such as community engagement meetings and science cafe’s. Advocacy work through various mechanisms at county and national level based on the findings of the study will be conducted. Results will be shared with the wider scientific community through presentations at national and international conferences, and through open-access peer-reviewed journal publications. In addition, we can submit the report of our findings to COMRE and national open data platform.
- ItemRestrictedComparison of malaria parasites clearance times during quinine and artesunate administration for cerebral malaria in Blantyre Malawi(Kamuzu University of Health Sciences, 2021-03-04) Saidi, Alexuse MustaphType of study: This study involves analyzing previously collected data and samples from cerebral malaria children admitted under Malaria Pathogenesis (MP) study, therefore; it will be a retrospective cross-sectional study type. The problem: A major current concern is the emergence of malaria resistance to a number of antimalarial drugs including artemisinin derivatives. Possible global antimalarial drug resistance emergence is threatening the worldwide goal of reducing the heavy burden of malaria. The global Technical Strategy for malaria 2016-2030 asks countries in endemic regions and all malaria partners to continuously monitor the effectiveness of anti-malaria drugs in order to contain and prevent the spread of resistance to other parts of the world. Our goal is to determine if increased usage of quinine or artesunate has led to increased drug resistance-which would in turn effect malaria parasite clearance times in children with cerebral malaria. Study Objective: To compare malaria parasites clearance times during quinine and artesunate administration periods in cerebral malaria children. Specific Objectives i. To monitor quinine and artesunate’s effectiveness in treating Plasmodium falciparum over a period of 3 and 5 years respectively. ii. To relate parasite clearance to parasitic load (as measured by HRP2). iii. To estimate parasite resistance development to quinine and artesunate. iv. To determine proportion of patients who were still parasitaemic after a standard treatment course of quinine or artesunate. Methodology: We will obtain blood film and Histidine Rich Protein-2 (HRP-2) concentration data and samples collected from cerebral malaria children admitted between the years 2010 to 2019. Each child’s blood film results will be arranged in sequential order of sampling points (every 6 hours). The investigator will be pulling blood film slides and plasma from the archive and quantify the parasitaemia and HRP-2 concentrations respectively for any missing sampling point results. Data collected will be analyzed using Parasite Clearance Estimator (PCE) beta 0.9. Expected Findings: We expect to see a significant difference in the parasite clearance time within each drug and in between the two antimalarial drugs, quinine and Artesunate. Results dissemination: Findings of this project are expected to be presented to COMREC, Malaria Study management team and to the general public through different research dissemination conferences and in journal clubs.
- ItemRestrictedDeveloping a digital platform for sub-district level malaria burden stratification mapping using routine health facility case data – guiding the national transition to targeted malaria control, version 1.0(Kamuzu University of Health Sciences, 2022-07-26) Stanton, Michelle; Chirombo, JamesStudy type: Secondary data analysis Research problem: With the continued reduction of malaria prevalence at the national level after many years of intensive malaria interventions, community-level transmission becomes more important. Focusing on the trends in malaria transmission at the national level may mask the heterogeneities that exist at the sub-district level. Therefore, it is important to understand the disease dynamics at the community level to inform strategies that can eventually lead to the elimination of the disease. Main objective: The main objective is to use routinely reported health facility-level malaria case data to produce sub-district level estimates of clinical malaria incidence in Malawi and stratify the country by different levels of incidence for more targeted malaria intervention. Specific objectives: • Develop standardised procedures for data collation and data management of routinely reported data • Undertake a spatial analysis to stratify the country into the predefined risk categories at regular intervals, using available data on current intervention coverage, climate/environment, and evidence of insecticide resistance. • Develop a digital dashboard which can be accessed by the National Malaria Control Programme (NMCP) and district programme coordinators to display interactive maps, summaries of the resulting analysis and generate automated reports • Train staff at the NMCP and the Central Monitoring and Evaluation Division (CMED) to update the data and maintenance analyses on a regular basis with the support of the Ministry of Health’s Digital Heath Division (DHD). • Support relevant technical working groups (TWGs) to use the maps when planning upcoming interventions. Methodology: We will obtain monthly aggregated malaria case data from the Health Management Information System (HMIS) known as DHIS21 at the health facility level. After data processing, we will apply geospatial statistical methods to estimate malaria incidence over time, incorporating the effects of climate, environment, and malaria intervention activities. Our results will then be visualised within a digital dashboard which will be integrated within NMCP surveillance systems at the national and district levels. Expected results and their dissemination We anticipate that our analysis will reveal the spatial and temporal heterogeneities in malaria transmission across the country. Results will be shared with COMREC and the Ministry of Health at relevant technical working group meetings and the joint KUHeS and MLW research dissemination conference. We will also publish the results in peer-reviewed journals.
- ItemRestrictedDifferential diagnosis for malaria and trypanosomes in areas where the diseases co-exist(Kamuzu University of Health Sciences, 2021-01-13) Makuluni, MarinaType of study: This is a cross-section study to investigate the co-infection of trypanosome and malaria parasites in areas where trypanosomiasis is endemic in Malawi. Problem: Malaria is ubiquitous, treatment of Human African Trypanosomiasis (HAT) tends to be delayed as the first diagnostic measure for any patient presenting with these symptoms gets malaria treatment first (Darby et al., 2008). Malaria in Malawi is mainly caused by Plasmodium falciparum and diagnosis requires a Malaria Rapid Diagnostic Test (mRDT) at the point of care which is an antibody/antigen test and microscopy of stained blood films is sometimes used. There are two main mRDT in use in Malawi, one developed based on Plasmodium histidine-rich protein (HRP) 2 (pHRP-2) antigen and the other based on Plasmodium lactate dehydrogenase (LDH) (pLDH) antigen both of which mainly target P. falciparum. HAT in Malawi is caused by T.brucei rhodesiense and standard of care diagnosis requires microscopy of stained blood smears although not sensitive when parasitemia is low (Manful et al., 2010). Published reports have revealed that Trypanosome parasite hide underneath the skin of some individuals although there may be no circulating parasites in the blood as one way of invading host adaptive immunity. The parasites may reside underneath the skin for years without being detected in blood circulation. This complicates the diagnosis of HAT as such individuals are diagnosed as microscopically negative for HAT disease and often sent home on antimalaria treatment without further diagnosis. Main objective: To investigate differential diagnosis of Malaria and Trypanosomiasis in Rumphi and Nkhokakota Specific Objectives: 1. To assess the magnitude of HAT patients that are missed out when using microscopy for diagnosis in comparison with a diagnostic HAT PCR. 2. To identify individuals co-infected with Malaria and Trypanosomes 3. To determine whether HAT positive individuals detected are infected with cutaneous trypanosomes. 4. To Identify differences in T.b. rhodesiense parasite gene expression when isolated in skin and or blood. Methodology: Patients that were pre-screened by medical personnel at the hospital for febrile symptoms and sent for Malaria test at the laboratory will be recruited for a period of two weeks to meet our sample size of 123 participants for both Nkhotakota and Rumphi district hospitals. Venous blood specimen will be collected from each participant for further laboratory analysis. Firstly, the blood will be parasites will be sent for treatment immediately following standard treatment guidelines for each disease used to screen for Malaria parasites using Malaria Rapid Diagnostic (RDT) test. Microscopy will be used to confirm individuals who are Malaria RDT positive. Lastly, the other part of the blood will be used for microscopic examination for diagnosis of HAT disease at the district hospital Blood samples that are microscopic negative for HAT will further be tested using a diagnostic HAT PCR at the College of Medicine to rule out any HAT cases that might be missed by the low sensitivity microscopic examination. Individuals that are HAT positive by either microscopy or PCR will be requested to have a small skin snip for further laboratory examination to identify cutaneous Trypanosomes. All participants who are positive for either Malaria or Trypanosome Expected Findings/Dissemination Study This study is expecting to identify the HAT cases that are missed during diagnosis in the two HAT endemic district hospitals of Malawi. The study will also help identify factors that influence mis-diagnosis of HAT in endemic areas of Malawi. Findings from this study will be disseminated at COMREC, College of Medicine Neglected Tropical Disease Research group, Trypanogen Project, Peer reviewed journals and research conferences.
