Clinical Research Directory

Positron Emission Tomography and Organ-Specific Changes in Participants Co-Enrolled in NIH Studies of Plasmodium Vivax Controlled Human Malaria Infection

Background: Malaria is a serious disease caused by parasites spread by mosquitoes. To better diagnose and treat malaria, researchers need to learn more about where the parasites go when they enter a person's body. They want to see if they can locate the malaria parasites in the body using imaging scans. Objective: To learn whether imaging scans can locate parasites in people with malaria. Eligibility: Healthy people aged 18 to 54 years. They must be enrolled in protocol IRB001970 or IRB002627 for controlled malaria infection. Design: Participants will be screened. They will have blood drawn and a physical exam, including an abdominal exam to check the size of their spleen. Participants for this study will have 2 or 3 positron emission tomography/computed tomography (PET/CT) scans: The first will be about 3 days before they are deliberately infected with malaria for a different study. The second will be about 13 days later, while they have the disease. The third scan is optional; it will be done about 3 and 1/2 weeks after the second scan. For each scan, participants will receive a radioactive tracer called fluorodeoxyglucose (FDG). FDG will be injected through a tube inserted into a vein. They will lie on a table that slides through a doughnut-shaped machine. PET/CT uses x-rays to create images of the inside of the body. All participants will have a follow-up visit about 3 and 1/2 weeks after the second scan. The blood draw and physical exam will be repeated. This visit may be combined with the third scan for those who choose it.

Host and Parasite Factors That Influence Susceptibility to Malaria Infection and Disease During Pregnancy and Early Childhood in Ouelessebougou and Bamako, Mali

Malaria caused by Plasmodium falciparum continues to be a global problem with devastating consequences. A greater understanding of the immunologic and parasitologic factors associated with infection and disease is badly needed; and will accelerate the development of highly protective vaccines for both mothers and children. Pregnancy malaria is associated with low birth weight, maternal anemia, and gestational hypertension, and both inflammation and the fetal response to infection may contribute to these poor outcomes. Childhood malaria is a major cause of mortality, and we have found that its risk is related to in utero exposure to pregnancy malaria, as well as other host factors like iron status and constitutive cytokine levels. Pregnancy malaria is caused by a distinct parasite binding phenotype, and as our primary hypothesis in this study we speculate that severe childhood malaria parasites may also have distinct features. A longitudinal cohort study will be conducted in Ouelessebougou, Mali, an area of intense seasonal transmission. Up to 2000 pregnant women and their infants and 2000 children aged 0-3 years will be enrolled and followed to age 5 years, with clinical evaluation and periodic venous and peripheral blood samples being obtained. In addition, up to 3000 febrile hospitalized and non-hospitalized children up to 10 years ofd age will be enrolled at the Ouelessebougou district health centers or the Gabriel Toure Pediatric Hospital in Bamako, Mali, with acute and convalescent samples being obtained and 500 pregnant women enrolled at the health centers and hospital in Ouelessebougou district or the Gabriel Toure Hospital in Bamako for a case-control study on pregnancy malaria and preeclampsia. Up to 1000 children originally enrolled at birth and completed the "pregnant women and their newborns study" will be re-enrolled and followed for up to 10 years as they age from later childhood through adolescence to early adulthood. Clinical, parasitologic and host response (including immunologic) endpoints will be analyzed using appropriate statistical methods, including possible confounders, to determine factors associated with infection and disease in pregnant women and young children....

Laboratory Evaluation of Pregnancy Malaria Vaccine Candidates/In-vitro Testing of Pregnancy Malaria Vaccine Candidates

Background: \- Malaria is a disease that affects many people in African countries. It is caused by germs that are spread by mosquito bites. It can be fatal if not diagnosed and treated right away. Children younger than 5 and pregnant women are most at risk to get malaria. Researchers want to create a vaccine that will prevent malaria infection during pregnancy. Objectives: \- To create a vaccine that will prevent malaria infection during pregnancy. To assess possible vaccines using in-vitro tests with parasites taken from pregnant women. Eligibility: \- Pregnant women ages 15-25 Design: * The study site is an area in Mali, West Africa. * Participants: * Will have blood drawn. * Will give consent for the blood sample to be used for future research. * May have a physical exam. * Participants who have malaria or anemia will get treatment.

