2023 Department of Pediatrics Academic Annual Report

Internationally, William Britt, M.D., and Drs. Boppana and Fowler have an ongoing project in Brazil (supported by the NIH). In Brazil, more than 30,000 women and their newborn infants are being enrolled in studies to define the natural history of congenital CMV infection in a population of women with universal immunity to CMV, a critical question in the design of prophylactic vaccines for this infection. Studies in Brazilian women and their offspring were initiated by Dr. Britt nearly 20 years ago and have provided significant information on the role of maternal immunity and congenital CMV infections that are designed to identify sources of virus infection in these women. The Brazilian study will also address the potential impact of behavioral interventions in the prevention of reinfections in pregnant women. Importantly, this team has proven that congenital infection can occur in seropositive women, albeit at a lower rate than primary infection. This finding has major complications for vaccine development. These studies are supported by the NIH and Merck & Co. Veronica Sanchez, Ph.D., and Drs. Britt, Boppana, Ross and Pinninti all lead robust laboratory research programs as well, with studies in basic molecular virology, virus-host interactions and correlates of protection. A significant effort led by Dr. Britt has been focused on understanding the role of virus-induced inflammation and brain development in a small animal model of CMV infection of the developing central nervous system. This system was developed in collaboration with investigators in Erlangen, Germany, and this collaboration continues today. This system has pointed to the role of inflammation in altered cell positioning in the developing brain, a finding that recapitulates aspects of the pathology of brain disease in infants with congenital CMV infection. A second major focus of this project is defining mechanisms of hearing loss in infants with congenital CMV infections. This small animal model closely recapitulates the findings of hearing loss in infants with congenital CMV infection, and findings generated from studies in this system have identified mechanisms of hearing loss, which include virus-induced inflammation. Dr. Britt has established an active collaboration with investigators in Croatia who have considerable expertise in innate immunity. This active collaboration in this area of study has been ongoing for more than 25 years. Dr. Sanchez has several ongoing projects that directly address key steps in the assembly in infectious CMV. Together with Dr. Britt, Dr. Sanchez’s research will enhance our understanding of fundamental aspects of virus replication and virus-host interactions. This work involves several projects directed at dissecting the roles of cellular and viral factors in the efficient production of infectious virus, which may identify novel targets for development of antiviral agents. In addition, these studies have explored the regulation of cellular functions by virus-encoded microRNAs. ANTIVIRAL THERAPIES PROGRAM Major clinical trials of the treatment of life-threatening viral infections have been performed by David Kimberlin, M.D., and Richard Whitley, M.D. Over the past three decades, their NIH-funded work has established the standard of care for the management of neonatal herpes simplex virus (HSV) disease and congenital cytomegalovirus (CMV) infection. New studies being conducted include leading the NIH’s assessment of Acute Flaccid Myelitis (AFM), which includes steering a group of up to 43 study sites in the United States, Canada, the United Kingdom and Peru. Through the Congenital and Perinatal Infections Consortium (CPIC), a member of the NIH Rare Diseases Clinical Research Network (RDCRN), large multicenter natural history studies of neonatal enteroviral and parechoviral sepsis are being conducted. Clinical Phase 1 trials of valacyclovir and letermovir in neonates are being launched, as is a retrospective follow-up study to determine the durability of treatment benefit on hearing in children previously enrolled in congenital CMV studies in the 2000s and 2010s. The Congenital and Perinatal Infections Consortium brings together 31 study sites, led by Dr. Kimberlin, to investigate the natural history and treatment of herpes simplex virus, cytomegalovirus and enterovirus in the neonatal population. Scott H. James, M.D., utilizes conventional and next-generation DNA sequencing techniques to identify and characterize treatment emergent antiviral resistance and viral subpopulations with diminished susceptibility to antiviral drugs from treated babies. ANTIVIRAL DRUG DEVELOPMENT AND DISCOVERY PROGRAM Dr. James leads an interdisciplinary team of investigators to help select molecules with optimal antiviral activity against a broad array of DNA viruses. In partnership with the NIH’s in vitro antiviral screening program, an NIH R01 subaward, as well as through independent research collaborations, Dr. James’ group provides preclinical data to support drug development and human clinical trials. The expertise of his laboratory has been expanded from herpesviruses and orthopoxviruses to a broad range of DNA viruses, including the adenoviruses, polyomaviruses and papillomaviruses. Collaborative research endeavors designed to serve the wider research community in the development of novel antiviral agents have led to national and international partnerships among universities, biotech companies and nonprofit organizations. Preclinical work performed in this laboratory has helped to support the advance of five drugs for the treatment of viral infections into clinical trials: maribavir (for CMV), brincidofovir (for CMV), tecovirimat (for smallpox) and most recently, filociclovir (for CMV), N-Methanocarbathymidine (for VZV) and ABI-1968 (for HPV). Dr. James’ antiviral program employs the study of antiviral drug resistance to help understand the molecular mechanisms of action of novel compounds and to help manage their clinical use. Molecular biology and reverse genetic techniques are used to identify the molecular targets of antiviral drugs in DNA viruses and to describe the essential functions of these enzymes in viral replication. Dr. James led preclinical studies of the novel compounds filociclovir and brincidofovir, including mechanism of action studies, in vitro efficacy and toxicity assays, and genomic studies of laboratory-generated resistant strains of CMV. In partnership with the Collaborative Antiviral Study Group and the Congenital and Perinatal Infections Consortium, his team also investigates the emergence of resistance to antiviral therapies during clinical trials in infants and children with viral infections and has characterized the rates of resistance in pediatric patients. Corollary to his area of research expertise, Dr. James has also been recruited to serve on an international multidisciplinary workgroup to develop clinical practice guidelines on the use of antiviral agents in children with COVID-19.

2023 Academic Annual Report

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