Clinical Research Directory

The Natural History of Severe Viral Infections and Characterization of Immune Defects in Patients Without Known Immunocompromise

Background: * Infections caused by viruses are common causes of illnesses: the common cold, many ear infections, sore throats, chicken pox, and the flu are caused by different viruses. Usually, these illnesses last only few days or, at most, a few weeks. Some virus infections like influenza are cleared from the body, and others such as the chicken pox virus remain in the body in an inactive state. However, some people may become quite ill when they are infected with a particular virus, possibly because part of their immune system does not respond properly to fight the virus. * Researchers have discovered some reasons why a person may not be able to clear an infection caused by a virus. Some persons have changes in the genes that involve the immune system that result in the inability to properly control infection with a particular virus. Identifying changes in genes that involve the immune system should help scientists better understand how the immune system works to protect people from infection and may help develop new therapies. Objectives: * To study possible immune defects that may be linked to a particular severe viral infection. * To determine if identified immune defects are genetic in origin. Eligibility: * Individuals of any age who have or have had a diagnosis of a virus infection that physicians consider to be unusually severe, prolonged, or difficult to treat. * Relatives of the participants with a severe viral infection may also participate in the study. We will use their blood and/or skin specimens to try to determine if identified immune defects are hereditary. Design: * Prior to the study, the participant's doctor will give researchers the details of the infection, along with medical records for review. Eligible participants will be invited to the NIH Clinical Center for a full evaluation as an outpatient or inpatient. * At the Clinical Center, participants will be treated with the best available therapy for the particular viral infection, and researchers will monitor how the infection responds to the treatment. * Researchers will take intermittent blood samples and conduct other tests (such as skin biopsies) to evaluate the immune system. - During and after the illness, researchers will conduct follow-up visits to determine the course of infection and response to therapy.

De-novo Initiation of Letermovir vs Valganciclovir for Cytomegalovirus Prophylaxis in AA Kidney Transplant Recipients

This study is being done to compare the effectiveness of de novo Letermovir versus valganciclovir in preventing the development of cytomegalovirus viremia or symptomatic disease in African American kidney transplant recipients within the first year after transplantation. There are two arms in the study: Arm 1: Prophylaxis: This group includes freshly transplanted high risk (CMV D+/R-) African American Kidney recipients who will be on prophylactic Letermovir for 6 month. Arm 2: Prophylaxis: This group includes high-risk African American kidney transplant recipients who had already completed the 6 month prophylactic course with the standard of care Valganciclovir.

ID-ENTITY Trial- Evaluating Serial T-ID Monitoring

To evaluate the association between time-updated CMV and BK viral loads measured monthly by T-ID and the risk of CMV disease and/or biopsy-proven BK virus-associated nephropathy (BKVAN) during the first 12 months following kidney transplantation, accounting for the net immune environment (TTV viral load) and allograft injury (donor-derived cell-free DNA, dd-cfDNA).

Combination Letermovir and Standard of Care Antiviral for Enhanced Antiviral Response in Cytomegalovirus Infection in Lung Transplant Recipients

The primary objective of the CLEAR-CMV trial is to evaluate the efficacy of letermovir therapy plus standard of care (SOC) antiviral compared to SOC plus placebo in achieving clearance of CMV viremia by week 3 in lung transplant recipients with active CMV infection.

Efficacy of Extended Letermovir Prophylaxis to Prevent CMV Reactivation in High-Risk Chinese Adults Undergoing Allogeneic HSCT

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), recipients are immunocompromised and at increased risk of complications, including cytomegalovirus (CMV) infection. International clinical guidelines for the management of CMV infection post-allo-HSCT recommend three main strategies: minimizing infection risk, prevention, and preemptive therapy. However, traditional antiviral agents have not been approved for CMV prophylaxis in allo-HSCT recipients and are associated with significant adverse effects and the development of resistance, leaving the CMV prevention needs of this patient population unmet. Recent studies have demonstrated that letermovir prevents potent and highly specific antiviral activity against CMV, and it has been approved for CMV prophylaxis within the first 100 days post-allo-HSCT. Furthermore, evidence suggests that extending letermovir administration up to 28 weeks further reduces the risk of CMV infection in the later post-transplant period without increasing drug-related mortality. In China, the post-allo-HSCT CMV prevention strategy faces challenges such as limited treatment options, unclear guideline recommendations, non-standardized drug usage in certain medical institutions, and insufficient monitoring. This study aims to provide robust, evidence-based support for the use of letermovir in high-risk CMV reactivation among adult allo-HSCT recipients, thereby broadening clinical treatment choices.