Collection of Human Biospecimens for Basic and Clinical Research Into Globin Variants

Background: Blood disorders like sickle cell disease and malaria affect many people around the world. Researchers want to learn more about blood disorders. To do this, they need to collect biological samples from people with blood disorders. They also need to collect samples from healthy people. Objective: To collect samples to use for research on blood disorders. Eligibility: People ages 18-70 who have blood disorders. Healthy volunteers without blood disorders are also needed. Design: Participants will be screened with a medical history, physical exam, and blood and urine tests. Participants will give one or more samples. They will give them over 5 years. They can choose not to give any of the samples: Saliva: Participants will spit into a tube. They may also have the inside of their mouth swabbed. Urine: Participants will urinate into a cup. Blood and blood waste products: Blood will be taken through a needle in the participant s arm. Fat samples: An area on the participant s belly or buttock will be numbed. A small cut will be made into the skin and a small piece of fat removed. Mucus and cells from the lungs: The participant will be sedated. A flexible tube will be inserted through the nose or mouth into the lung airways. These participants will also have a physical exam, chest x-ray, and heart tests after the procedure.

Evaluation, Treatment and Monitoring of Patients With a Known or Suspected Parasitic Infection

The purpose of this study is to evaluate, treat and follow patients with parasitic infections. People with a known or suspected parasitic infection who are at least 1 year old may be enrolled. This study does not involve any experimental treatments. Participants will have a physical examination and laboratory tests on blood, stool, or urine. Blood samples may be collected at regular intervals, but no more than 450 ml (15 ounces) of blood will be drawn from adults, and no more than 7 ml (1-1/2 teaspoons) per kg (2.2 pounds) of body weight from children, in any 6-week period. Other tests may include x-rays, electrocardiogram (EKG), or tissue biopsy (surgical removal of a small tissue sample), depending on the individual s condition. Patients may be offered treatment or may be referred to another study that is more appropriate for the problem. Any treatment provided in this study will be according to standard medical practice for the patient s specific medical problem. Patients responses to treatment will be evaluated at regularly scheduled clinic visits. The length of time between visits and the total duration of the study for a given individual will be determined by the study doctor, based on that person s medical condition.

L9LS MAb in Malian Infants

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of L9LS in infants in Mali and to evaluate the impact of L9LS on subsequent R21/Matrix-MTM vaccine immunogenicity.

Induced Blood-Stage Malaria in Healthy Malaria-Naive Adults to Assess the Safety and Infectivity of Plasmodium Vivax Challenge Agent and Evaluate Transmission in Mosquito Feeding Assays

Background: Malaria is a disease caused by parasites transmitted to people by mosquitoes. Around the world, there were 241 million cases and 627,000 deaths from malaria in 2020. Researchers are working to develop vaccines and treatments for this disease. Objective: To learn how malaria develops in people; how the body's immune system reacts to malaria; and how malaria spreads from people to mosquitoes. Eligibility: Healthy people in the Washington DC area, aged 18 to 54 years. They cannot live alone during parts of the study. Design: Participants will be infected with a parasite that causes malaria. The parasite will be in donated blood; it will be given through an IV. Participants will likely develop symptoms within a week after the injection. Researchers will call daily to check on their health. After about 6 days, participants will come to the NIH clinic each day for blood tests. Participants will check in to the NIH clinic around 10 days after the injection. They will stay in the clinic 3 to 6 days. They will have multiple blood tests every day. Participants will be bitten by mosquitoes up to 4 times. Cups containing mosquitoes will be held against their skin for 15 minutes. Participants will begin taking chloroquine close to the end of their clinic stay. Chloroquine is a pill taken by mouth once or twice a day for 3 days. It is FDA-approved to treat malaria. Participants will have follow-up visits 1 and 3 weeks after discharge.