- ItemRestrictedThe effect of repeated washing of the royal guard, Interceptor G1 and G2 nets on behaviour (Host seeking and blood feeding) and survival of anopheles mosquitoes(Kamuzu University of Health Sciences, 2022-08-17) Banda, Judith SinkanakoInsecticide treated mosquito nets on behaviour and survival of Anopheles mosquitoes the effect of repeated washing of the royal guard and interceptor G2 nets on behaviour (host seeking and blood feeding) and mortality on Anopheles mosquitoes. This is a sub study which will be conducted under ESSENTIALS project IRB number P.10/20/3155 being hosted by the Malaria Alert Centre in Blantyre. Problem statement Insecticide-treated nets remain important in preventing transmissions of mosquito borne pathogens. Long-lasting insecticide-treated nets (LLINs) offer longer time protection against such bites because they are more wash resistant, and are preferred to conventionally treated nets. Whether the new LLINs (IG2 and RG) are wash resistant compared to the conventional nets is unknown. Moreover, how the repeated washing affects host seeking and feeding behaviour and survivor of Anophelines success remains elusive. Therefore, this study will assess the effect of Royal guard, Interceptor G1 and G2 on blood feeding, host seeking behaviours and survival of the effect of repeated washing of insecticide treated mosquito nets on behaviour and survival of Anopheles mosquitoes after repeated washing under laboratory conditions Main objective To assess the effect of repeated washing of insecticide treated mosquito nets on behaviour and survival of Anopheles mosquitoes To assess the effect of repeated washing of the royal guard, interceptor g1 and g2 nets on host seeking and blood feeding behaviour and survival of Anopheles mosquitoes Specific objectives 1. To determine the number of knocked down and dead mosquitoes post exposure to both washed and unwashed nets 2. To determine the number of blood fed mosquitoes post exposure to washed and un washed nets. 3. To evaluate the host seeking behavior of mosquitoes post exposure to washed and un washed net. 1. To assess the knockdowns and survival of mosquitoes when exposed to unwashed nets and washed nets. 2. To determine the number of blood fed mosquitoes post exposure to washed and un washed nets. 3. To evaluate the host seeking behaviour of mosquitoes post exposure to washed and un washed net. Methodology The researcher will conduct a cross-section study and will perform host seeking and WHO Cone bioassays on Kisumu, Anopheles funestus and Anopheles gambiae. Data will be collected and recorded in a laboratory note book. Collected data will be manually entered into Microsoft excel and analyzed using R software version 20. Expected Findings and Dissemination The researcher hypothesizes that blood fed mosquitoes and host seeking behaviour will increase with increase in number of net washes while mortality of mosquitoes will decrease with increase in the number of net washes. Findings from this study will be disseminated through peer-reviewed publications, presentations at scientific conferences including the KUHeS annual dissemination conference. A researcher will submit a project completion report to the College of Medicine Research and Ethics Committee and Liverpool school of tropical medicine.
- ItemRestrictedEfficacy, safety and pharmacokinetic exposure of artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in HIV infected Malawian children on antiretroviral treatment(Kamuzu University of Health Sciences, 2021-03-17) Mbeye, NyanyiweType of research study: A prospective observational study will recruit and follow up two groups of children aged between 6 months and 16 years diagnosed with uncomplicated malaria in Lilongwe district. One group will be HIV infected and on antiretroviral treatment and another one will be HIV uninfected. The problem: There is paucity of consolidated evidence to guide optimisation of the current arsenal of drugs that are used to fight malaria in individuals co-infected with HIV especially in key at-risk subpopulations such as children. Potential drug-drug interactions between antimalarial drugs and antiretroviral therapy (ART) raise concern in the control of malaria in children who are co-infected with HIV. Artemether-lumefantrine (AL) is a commonly used artemisinin-based combination therapy (ACT) in most malaria programmatic settings but there is limited understanding of its efficacy in malaria and HIV co-infected children in light of the potential drug-drug interactions between ACTs and ART. WHO recommends countries to evaluate efficacy of their first-line antimalarial drugs at least once every two years. Since these studies are done in HIV negative children, there is an important need to assess the efficacy of first-line antimalarial drugs in HIV infected children on ART as well. Objective: This study aims to evaluate the efficacy and safety of artemether lumefantrine (AL) for the treatment of uncomplicated P. falciparum malaria in HIV infected and HIV uninfected children in Lilongwe, Malawi. Methodology: A prospective observational study of antimalarial efficacy will be conducted in a total of 71 HIV-malaria coinfected children on ART and 141 HIV uninfected children with confirmed malaria who meet the inclusion criteria. Once enrolled, participants will be given AL for treatment and followed up for 28 days. The follow up will consist of fixed schedule of visits (at Day 1,2,3,7,14,21 and 28) with corresponding clinical and laboratory examinations. The proportion of participants experiencing therapeutic failure during the follow-up period will be used to estimate the efficacy of AL. PCR analysis will be used to distinguish between recrudescence and reinfection. On day 7, post treatment initiation, a blood sample will be collected to quantify lumefantrine concentrations, as a predictor of overall lumefantrine exposure. These concentrations will be correlated with AL treatment efficacy. The design has adapted some procedures of the recommended WHO methods for surveillance of antimalarial drug efficacy. Expected findings and their dissemination: This study is designed to generate the information required to assess whether AL is efficacious in HIV infected children on ART. It is anticipated that the study results will improve the management of malaria in HIV infected children on antiretroviral drugs in areas affected by both HIV and malaria. This study will also provide information on the pharmacokinetics of AL and its efficacy that would contribute to the development of appropriate approaches/options for optimal effectiveness of the treatment. The findings of this study will be published in peer-reviewed journals and shared with all relevant stakeholders.