VIROMARKERS GA n.101194735 - CMV and TTV Biomarkers Study Protocol

The study is one of the researches carried out in the VIROMARKERS Project. The project VIROMARKERS is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement No 101194735. The JU receives support from the European Union's Horizon Europe research and innovation programme and COCIR, EFPIA, Europa Bio, MedTech Europe, Vaccines Europe, and Roboscreen. To date, the virological surveillance for CMV replication relies basically on the quantification of CMV-DNA in blood or plasma by using Real-Time PCR assays, and CMV-DNAemia is known to correlate with both CMV-related disease and non-relapse mortality \[Ljungman, 2025\]. However, the detection of CMV-DNAemia is not always associated with an active CMV replication, particularly in patients exposed to letermovir. Therefore, the identification of new virological markers to accurately monitor CMV activity in the early and late post-HSCT phases, remains a crucial issue especially in individuals receiving letermovir as prophylaxis to ensure a proper diagnosis of CMV infection/disease and to guide prophylactic and pre-emptive antiviral treatment. In this setting, the quantification of CMV-RNA represents a potential candidate marker capable of better reflecting the presence of complete, infectious CMV virions than CMV-DNAemia. Despite several data support a correlation of CMV UL21.5-mRNA with viral activity \[Nicastro, 2025\], studies investigating the kinetics of this viral mRNA among immune-suppressed patients at risk of CMV re-uptake are largely missing, especially in the setting of patients receiving antiviral prophylaxis with letermovir after HSCT. TTV-DNA load was mostly investigated in solid organ transplant patients (SOT), where it showed a good correlation of high viral load and degree of immunosuppression. In HSCT patients the interaction of the immune system, which is under reconstitution, and clinically relevant CMV infection is more complex. First data have been reported by our group \[Gilles et al., 2017\] showing high TTV load as a prognostic marker for risk of complications after HSCT. Little information is available for HSCT patients under letermovir prophylaxis. Specific primary objectives related to CMV monitoring in the HSCT setting are the following: Primary In participants who received HSCT, to estimate the rate of initiation of anti-CMV therapy during letermovir-based prophylaxis and the rate of CMV re-activation (based on symptoms, signs of organ dysfunction and CMV-DNAemia) after suspension of letermovir. To evaluate the kinetics of CMV-RNAemia, CMV-DNAemia and TTV-DNAemia and their correlation during prophylaxis with letermovir. To establish whether early quantitative CMV-RNA level or the early kinetics of CMV-RNAemia and TTV-DNAemia during prophylaxis can predict initiation of anti-CMV therapy. In participants not initiating anti-CMV therapy during prophylaxis, to establish whether quantitative CMV-RNA level at time of letermovir suspension or the kinetics of CMV-RNAemia and TTV-DNAemia during prophylaxis can predict CMV re-activation (based on symptoms signs of organ dysfunction and CMV-DNAemia) after suspension of letermovir. Secondary objectives include to establish a cut-off for CMV-RNAemia and TTV DNAemia to maximize the accuracy of prediction of CMV re-activation after suspension of prophylaxis; to explore the kinetics of CMV-RNAemia and TTV-DNAemia in participants treated with anti CMV drugs. The information used from this study on participants in the HSCT setting will be rapidly analyzed and shared broadly to guide policymakers for the use and monitoring of CMV-DNAemia, CMV-RNAemia and TTV-DNAemia in CMV disease and to design future studies. For exact plans regarding the expected date of study completion and plans for dissemination please refer to separate documents produced within the WP5 of VIROMARKERS.