Safety, Tolerability, Pharmacokinetics, and Mosquitocidal Activity of Lotilaner in Healthy Participants in Mali.

This is a Phase 1b, single-cente, randomized, double-blind, placebo-controlled proof-of-concept study evaluating the safety, tolerability, pharmacokinetics and mosquitocidal activity of single oral doses of lotilaner in healthy, adult participants living in Mali.

Malaria Rapid Diagnostic Tests (RDTs) in Pregnancy: Detection of Placental Malaria

This study seeks to determine whether screening pregnant women for malaria with malaria rapid diagnostic tests (RDTs) may detect placental infection and predict risk of poor birth outcomes due to malaria in areas of varied malaria transmission in Africa.

Validation of a CDSA Strategy to Reduce Antibiotic Prescription in Senegal

This trial aims to validate a novel clinical care strategy based on a electronic clinical decision support algorithm (CDSA) combined with point of care rapid diagnostic tests by evaluating its impact on antibiotic prescription and clinical outcome of children and adolescent presenting at primary healthcare facilities with non-severe acute illness compared to routine practice. The trial also aims to assess the usability of the CDSA strategy. The study will be conducted in primary healthcare facilities across different epidemiological regions of Senegal.

Safety Evaluation of PfSPZ Vaccine in Pregnant Women in Mali (MalVIP1)

Background: Malaria is a disease that affects many people in Africa. It is caused by germs carried by some mosquitoes. A person bitten by an infected mosquito will get malaria. Most malaria infections cause only mild symptoms or none at all, but sometimes the disease can be deadly. Malaria can also harm pregnant women. They may lose their pregnancies or deliver too early, and the mother and newborn may die. An experimental malaria vaccine (PfSPZ) has shown some protection against malaria infection. It is not yet known if PfSPZ is safe for pregnant women. Objective: To test the PfSPZ vaccine in pregnant women. Eligibility: Healthy women aged 18 to 34 years at 14 to 32 weeks gestation with 1 fetus. Design: The study will be in Mali. Participants will have about 40 clinic visits over 20 months. They will be screened. They will have an ultrasound exam and a test of their heart function. They will have blood and urine tests. Participants will receive an injection through a needle into a vein on 3 visits over 1 month. Some will receive the PfSPZ vaccine; others will be injected with salt water. They will not know which injection they are getting. After the last injection, participants will visit the clinic every 2 weeks. They will have blood tests at each visit. After giving birth, participants and their infants will visit the clinic every 2 weeks for 4 months; then they will have visits each month until the infant is 1 year old. The infant will be examined and will have blood tests at each visit.

Intermittent Preventive Treatment of Malaria in School-age Children to Decrease Community Transmission

The CRITICal study aims to estimate the effectiveness of intermittent preventive treatment in school children (IPTsc) with dihydroartemisinin-piperaquine (DP) for reducing community level malaria burden. Given that school-aged children are the primary drivers of transmission, the study hypothesis is that IPTsc will reduce this infectious reservoir and thus the burden of malaria in persons of all ages in surrounding communities.

Perennial Malaria Chemoprevention (PMC) in Cameroon

The Plus Project will assess the impact, operational feasibility, efficacy, effectiveness, and cost-effectiveness of PMC. Specifically, the impact evaluation will involve monitoring a passive cohort of all children in the study area reporting all doses of SP received and the number of confirmed cases of malaria and anaemia, as well as a prospective active cohort of children who will have seven home visits over an 18-month period. The total number of participants is expected to be approximately 2,080 children in the areas served by 35 health centres in Cameroon. The results of this study will allow direct evaluation of the protective efficacy of PMC on malaria incidence, severe anaemia, and malaria mortality.