- ItemRestrictedExamine gut microbiota between and as a potential cause of severe versus asymptomatic malaria.(Kamuzu University of Health Sciences, 2020-06-15) Schmidt, Nathani] Type of Research Studies Gut microbiota and human malaria: Examine gut microbiota between and as a potential cause of severe versus asymptomatic malaria Case-control cohort study. ii] Problem to be Studied The majority of Plasmodium falciparum infections are asymptomatic. While some infections progress to clinical uncomplicated malaria, which is debilitating in its own right, a small percentage of infections progress to clinical forms of severe malaria (e.g., severe malarial anemia and cerebral malaria), which are responsible for P. falciparum related deaths. To date, it is not fully understood what factors contribute towards the susceptibility of P. falciparum infection progressing to clinical uncomplicated malaria or severe malaria. This knowledge gap hinders discovery of new strategies to prevent this evolution. iii] Objectives 1. compareCompare gut microbiota compositions and functions between children with strictly defined asymptomatic P. falciparum parasitemia and life-threatening P. falciparum cerebral malaria and determine the effect of gut microbiota differences on both the host humoral immune response and severity of disease.Characterize gut microbiota in participants with asymptomatic P. falciparum compared to participants with life-threatening cerebral malaria. 2.1. Examine biomarkers, including plasma cytokines, circulating antibodies, and immune cell populations, of the humoral immune response to P. falciparum in children with asymptomatic infections compared to children with cerebral malaria. 3.2. Determine the ability of gut microbiota in the stool of donors to impact the severity of malaria by Use stool samples collected from participants with asymptomatic infections and cerebral malaria to colonizinge germ-free mice with patient stool samples followed by infection with rodent malaria. to determine ability of gut microbiota in the stool donors to impact the severity of malaria. iv] Methodology We propose to conduct a case-control cohort study in the catchment area of Queen Elizabeth Central Hospital, Blantyre, Malawi. 1. Cerebral malaria cases – These will consist of children aged 12-96 months presenting to the Pediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre, Malawi. Children must meet the WHO classification for cerebral malaria (Blantyre Coma Score ≤ 2, peripheral P. falciparum parasitemia, and no other discernible cause for coma) as well as be retinopathy positive. These cases will be recruited from a larger ongoing study investigating the pathogenesis of cerebral malaria. COMREC P.09/16/2024 (PI Taylor). A venipuncture sample and stool sample will be collected for a detailed analysis of the host and parasite factors leading to the persistent asymptomatic infection 2. Asymptomatic controls – Children will be recruited into this group upon escorting of cerebral malaria cases home post-discharge. They will be from adjacent households to the cerebral malaria case and will thus be matched in geographic location to the cerebral malaria cases. Twelve participants within one year in age and of the same sex will be chosen to match with each cerebral malaria case. This will be necessary to increase the likelihood of obtaining a child that is asymptomatically infected. Finger prick samples of blood will be collected onto filter paper monthly for two months from asymptomatic children, aged 12-96 16-Sep-2020 Gut microbiota and human malaria: Examine gut microbiota between Version 1.25 and as a potential cause of severe versus asymptomatic malaria 24 April15 June 2020 4 months. PCR analysis of filter papers will be carried out on a monthly basis, and when a participant has two consecutive positive samples (whilst asymptomatic), a venipuncture sample and stool sample will be collected for a detailed analysis of the host and parasite factors leading to the persistent asymptomatic infection. v] Expected Findings and Dissemination We anticipate finding that gut microbiota will be different between children with cerebral malaria and asymptomatic infections, which will alter the host immune response to Plasmodium and collectively be a contributing factor to determining the severity of malaria disease. Results will be disseminated in peer-reviewed journals, international conferences, the University of Malawi College of Medicine Research Dissemination Conference, and will be provided to COMREC and community leaders.
- ItemRestrictedExploring factors shaping outdoor individual’s exposure to malaria vectors in Malawi: Chikwawa District(Kamuzu University of Health Sciences, 2021-11-09) Kayira, LusunguType of research: This is an explorative qualitative study aiming at at understanding about how people living in the Chikwawa district are exposed to malaria vectors. Focusing on the way of life of the study participants to learn how the environment they live in shapes their vulnerability to malaria transmission. The problem: Despite the nationwide distribution of ITNs in Malawi, Malawi remains endemic to malaria, with districts such a Chikwawa still registering high numbers of malaria cases[1]. Most research informing vector control interventions are based on entomological aspects and forgo the social aspects in which individuals live, exposing them to malaria transmission. Study objective: This study proposes to explore factors shaping outdoor exposure to malaria transmission and who are vulnerable based on the settings of the environment they live in during conventional mosquito biting times of 6 pm to 6 am. Methodology: This will be a qualitative study. Data will be collected on the activities that may result in a higher risk of exposure to malaria vector bites through participant observation and engaging with prospective research participants on a daily basis. Some of the domains I hope to explore with this approach are work patterns, intra-household allocation of bednets, and social activities (e.g. religious events). Interviews and focus group discussions will be used to learn about individuals' and caregivers' understanding of malaria transmission and perception of bednet use. Using the concept of structural vulnerability and the socio-ecological model, this study will explore outdoor factors which expose individuals to malaria vectors during conventional mosquito biting times in Domasi village, Chikwawa district Sample size: The highly qualitative nature of the study, which relies on convenience and purposive sampling, lends itself to sample size estimates better than to exact indicators, as it is difficult to foresee precisely how many individuals will be present in the study communities at any point throughout the study. However, I estimate that I will include up to 100 individuals for participant observations, 15-20 people for IDIs and up to 32 individuals for FGDs. to 100 participants will be included in the participant observation exercise; between 15-20 participants for in-depth-interviews (IDIs), between 24 and 32 for focus group discussions (FGDs) (to be divided into 4-6 groups) Data management and analysis: Field notes will be written throughout the fieldwork and will, with the participants' permission, record audio files during IDIs and FGDs. Data will be transcribed uploaded on a password-protected folder. Inductive content analysis will be employed for the data. Expected results and dissemination: The results from this study are expected to fill the gap on knowledge of the relationship between the environment in which bed-net users live and malaria transmission. The results will be disseminated with: (1) KUHeS; (2) the host communities; (3) the College of Medicine Research Ethics Committee (COMREC), including participation to the Research Committee Dissemination Day; (5) the funders -PIIVeC partners; and (6) in academic venues, such as journals and conferences.