Phase 3 Randomized Trial for Refractory ADV or CMV Infection With Family Matched CTLs and Standard of Care (SOC) vs SOC Alone

Patients with refractory ADV or CMV infection post allogeneic stem cell transplant will be randomized to either Family donor-derived viral specific cytotoxic T lymphocytes (CTLs) plus standard of care (SOC) vs SOC alone.

CMVIG Prophylaxis in Belatacept Conversion Kidney Transplant Recipients

The purpose of this study is to study how CMVIG interacts with the body and to see if it might work to prevent kidney transplant patients from becoming infected with CMV.

CMV-TCIP Directed Letermovir Prophylaxis After Allo-SCT

This is a phase 2, prospective cohort clinical trial evaluating the utilization of CMV T Cell Immunity Panel (CMV-TCIP) assay to guide the duration of primary CMV prophylaxis in CMV-seropositive recipients of allogeneic stem cell transplant or recipients receiving a stem cell graft from a CMV serology positive donor.

Efficacy and Safety of Low-dose IL-2 in SLE Patients With CMV Viremia

This clinical trial will assess the efficacy and safety of low-dose interleukin-2 (IL-2) treatment in systemic lupus erythematosus (SLE) complicated with cytomegalovirus (CMV) viremia.

Expansion of Virus-Specific Lymphocytes for Cell Therapy

Infections and reactivation of human cytomegalovirus (CMV), adenovirus, Epstein-barr and polyoma virus infections are frequent causes of morbidity and mortality and are a source of serious complications in patients undergoing allogeneic bone marrow transplantation. In this project we will prepare specific T lymphocytes from blood donor, select cells CMV-specific by interferon gamma capture and treat patients with CMV viral infections. These cells will be used as antiviral therapy in transplanted patients whom do not respond to conventional therapies or in patients whose conventional therapy may be toxic in the context of transplantation. In this context, CMV reactivation can lead to serious complications in patients, such as irreversible neurological changes, pulmonary, gastrointestinal and ophthalmologic complications, among others, in addition to prolonged hospitalizations, leading to significant morbidity and mortality , both in the health sector public as private. This project may represent an important therapeutic modality using cell of the shelf as a source of therapy for different patients and contributing to reduced morbidity / mortality after transplantation, as well as a reduction in the hospitalization period.

Prophylaxis of Cytomegalovirus Infection With Adoptive Cell Inmunotherapy

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality for recipients of allogeneic hematopoietic stem cell transplantation(HSCT). Recently, strategies based on immunotherapy adoptive cells (IAC) with anti-CMV Cytolitic T Lymphocytes (CMV-CTLs) has been incorporated to prevent or treat CMV after HSCT. The aim to study donor derived CMV-CTLs after haploidentical HSCT (HAPLO) as prophylaxis for CMV infection in transplant patients. CMV-CTLs will be administer at day 21 (+-7 days) post-HAPLO. CMV DNA levels with quantitative PCR will be weekly monitored.

Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants

The overall goal of this study is to determine the clinical benefit and safety of antiviral therapy for asymptomatic congenital cytomegalovirus (cCMV) infected hearing-impaired infants. We will conduct a multi-center double-blind randomized placebo-controlled trial to determine whether hearing-impaired infants with asymptomatic cCMV have better hearing and language outcomes if they receive valganciclovir antiviral treatment. We will also determine the safety of antiviral valganciclovir therapy for asymptomatic cCMV-infected hearing impaired infants. This study will be unique in that the cohort enrolled will only include hearing-impaired infants with asymptomatic cCMV. Primary Objective: To determine if treatment of cCMV-infected hearing impaired infants with isolated hearing loss with the antiviral drug valganciclovir reduces the mean slope of total hearing thresholds over the 20 months after randomization compared to untreated cCMV-infected infants with isolated hearing loss. Main Secondary Objectives: 1. To determine if valganciclovir treatment improves the following outcomes when compared to the control group: 1. The slope of best ear hearing thresholds over the 20 months after randomization. 2. The MacArthur-Bates Communicative Development Inventory (CDI) percentile score for words produced at 20 months of age. 2. To evaluate safety measures based on all grade 3 or greater new adverse events designated by the NIAID Division of AIDS (DAIDS) toxicity tables.