Perennial Malaria Chemoprevention (PMC) in Côte d'Ivoire

The Plus Project will assess the impact, operational feasibility, efficacy, effectiveness, and cost-effectiveness of PMC. Specifically, the impact evaluation will involve monitoring a passive cohort of all children in the study area reporting all doses of SP received and the number of confirmed cases of malaria and anaemia, as well as a prospective active cohort of children who will have seven home visits over an 18-month period. The total number of participants is expected to be approximately 1568 children in the areas served by 19 health centres in Côte d'Ivoire. The results of this study will allow direct evaluation of the protective efficacy of PMC on malaria incidence, severe anaemia, and malaria mortality.

OPTIMAL LEAP: Optimizing Dihydroartemisinin-Piperaquine IPTsc Intervals to Advance Learning, Executive Function, Attendance, and Antimalarial Resistance Surveillance in Kenyan Schoolchildren

Malaria remains a major cause of illness among school-aged children in sub-Saharan Africa, many of whom carry asymptomatic Plasmodium falciparum infections that may contribute to anemia, inflammation, school absenteeism, and impaired cognitive performance. Intermittent preventive treatment in school-aged children (IPTsc) is recommended by the World Health Organization in settings with moderate-to-high malaria transmission, but the optimal dosing frequency remains uncertain. This cluster-randomized trial will compare monthly versus quarterly administration of dihydroartemisinin-piperaquine (DP) among 1,500 children aged 6-10 years attending six primary schools in Siaya County, Kenya. The primary objective is to determine whether monthly IPTsc results in greater improvements in executive functioning compared with quarterly IPTsc. Secondary objectives include evaluating effects on literacy, numeracy, school attendance, malaria infection, anemia, inflammatory and metabolic biomarkers, and molecular markers of antimalarial resistance.

A Clinical Trial to Evaluate the Safety, Efficacy and Immune Responses After Vaccination With an Investigational RNA-based Vaccine Against Malaria

This was a randomized, dose-escalation Phase I/IIa study to evaluate safety, tolerability, immunogenicity and efficacy of an investigational RNA-based vaccine (BNT165e) for prevention of P. falciparum malaria in healthy malaria-naive adults. The multi-antigen malaria vaccine (designated BNT165e) is a combination of three distinct RNAs, BNT165c and BNT165d (composed of BNT165d1 and BNT165d2), encoding P. falciparum antigens encapsulated in lipid nanoparticles. The BNT165c RNA encodes the full Plasmodium falciparum circumsporozoite protein. The BNT165d1 and BNT165d2 RNAs both encode conserved, immunogenic segments of liver stage-expressed proteins.

Screening of Healthy Volunteers for Investigational Antimalarial Drugs, Malaria Vaccines, and Controlled Human Malaria Challenge

Background: Malaria is a serious infection caused by a parasite. People get malaria when an infected mosquito bites them. Malaria can cause major health and social problems in places were malaria is common, such as Africa but can also affect travelers who have never been exposed to malaria. Researchers at the NIH want to find a safe and effective malaria vaccine, antimalarial drugs, or prevention regimen. To do this, healthy volunteers are recruited under a general screening study in order to see if are qualified to join a future malaria study. Objective: To screen healthy volunteers to see if they are eligible to join investigational malaria studies. The studies will be trials of investigational antimalarial drugs, malaria vaccines, or prevention regimens. They may also involve controlled human malaria infection trials. Eligibility: Healthy people ages 18 50 Design: Participants will first be prescreened by phone. Participants will be screened with: Medical history Physical exam Blood and urine tests Participants may go more than 1 year without joining a clinical trial. If this happens, they may be re-contacted to see if they still want to be part of this screening protocol. Those who still want to participate and have had relevant medical changes will be rescreened.