- ItemRestrictedIdentifying Determinants of Submicroscopic Malaria in Malawi, version 1.0(Kamuzu University of Health Sciences, 2022-07-12) Msowoya, GiftType of Study This is a cross sectional study that aims at identifying factors associated with submicroscopic malaria infection in three districts in Malawi; Blantyre, Chikwawa and Thyolo districts. Malaria continues to be a burden to the health of people globally with about 229 million cases with a reported 409 000 deaths in 2019 alone. In Africa specifically sub-Saharan Africa malaria also continues to be a big burden with 95 percent of all malaria cases in the world occurring in this region of which resulted into 12 percent increase in deaths in 2020 as compare to 2019. In Malawi malaria is big burden contributing to about 23 percent of all outpatient visits and 5.2 million cases in 2019 alone. Submicroscopic malaria which is malaria infection that is negative on microscopy testing and positive on polymerase chain reaction (PCR) test contributes to the human reservoir for the plasmodium parasites that ensures continuous presence of the parasites in the population hence favoring onwards transmission. The human reservoirs are people who are infected but are not sick harboring either microscopic or submicroscopic infection. Because they are not sick these are the populations which are not treated hence making malaria control and elimination difficult. Problem; In Malawi there is paucity of data on determinants of submicroscopic malaria which would help with mass drug administration as a strategy in targeting those human reservoirs of plasmodium. If factors associated with submicroscopic malaria could be studied it would help in targeting the screening and treatment plus in targeting the right group for mass drug administration (MDA) to deal with these cases of these submicroscopic cases in order to reduce the human reservoirs of plasmodium. This study therefore seeks to identify factors associated with submicroscopic infection in different transmission settings in Malawi. If we can identify those at risk of submicroscopic malaria infection, we can then better tailor interventions to target them hence reducing the prevalence and helping with malaria control while contributing to malaria elimination in the long run. Broad objective: To establish the determinants of submicroscopic malaria across different transmission settings in Malawi. Specific objectives: 1. To determine prevalence of malaria cases among population from Blantyre city, Chikwawa and Thyolo districts 2. To estimate the proportion of submicroscopic malaria infections among population from Blantyre city, Chikwawa and Thyolo districts. 3. To analyze determinants of submicroscopic malaria infection in the population from among populations from Blantyre city, Chikwawa and Thyolo districts Methodology Type of study: This is a cross sectional study design which will utilize secondary data that was collected for cross sectional survey conducted by malaria alert center in three districts names; Blantyre city, Thyolo and Chikwawa between 2012 and 2016. In the surveys, houses were sampled from sampled areas withing these districts and all people belonging to selected household were interviewed, their blood samples collected, the area around the house inspected and mosquitoes collected from the houses for analysis. Microscopy was done to test for malaria parasites and those that tested negative were tested using PCR to determine those with submicroscopic infections. We will look at those with submicroscopic infection to look for determinants of this infection. Expected findings and Their dissemination The project is expected to produce results on determinants of submicroscopic malaria infection which will be added knowledge to the already known prevalence of submicroscopic malaria in these districts which could help drive policy as well as strategies to help with control and elimination of malaria in Malawi. Results will be disseminated locally at the Malaria alert center, college of medicine, Kamuzu college of health sciences, college of medicine research ethics committee, and shared with the district health officers and other partners in malaria control and management working in these districts as well as published in medical journals.
- ItemRestrictedIdentifying functional antibody responses that protect against malaria in children, version 1.0(Kamuzu University of Health Sciences, 2022-08-03) Rogerson, Stephen; Seydel, KarlType of study: Observational cohort study The Problem: Although antibodies have been shown to be important for the protection against malarial disease, the specific characteristics of these protective antibodies have not been well delineated. Methodology: The study population of interest will be children aged 1-8 years of age drawn from three ongoing COMREC-approved studies. This is a secondary analysis of samples already being collected from three ongoing COMREC-approved studies. Children in the ongoing “Treatment of brain swelling in pediatric cerebral malaria” study (P. 09/16/2024, PI: Taylor) with cerebral malaria will be matched with children with uncomplicated malaria from the study “Characterization of Plasmodium falciparum var/PfEMP1 type and immune response to PfEMP1 in severe and uncomplicated clinical malaria” (P.01/15/1668, PI:Kim) and children with asymptomatic parasitemia from the “Malaria pathogenesis: Progression cohort and extremes, case control study” (P.11/18/2530, PI: Seydel). Children with no evidence of malaria infection in the “Malaria pathogenesis” study will be used as uninfected controls. After obtaining informed consent from their primary caretaker, a brief medical history and demographic information will be collected from all participants. Children with cerebral malaria are having a 10ml blood sample collected. Children in the uncomplicated and asymptomatic cohorts are having 4mls of blood collected. Plasma from this sample, as well as peripheral blood mononuclear cells from these samples will be purposed for this proposed study. No additional blood will be drawn for the purpose of this study. The serum from these studies will first be used in a Luminex assay to determine the strongest candidates that might be leading to protective immunity. Antibody and PBMC responses to these antigens will then be prioritized in the subsequent assays. These assays will involve the functional and biochemical characterization of antibodies in ~50 ways (see Research Strategy below). Comparison groups will be among the three disease severity types as well as between acute and convalescent sera. Data from these assays will be analyzed using elastic net regularized logistic regression and partial least squares discriminant analysis to identify the antibody characteristics associated with disease severity. Broad Objective: To identify the biophysical and functional characteristics of antibodies that protect against clinical malaria in children. Specific Objectives: 1) To use the Luminex bead approach to identify a subset of five P. falciparum expressed proteins that serve as targets of protection against cerebral malaria. To use the Systems Serology approach to identify biophysical and functional characteristics of antibodies against the targets identified in Aim 1, that either protect from cerebral malaria or develop during convalescence from cerebral malaria. 3) To use the Systems Serology approach to identify the biophysical and functional characteristics of antibodies that are present in children with asymptomatic P. falciparum infection and not in children with clinical disease. Expected Findings: We expect to find a subset of PfEMP1 domains, as well as a subset of proteins expressed on the merozoite stage of the parasite, that are most important in the protection of children from severe malaria. We also expect to find a distinct antibody profile that is most effective at controlling the P. falciparum infection. This will be accomplished by comparing the antibody characteristics seen in children with severe disease to those seen in children with milder infection, and (for the second question) comparing antibody responses in children with asymptomatic parasite infection to children with symptomatic malaria. Dissemination: Results will be disseminated to the medical community through peerreviewed publications and presentations at relevant scientific conferences. Results will also be shared with KUHeS at the annual Research Dissemination Conference. Annually, we will also be providing COMREC updates as required in the annual report.
