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com.Human cytomegalovirus (HCMV) infections are among the most common complications arising in transplant patients, elevating the risk of various complications including loss of graft and death. HCMV infections are also responsible for more congenital infections worldwide than any other agent. Cyclosporin A concentration Congenital HCMV (cCMV) infections are the leading nongenetic cause of sensorineural hearing loss and a source of significant neurological disabilities in children. While there is overlap in the clinical and laboratory approaches to diagnosis of HCMV infections in these settings, the management, follow-up, treatment, and diagnostic strategies differ considerably. As yet, no country has implemented a universal screening program for cCMV. Here, we summarize the issues, limitations, and application of diagnostic strategies for transplant recipients and congenital infection, including examples of screening programs for congenital HCMV that have been implemented at several centers in Japan, Italy, and the United States. Published by Oxford University Press for the Infectious Diseases Society of America 2020.The natural history of cytomegalovirus (CMV) infection is complex. Individuals may experience primary infection, reactivation of latent infection, or reinfection with a new strain despite natural immunity. The ability of this virus to continue to replicate despite substantial immune responses is attributable to the many immune evasion genes encoded within its genome. Given this complex natural history and immunology, the design of clinical trials of CMV vaccines may require components not usually found in trials of vaccines designed to protect against viruses that cause only acute infections. In this article, we focus on specific aspects of clinical trial design that could be adopted to address the complexities of CMV infections. We consider women of childbearing age, toddlers, recipients of solid organ transplantation, and stem cell transplant patients, emphasizing the parallels between women and solid organ transplantation that could allow vaccines to be developed in parallel in both these patient groups. We emphasize the potential for studies of passive immunity to inform the selection of immunogens as candidates for active immunization and vice versa. We also illustrate how application of whole-genomic sequencing could document whether vaccines protect against reactivation or reinfection of CMV or both. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.The considerable public health burden due to cytomegalovirus (CMV) supports current interest in vaccine development. Clinical studies intended to support regulatory action should be designed to demonstrate substantial evidence of effectiveness. However, design and conduct of clinical endpoint studies may be hampered by low incidence of disease, especially for congenital CMV. Discussion and experience from other vaccines directed against congenital disease (including rubella and Zika) may be instructive. This article summarizes current scientific and US regulatory considerations related to design of studies of vaccines intended to prevent congenital CMV and complications of CMV in transplantation, as discussed at the 2018 workshop entitled "Cytomegalovirus Infection Advancing Strategies for Prevention and Treatment." Published by Oxford University Press for the Infectious Diseases Society of America 2020.The way to a successful vaccine against human cytomegalovirus is hampered by the peculiar biology of this infection. However, some candidate vaccines have been shown to protect seronegative women and transplant recipients, and we should know soon whether they can prevent congenital infection. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV) infections; nevertheless, recent developments in the treatment of CMV infections have resulted in improved human health and perhaps will encourage the development of new therapeutic approaches. First, the deployment of ganciclovir and valganciclovir for both the prevention and treatment of CMV infections and disease in transplant recipients has been further improved with the licensure of the efficacious and less toxic letermovir. Regardless, late-onset CMV disease, specifically pneumonia, remains problematic. Second, the treatment of congenital CMV infections with valganciclovir has beneficially improved both hearing and neurologic outcomes, both fundamental advances for these children. In these pediatric studies, viral load was decreased but not eliminated. Thus, an important lesson learned from studies in both populations is the need for new antiviral agents and the necessity for combination therapies as has been shown to be beneficial in the treatment of HIV infections, among others.