Evaluation of a Comprehensive School Health Programme in Zambia

In Zambia, the health and well-being of children aged 5 to 14 has often been overlooked, leading to various health challenges affecting their development and education. The Healthy Learners (HL) program, in collaboration with the Zambian Government, aims to address this gap by implementing a comprehensive school health program. Trained teachers, known as school health workers (SHWs), play a key role by delivering health education, coordinating preventative care with local clinics, and overseeing a 'school health room' for sick students. This study is a large cluster-randomized control trial in 225 schools. The goal of this trial is to compare the effects of the comprehensive school health programme (SHP) developed by HL against two alternatives: the current level of school health provision and the current school health activities enhanced with deworming and vitamin A coordination by HL, with their technical and financial support ensuring the reliable delivery of all health activities currently planned by the government. 1. What is the impact of the program on health-seeking, health, and education outcomes? 2. What are the indirect effects of the program on teachers and clinics? 3. What is the added value of such a comprehensive SHP, compared to (i) optimized (ii) or imperfect (status-quo) delivery of a limited range of school health activities (e.g., deworming and vitamin A supplements)? 4. How costly is the comprehensive SHP, and what factors affect its implementation? 5. What are the potential benefits of the program for long-term human capital accumulation (learning, well-being etc)?

First-in-Human PfSPZ-LARC2 Vaccination/CHMI

This randomized, double-blind, placebo-controlled, Phase 1 trial will enroll up to 22 malaria-naïve, adult participants to test safety, tolerability, immunogenicity, and efficacy of the genetically attenuated Plasmodium falciparum sporozoite vaccine (PfSPZ-LARC2) Vaccine. PfSPZ-LARC2 Vaccine is a late-arresting, replication-competent whole Plasmodium falciparum sporozoite product. We hypothesize that the PfSPZ-LARC2 Vaccine will be safe from breakthrough infection by virtue of deletion of two key parasite genes Mei2 and LINUP and may be more immunogenic and protective than previously tested early arresting sporozoite vaccines. The primary objective is to assess the tolerability and safety of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation.

A Study of the Plasmodium Falciparum Malaria Vaccine Candidate Pfs48/45 in Matrix-M Adjuvant in the UK

This is an open label, single-site, first-in-human, dose-escalation Phase Ia study to assess safety and immunogenicity of the Plasmodium falciparum malaria vaccine candidate Pfs48/45 in Matrix-M adjuvant in healthy adults living in the UK

A Study of Oral E1018 in Healthy Adult Participants

The primary purpose of the study is to evaluate the safety and tolerability of single ascending oral doses of E1018 in healthy adult participants and to evaluate the pharmacokinetics (PK) of E1018 in plasma and urine after single oral dose administration.

Assessing Vaccine Effectiveness of R21/Matrix-M Across Malaria Transmission Settings (AVERT)

The AVERT study is a prospective observational test-negative case control study evaluating the real-world effectiveness of the R21/Matrix-M malaria vaccine among children younger than 5 years in Burkina Faso and Uganda. Children who seek outpatient care with suspected malaria and are eligible for the national R21/Matrix-M vaccination program will be enrolled. Malaria infection will be determined by blood smear microscopy. Children with a positive microscopy result will be classified as cases and children with a negative result as controls. Vaccination history, including the number and timing of doses, will be obtained primarily from vaccination cards or other written records. Vaccine effectiveness will be estimated by comparing the odds of vaccination among cases and controls.

A Clinical Study of Piperaquine, Pyronaridine, and Artesunate Administered in Combination in Healthy Adults

This is an open-label pharmacokinetic study in 24 healthy Thai participants. Participants will be admitted in the inpatient ward and each participant will attend a total of 4 visits, including one screening visit and three hospital admissions. Participants will be randomized into one of six groups. Each group will receive 3 drug regimens consisting of (1) piperaquine, (2) pyronaridine plus artesunate, or (3) piperaquine, pyronaridine, and artesunate, administered once per day for three consecutive days in different sequential orders. After each regimen, participants will be followed up for six weeks for clinical assessments and laboratory evaluations to study the pharmacokinetics. A washout period of at least eight weeks will be implemented between each regimen. This study is funded by the Global Health Innovative Technology Fund (GHIT Fund), Tokyo, Japan, under grant number G2025-117.