- ItemRestrictedImpact of pneumococcal and malaria vaccines for children on antimicrobial resistance in Malawi(Kamuzu University of Health Sciences, 2021-03-15) Swarthout, ToddType of research study: A series of community and health centre based cross-sectional surveys Problem: Pneumonia is a leading cause of child mortality globally and Streptococcus pneumoniae a leading cause of lower respiratory tract infections (LRTI) in under-fives. Malaria remains endemic in much of sub- Saharan Africa, commonly causing febrile illness in children and despite substantial progress with control programmes, Malaria continues to be a leading cause of child mortality. Vaccination is therefore an attractive solution. Vaccines are thought to be crucial to Anti-Microbial Resistance (AMR) control but their impact on AMR may be more complex than originally thought. Both the direct and indirect impacts of vaccine on AMR require a systematic evaluation. In collaboration with the Malawi Ministry of Health, we are commencing two funded, regulatory approved, cluster-randomised evaluations of vaccines that target two of the commonest causes of febrile illness and life-threatening disease in children under 5 years in Africa: pneumococcal invasive infection, and malaria. This study will leverage two large funded cluster randomised vaccine evaluations (13-valent Pneumococcal Conjugate Vaccine (PCV13) schedule change of 3+0 to 2+1 and RTS,S/AS01 (trade name Mosquirix) malaria vaccine introduction). We will assess the selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness and antibiotic usage in children <3 years. Hypothesis: Extending vaccine-mediated protection against Streptococcus pneumoniae through a 3+0 to 2+1 schedule change will be associated with a reduction in the prevalence of S. pneumoniae carriage isolates with increased AMR in children <3 years. The introduction of the malaria vaccine will reduce the frequency of healthcare attendances resulting in antibiotic prescription, reduce the prevalence of Extended spectrum beta-lactamases (ESBL) Escheriquia coli or Klebsiellae in the stool of children <3 years, and change the upper respiratory tract resistome profile in children <3years. Aim: To establish the direct and indirect selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness, and antibiotic usage in young children in Malawi. Objectives: 1. To establish the antibiotic resistance profile of S. pneumoniae carriage isolates from children <3 years following a PCV13 schedule change that extends protection (2+1 vs. 3+0), or the introduction of malaria vaccine (RTS,S/AS01) 2. To assess the frequency of febrile illness and antibiotic use in children <3 years after PCV13 schedule change or malaria vaccine introduction 3. To investigate change in the upper respiratory tract resistome in children <3 years after PCV13 schedule change or malaria vaccine introduction. Methodology: Cross sectional surveys shall be conducted at baseline of PCV13 2+1 and RTS,S/AS01 introduction, 18 months after introduction, and 33 months after introduction in clusters defined through two large cluster-randomised vaccine evaluation studies. These will include the collection of nasopharyngeal and rectal swabs, and the completion of an Individual questionnaire on febrile illness episodes and antibiotic usage. Data on Febrile illness episodes (malaria Rapid Diagnostic Test (RDT) use) and antibiotic usage will be obtained from Health Centre (HC) records. Expected Results Nasopharyngeal and rectal swabs obtained from participants will be tested for the presence of S. pneumoniae, and E. coli and Klebsiella isolates respectively. Bacterial isolates will be tested for the presence of AMR genes, and resistance profiles will be analysed in relation to their association to either the introduction of the RTS,S/AS01 vaccine or the PCV13 schedule change, and in the context of antibiotic prescription and usage for febrile illness episodes. Outcome Measures: Primary: The antibiotic resistance profile of S. pneumoniae carriage isolates from children <3 years following a PCV13 schedule that extends protection (2+1 vs. 3+0) or the introduction of malaria vaccine (RTS,S/AS01) Secondary: The frequency of febrile illness and antibiotic use in children <3 years after PCV13 schedule change or malaria vaccine introduction. The stool carriage of ESBL E. coli or Klebsiella in children <3 years after PCV13 schedule change or malaria vaccine introduction. The change in the upper respiratory tract resistome in children <3 years after PCV13 schedule change or malaria vaccine introduction. Population Eligibility: Each cross-sectional survey shall recruit children between the ages of 15 and 24 months old, resident in Blantyre or Mangochi district, recruited from the community and health centres (PCV13), and community-based visits (RTS,S/AS01). Findings dissemination: Investigators will seek timely publication in peer-reviewed journals. Partial results and interim analyses will be shared with the Malawi Ministry of Health (MoH), and other relevant policymakers and decision-making stakeholders. Partial and final findings will be presented at the College of Medicine (COM Research Dissemination Day, Malawi-Liverpool Wellcome Trust (MWL) research in progress meetings and international scientific conferences. A copy of all published materials and reports will be shared with College of Medicine Research Ethics Committee (COMREC), and the Malawi College of Medicine Library.
- ItemRestrictedMalaria breath biomarkers across the spectrum of malaria disease severity(2022-05-12) John, Audrey Odom; Seydel, KarlType of study: Observational cohort study The Problem: The need for rapid, accurate, affordable, and non-invasive diagnostic methods for malaria remains urgent, particularly in peripheral health centers. Methodology: The study population of interest will be children aged 4-8 years drawn from two ongoing COMREC-approved studies at Queen Elizabeth Central Hospital in Blantyre. Fifty children in the ongoing “Treatment of brain swelling in pediatric cerebral malaria” study (P. 09/16/2024, PI: Taylor) with cerebral malaria will be matched with fifty children with asymptomatic parasitemia from the “Malaria pathogenesis: Progression cohort and extremes, case control study” (P.11/18/2530, PI: Seydel). Fifty children with no evidence of malaria infection in the “Malaria pathogenesis” study will be used as uninfected controls. After obtaining informed consent from their primary caretaker, a brief medical history and demographic information will be collected. For children with cerebral malaria (CM), breath will be collected through a mask with two one-way valves – allowing for inspiration through one valve and exhalation through a separate valve. Asymptomatic children and children confirmed to not have malaria by qPCR (controls) will provide exhaled breath gas samples after 5 minutes of sitting or lying quietly. A full breath will be exhaled into a small plastic device attached to an inflatable plastic bag. Once the exhaled breath is collected, the sample will be filter concentrated into a sorbet trap that absorbs nonpolar organic molecules. These samples can then be stored refrigerated and shipped at 4-6°C. A finger prick blood sample will be taken on a filter paper at the same time to be used for PCR quantification of asexual parasites and gametocytes. A nasopharyngeal swab will be taken from the children with CM to test for viral and bacterial respiratory pathogens. Following sample collection, children with CM will receive routine medical care for their malaria, including usual antimalarial therapy as warranted. The asymptomatic children will be tested for malaria with a mRDT and treated with standard anti-malarial therapy (LA) if found to be positive. The children with no evidence of malaria will also be tested by mRDT and treated with LA if found to be positive. The breath samples will be analyzed for VOCs by thermal desorption (TD) mass spectrometry. The mass spectrometry resource facility at Children’s Hospital of Philadelphia (CHOP) has successfully detected VOCs emitted by cultured malaria parasites (1) and in breath of Malawian children (2) and will again be engaged to seek these compounds in the breath from patient specimens. Objectives: To develop a novel non-invasive, rapid, accurate, reusable, and affordable malaria diagnostic method capable of detecting P. falciparum even at sub-mRDT parasitemias. This will be achieved through two specific aims:12-May-2022 Breath malaria biomarkers COMREC submission Version 1.2, 26 Feb 2022 Page 5 of 22 5 a) To collect and analyze breath from fifty children with asymptomatic malaria and fifty children without malaria infection to determine the possible presence of biomarkers able to distinguish these populations b) To collect and analyze breath from fifty children with cerebral malaria and simultaneously evaluate these children for the presence of respiratory pathogens, allowing us to characterize the possible role of respiratory pathogens in altering the malaria breathprint. Expected Findings: We hypothesize that VOCs will be detected in the breath of children with malaria even at the very low levels of parasite infection seen in many asymptomatically infected children. Furthermore, we hypothesize that co-infection with respiratory pathogens will shift the VOC profile – but that an underlying ‘breathprint’ can be identified that is malaria specific. These core VOCs can then be explored as novel biomarkers of malaria infection that could be used to screen for asymptomatic infection serving as the basis for future non-invasive malaria diagnostic devices. It is the hope that, in addition to being non-invasive, these devices could be portable, reusable, affordable, and accurate so that they could be used in rural health facilities and communities to identify the population of children who are asymptomatically infected and thus serving as a transmission reservoir. Dissemination: Results will be disseminated to the medical community through peer- reviewed publications and presentations at relevant scientific conferences. Results will also be shared with KUHeS at the annual Research Dissemination Conference. We will also report our findings and publications to COMREC
- ItemRestrictedMalaria disease severity and correlation with Plasmodium falciparum gametocyte burden and sex ratio in children treated at health facilities in Blantyre, Malawi(Kamuzu University of Health Sciences, 2021-01-11) Gama, Syze ChogaType of study This is a Retrospective Cohort study which will use previously collected samples from the paediatrics malaria research ward at Queen Elizabeth Central Hospital (QECH) and Gateway clinic of Blantyre District Health Office. The Problem Malaria continues to be an endemic public health problem in Malawi causing an estimated six million cases annually. According to the Demographic Health Survey of 2010, it still remains the leading cause of morbidity and mortality in under -five children and pregnant women. Over 95% of the malaria cases are caused by Plasmodium falciparum(1). People presenting with the disease are often diagnosed microscopically for the presence of ring stages (asexual stage) of the parasite and receive anti- malarial treatment if found positive. The gametocyte (sexual stage) is responsible for production and transmission of the from human to the mosquito vector. Despite not being tracked in microscopy diagnosis, the number of gametocytes and ratio of female to male gametocytes, determines the transmissibility of malaria. Malaria disease severity is determined by the clinical evidence of vital organ dysfunction and thus understanding the association of malaria disease severity and gametocyte burden and sex ratio will assist in determining the children who might take transmissible parasites back to the community even after taking anti-malaria treatment. This knowledge will help to tackle this vast reservoir of transmission between the human host and the mosquito vector. Objectives To determine the correlation between malaria disease severity and Plasmodium falciparum gametocyte burden and sex ratio in children treated at health facilities in Blantyre, Malawi. Methodology This is a Retrospective cohort study which will use blood samples (Dried Blood Spots) collected in the malaria pathogenesis study at malaria research ward at QECH and Gateway clinic. Laboratory analysis of these samples will be done using quantitative Polymerase Chain Reaction (qPCR) technique.The Mann-Whitney test will be used to test if there will be any statistical significance in the difference of gametocyte sex ratio between the two groups. The mean, median and the inter-quartile range in each group will be analyzed for gametocyte burden and they will be compared. Expected findings and dissemination This study will look at the correlation between malaria severity and P. falciparum gametocytes burden and sex ratio in children treated in health facilities in Blantyre. The final findings will be documented in a report which will be sent to the hospital management, COMREC as well as policy makers. Oral presentation of the results will be done to the hospital management, and at the COM research dissemination conference. The results will also be published in a peer review journal.
- ItemRestrictedMolecular mechanisms in pediatric cerebral malaria pathogenesis and Immunity(Kamuzu University of Health Sciences, 2021-07-21) Seydel, KarlType of Research Study: Prospective case control study Problem: Malaria, caused by the parasite P. falciparum, remains a significant public health problem in Malawi. Objectives: We plan to 1) determine which subset of parasites are responsible for binding to the microvessels of the brain and gut, and 2) investigate the role of lactate in altering the binding characteristics of parasitized erythrocytes to microvessels. Methodology: We have devised a novel 3D microvessel model that accurately mimics the flow velocity and wall shear stress present in the microvessels of the brain. We are able to create an in vitro model of the human brain microcirculation by forming very small 3D blood microvessels from primary human brain endothelial cells, thus accurately mimicking both the cellular and fluidic environment that a parasitized erythrocyte would encounter in the brain. We will use this 3D human brain microvessel model, as well as characterized parasites from malaria patients to investigate the receptors and milieu contributing to life-threatening cerebral malaria infections. Expected findings and dissemination: We anticipate finding a subset of parasites, those expressing a certain subset of PfEMP1 molecules on their surface, that are most adept at binding to brain endothelial cells. We anticipate that the innovative 3D microvessel model will elucidate parasite binding differences under certain flow-based, shear stresses that have not previously been appreciated, given previous models were unable to mimic physiologic flow and the curvature of a blood vessel wall. We also anticipate being able to use this unique model, in combination with known antibodies and shRNA techniques to determine the role of various proteins on the endothelial cell surface in mediating this binding. Moreover, we will determine if different subsets of parasites will adhere to brain and gut microvessels, which are the predominant organs of parasite accumulation in deadly malaria infections. Finally, we will be able to use this model to evaluate the role of external molecules, such as lactate, on infected erythrocyte binding in a physiologically relevant model system. Results will be disseminated in peer-reviewed journals, international conferences, the University of Malawi College of Medicine Research Dissemination Conference, and will be provided to COMREC and community leaders.