Monoclonal Antibodies in Children With Severe Anaemia or Severe Malaria to Prevent Malaria After Hospital Discharge

Background and rationale: Hospitalised children with severe anaemia remain at high risk of dying or requiring hospital readmission for at least 6 months after discharge. In highly malaria-endemic settings, malaria is a major contributor to these post-discharge readmissions and deaths. In 2022, the World Health Organisation (WHO) recommended post-discharge malaria chemoprevention (PDMC) for children hospitalised with severe anaemia living in malarious areas. Kenya, together with several other countries in sub-Saharan Africa, aims to expand WHO's recommendation and introduce PDMC in children hospitalised with severe anaemia or severe malaria, including children with severe malaria who do not have severe anaemia (e.g. cerebral malaria). PDMC consists of full 3-day treatment courses with long-acting antimalarials given monthly three times after discharge. PDMC is very effective in clinical trials. However, adherence to these monthly 3-day drug treatments is limited under real-life conditions. Furthermore, PDMC provides chemoprevention for about 3.5 months only, while the risk of dying or needing to be readmitted remains high for several more months. The US National Institutes of Health (NIH) has developed two monoclonal antibodies targeting Plasmodium falciparum malaria (mMAb). These proteins specifically target a highly conserved epitope found on the circumsporozoite protein-1 (CSP-1) of P. falciparum to neutralize it and prevent malaria infection. A key feature of mMAbs is that they can provide protection for up to 6 months with a single dose and thus serve as a "long-acting" drug. Recent placebo-controlled studies in healthy adults in Mali suggest that the first mMAb, CIS43LS, when administered at a dose of 40 mg/kg intravenously (IV), can block 88% of malaria infections for at least 6 months. More recently, studies with a newer mMAb called L9LS, which is anticipated to be more potent than CIS43LS, showed a 74% reduction in uncomplicated clinical malaria by 6 months when administered subcutaneously to healthy Malian children aged 6-10 years by a single subcutaneous (SC) dose of 10-20 mg/kg (NCT05304611). Similar studies with L9LS are ongoing in healthy children under 5 years of age in Siaya, western Kenya (NCT05400655). Young children admitted to hospitals in highly malaria-endemic areas with severe anaemia or severe malaria are an ideal target group for passive immunoprevention with mMAbs as a single infusion with mMAb while in the hospital could protect this high-risk group during the entire vulnerable post-discharge period. Overview design: investigators will conduct a 2-arm, multi-centre, individually randomised, placebo-controlled non-inferiority trial in 398 children with severe malaria or severe anaemia. Children will be randomly assigned (1:1) using minimum sufficient balance (MSB) randomisation to receive either mMAb before discharge or 3 courses of monthly PDMC after discharge, according to WHO guidelines. The study will be placebo-controlled. Children in the PDMC arm will receive a placebo infusion with normal saline before discharge; children in the mMAb arm will receive placebo-PDMC. All children will receive standard in-hospital care, including a blood transfusion and treatment for severe malaria where indicated. They will also receive a full 3-day treatment course with the antimalarial artemether-lumefantrine (AL) to clear any existing malaria infections as soon as they have recovered and can take oral medication. The primary endpoint is the incidence of clinical malaria detected by passive case detection by 6 months post-discharge (the intervention period). Key secondary endpoints include the rates of readmissions and deaths (all children). Children will be followed for another 6 months (post-intervention period) to determine the duration of protection, any long-term impact (e.g., growth) and if mMAbs result in a delayed acquisition of natural protective immunity against clinical malaria Study Interventions: All children will receive standard in-hospital care, including a blood transfusion, antibiotics, and treatment for severe malaria where indicated. All children in both arms will be empirically treated for malaria infection around discharge with a 3-day regimen with artemether-lumefantrine to ensure parasite clearance of any existing parasites. Participants in the mMAb arm will receive the study agent L9LS IV with a target dose of 30 mg/kg. The IV dose will use 1 kg step increases. During the 6-month intervention period, children in the placebo-mMAbs arm will receive three courses of monthly PDMC as per WHO guidelines with dihydroartemisinin-piperaquine (DP) at 2, 6 and 10 weeks post-discharge. Those in the mMAbs arm will receive an identical placebo PDMC