- ItemRestrictedAn MRI Ancillary Study of Malaria fever (RCT)(Kamuzu University of Health Sciences, 20-09-16) Birbeck, GretchenDespite eradication efforts, ~400,000 African children sustained brain injuries as a result of CNS malaria in 2016. A higher maximum temperature (Tmax) during the acute malaria infection is an established risk factor for neurologic sequelae and a randomized controlled trial (RCT) of aggressive antipyretic therapy with acetaminophen and ibuprofen began enrollment in Malawi in 2019 (R01NS102176) with expansion into Zambia pending. In this clinical trial, the primary outcome is Tmax during the acute infection. However, the antipyretic therapies used in this RCT may offer neuroprotective effects without affecting Tmax--for example, neuroprotection through anti-inflammatory mechanisms. In this ancillary study, we propose to use neuroimaging in the context of the RCT to further evaluate the potential neuroprotective effects of aggressive antipyretic therapy for CNS malaria and explore possible mechanisms for these effects. Comparing children allocated to aggressive antipyretic therapy vs. usual care on the prevalence of structural brain abnormalities after recovery from CNS malaria will facilitate the evaluation of non-fever pathways for neuroprotection. Both Zambia and Malawi have an unusually well-developed infrastructure for advanced imaging in the academic centers where the RCT using aggressive antipyretic therapy will be conducted have MRI facilities. Brain MRIs will be obtained in children enrolled in the RCT at 1- and 12-months post recovery. Analyses will be completed comparing the odds of having any structural injury based upon RCT treatment allocation and based upon (Tmax) stratified by treatment allocation to assess changes specifically related to response to therapy in terms of fever reduction. Potential mechanisms of aggressive antipyretic-related injury will be evaluated including assessments for treatment-related CNS bleeds. Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury including in pediatric CNS malaria. Adding this MRI ancillary study to our fever RCT may elucidate mechanisms of treatment-associated injury and allow for early identification of neuroprotection from aggressive antipyretic use that would otherwise require long-term follow-up for cognitive and behavioral assessments. This MRI ancillary study when added to the Fever RCT will provide critical insights that could inform future neuroprotective studies of malaria that might incorporate imaging to optimize study design.
- ItemRestrictedOptivants – Optimising vaccination for iNTS disease in Africa(Kamuzu University of Health Sciences, 2021-07-26) Gordon, MelitaStudy design: Prospective systems serology analysis of serological samples collected in several studies of children 0-5 years across sub-Saharan Africa: 1. STRATAA – 500-1000 paired samples available collected between 2015-2018 in peri-Urban Malawi, 2. SAiNTS 2000 paired samples due to be collected 2021-2022, 3. 1000 single samples VacciNTS sites in Kenya, Burkina Faso, Ghana 2021-2022. Problem statement: Invasive non-Typhoid salmonella (iNTS) is responsible for >500,000 illnesses, 77,500 deaths, and the loss of 4,263,500 DALYs every year. Despite its high burden, iNTS remains a Neglected Infectious Disease. It is pre-dominantly a disease of infants in sub-Saharan Africa (sSA). Although risk is amplified by HIV co-infection, this is a factor in only a minority of paediatric cases. The key feature of severe infection is systemic spread from the gut to systemic sites. The two major strategies to control these invasive infections are antimicrobial treatment and vaccination. However, emerging anti-microbial resistance limits benefit and there is no licensed vaccine currently available against iNTS. Broad Objective: To comprehensively elucidate the effector functional humoral profiles and antigenspecificities of protective antibody against iNTS to define a correlate of humoral protection that can be applied to vaccine design and evaluation. Specific Objectives: 1. Identify key novel antigens (Ags), in addition to those already known, that induce protective antibodies (Abs). 2. Describe the mechanisms of action by which different subclasses of antibodies control NTS. 3. To contextualize the value of single-antigens vs multi-component vaccines against iNTS 4. Understand how different co-morbidities (malaria, malnutrition, and anaemia) modulate these functional immune responses and specific protective functions. 5. Provide robust Correlates of Protection (CoP) to accelerate licensure of both current and new vaccines. Methodology: This will be a lab based cross-sectional study conducting systems serology analysis utilising pre-existing serological samples from approved studies in Malawi and across sub-Saharan Africa. STRATAA samples will be utilized for the antigen discovery phase, SAiNTS samples are set for evaluating the range of antigenic exposure to different NTS strains right across the continent, and detailed characterisation of susceptibilities, allowing further dissection and validation of the systems serology signature, to be layered onto the findings from the initial STRATAA discovery cohort. Expected findings and their dissemination: Firstly, Identification of functional-correlates of protection which may provide critical insights for the selection of promising adjuvants that may directly influence the functional (isotype, subclass, and Fc-glycosylation) quality of the humoral immune response. Secondly, data generated under this consortium is likely to provide key insights into the specific assays that interrogate and capture readouts of protective immunity. Linked to Ag discovery, qualified, and validated assays may be rapidly developed and deployed to support the evaluation of current and future vaccines. Finally, these data may provide critical clues for the generation of functionally optimized monoclonal therapeutics that can act to complement or replace current antibiotic strategies, considering the emergence of multi-drug resistance. The results will be presented locally (MLW, COMREC and Joint COM/MLW Research Dissemination conference), nationally, and internationally including other partner sites in the sero-epidemiology work package of the VacciNTS consortium contributing to key knowledge for vaccine development and deployment. This will have relevance for policy decision regarding iNTS control in Malawi and other sub-Saharan African countries. Results will be submitted for publication in a peer reviewed academic journal.
- ItemRestrictedA pharmacokinetic randomised interventional study to optimise dihydroartemisinin-piperaquine dosing for malaria preventive treatment in Malawian infants (OPTIMAL Study) version 1.0(Kamuzu University of Health Sciences, 2022-09-08) Banda, Clifford George Dr.Type of study This is an open-label randomised interventional study (with 1:1 allocation into intervention and control groups) to optimise the dosing of an antimalarial drug, dihydroartemisininpiperaquine (DP), administered with routine vaccinations, for malaria preventive treatment in infants. Problem to be studied The World Health Organisation (WHO) recommends the use of sulphadoxine-pyrimethamine (SP), administered with routine immunisation, for intermittent preventive treatment of malaria in infancy (IPTi) in areas of moderate to high transmission in sub-Saharan Africa. However, there is limited uptake of this recommendation and increasing resistance of malaria parasites to SP. Fortunately, another antimalarial drug, DP, has shown higher protective efficacy than SP. Nevertheless, there is a paucity of evidence to guide its optimal dosing when administered together with routine vaccinations in infancy. The present study seeks to define the optimal dose of DP for IPTi when administered with routine vaccinations. Overall objective The overall objective of this study is to define the optimal dose of DP for IPTi when administered with routine vaccinations Specific objectives 1. To describe age-related changes in population pharmacokinetic properties of piperaquine following partially supervised administration of IPTi-DP at four different routine immunization time points in infancy (i.e., at 10-, 14 weeks, 6 months, and 9 months of age). 2. To evaluate the association between piperaquine exposure and incidence of symptomatic and asymptomatic malaria during IPTi-DP. 3. To compare the safety and tolerability of DP following supervised administration of IPTi-DP at routine immunizations with routine immunizations alone. 4. To apply population pharmacokinetic modelling and simulation techniques to optimise the dose of piperaquine when administered as IPTi-DP Methodology 220 infants will be randomised, from 10 weeks of age, to receive DP with routine vaccines (intervention group, n=110) or standard of care; routine vaccines only (control group, n=110). They will be followed up until 12 months of age. In the intervention group, infants will contribute capillary samples for piperaquine concentrations, at different time points after administration of DP, and capillary samples to quantify malaria parasitaemia using microscopy and quantitative PCR. In the control group, infants will contribute capillary blood samples at the same time points as those in the intervention group for malaria parasitaemia over the first year of life. Additionally, the safety and tolerability of DP for IPTi with routine vaccinations will be monitored by comparing adverse events in the intervention and control groups Expected findings and their dissemination Optimised dosing regimens of DP for IPTi will be developed by applying population pharmacokinetic-pharmacodynamic modelling techniques on data obtained from: 1. Understanding age-related changes in piperaquine pharmacokinetics from infants in the intervention group. 2. Evaluating the pharmacokinetics, efficacy and safety of DP for IPTi in infants in the intervention group compared with malaria incidence and adverse events in the control group. This work will provide the much-needed evidence to inform DP dosing for IPTi when administered with routine immunisation. Additionally, it will inform future work on optimal DP dosing for malaria treatment in infants. The findings will be disseminated to study participants, in peer-reviewed scientific journals, WHO, national malaria control programs in malaria-endemic settings and ethics committees that will review and approve the study (COMREC, LSTM REC and UCT HREC).
- ItemRestrictedPredicting acute and post-recovery outcomes in cerebral malaria by Optical Coherence Tomography(Kamuzu University of Health Sciences, 2022-06-02) Beare, NicholasType of study This is an observational cohort study of children with cerebral malaria (CM) and other comas conducted at a single-site. We will assess ocular imaging techniques as methods to identify severe brain swelling during the acute illness, and predict neurodevelopmental deficits after CM. Problem Children in Africa continue to die in large numbers from CM, mostly with severe brain swelling. New treatments for severe brain swelling and to reduce intracranial pressure (ICP) in CM are under clinical trial, but rely on MRI scans to identify severe brain swelling. Hardly any children with CM have access to MRI scanning, so those likely to benefit from new treatments are not identifiable. Children in coma for other causes would also benefit from the identification of raised intracranial pressure. Children who survive CM are at high risk of neurological and developmental complications. It is thought that this may be due to cerebral ischaemia but at present there is no method to identify these children other than waiting for their deficit to become manifest. Identifying CM patients at risk of neurological deficit or developmental delay would enable early intervention. Identifying a link between cerebral ischaemia and neurodevelopmental deficit (NDD) would also support the development of new treatments for CM which mitigate ischaemic injury. Optical Coherence Tomography (OCT) is a non-invasive ocular imaging modality which uses low-coherence light to obtain detailed cross-sectional images of the retina and optic nerve head (ONH). The ONH swells with raised intracranial pressure (papilloedema). Objectives Broad objective To develop an OCT based bedside test to identify and quantify brain swelling in CM and other comas, and predict NDD in CM. Specific objectives 1. To determine the accuracy of OCT measures of ONH swelling to detect severe brain swelling in children with CM compared to brain MRI. 2. To ascertain the accuracy of OCT measures of macular ischaemia to predict NDD in children with CM at 1 and 2 years post-recovery. 3. To establish if large accumulation of retinal haemorrhages predicts progression to severe brain swelling in children with CM. 4. To determine if OCT measures of ONH swelling can detect and quantify raised ICP in other comas in children. 5. To establish if a low-cost handheld OCT with AI analytics and tested to ISO standard can replace the commercially available OCT and human image analysis. Methodology Participants will be recruited on admission with CM and other comas. During the acute illness participants will have OCT of the ONH and macula, and fundus imaging, in addition to standard care which includes funduscopy and an MRI brain scan. Children with CM will be followed up over 2 years with OCT, MRI and neurodevelopmental assessments. We will test the value of OCT-measured ONH parameters to identify severe brain swelling determined by MRI (gold standard). We will use Receiver Operating Characteristic (ROC) curves to determine the utility of OCT of the ONH to identify severe brain swelling, and which parameter(s) have the best specificity and sensitivity.OCT in CM. Version 32.0. Date 14th 2nd Mayrch 2022 6 of 20 Formatted: Superscript OCT of the retina can identify retinal ischaemia manifest as hyper-reflective signal. Similar statistical methods will be employed to determine the value of OCT of the central retinal (macula) to identify patients developing NDD (either at discharge or during follow up). Children will have Malawi Developmental Assessment Tool (MDAT)(<5yrs) or Kaufman Assessment Battery for Children (ABC)(>5yrs) developmental assessment as well as Liverpool Outcome Score to identify NDD over two years. Expected findings and dissemination We expect to find that OCT of the ONH can identify patients with severe brain swelling, and to determine which ONH parameter(s) has the best sensitivity and specificity. The links between retinal, cerebral ischaemia and neurological outcomes in CM are less well established, but the study will determine whether OCT of the macula has predictive value for NDD. The study findings and results will be shared in a timely manner with COMREC, UoL sponsor, QECH Medical Director and Wellcome Trust. Results will be presented at Malawi, UK and international scientific meetings, and by open-access publication (as required by the funder). This will include the KUHeS Research Dissemination Day and MLW Annual Scientific Meeting.