Implementing Vaccine and Treatment Evaluation Unit (VTEU) Clinical Site

University Of Maryland Baltimore, Baltimore MD

Investigators

Linked publications & trials

Abstract

DMID 24-0003 PROMISE “A prospective, quasi-interventional Phase 4 study of the safety and serology of maternal RSVpreF (ABRYSVO) vs. infant nirsevimab (BEYFORTUS) vs. administration of both products in infants during the first year of life”. Summary/Abstract RSV is the leading cause of lower respiratory tract infections in infants and young children. It is also a leading cause of mortality in children <5 years of age worldwide. Until recently, no FDA-approved vaccines were available to prevent RSV infection in infants. Only the monoclonal antibody palivizumab was available to high-risk infants, but administration was limited to those with extreme prematurity, chronic lung disease, or hemodynamically significant congenital heart disease. However, in 2023, the FDA approved two products designed to prevent RSV lower respiratory tract disease in all infants: an active RSV vaccine based on the pre-fusion F protein (RSVpreF, ABRYSVO, Pfizer) administered during pregnancy and a passive, long-acting monoclonal antibody (nirsevimab, BEYFORTUS, AstraZeneca) administered to infants at birth or at the start of the first RSV season. Both products have been evaluated in phase 3 pivotal clinical trials and have been found to have high efficacy in the prevention of RSV lower respiratory tract disease in infants. However, the magnitude and durability of antibody responses following administration of the products have not been directly compared. Furthermore, the added benefit of administering both products to an infant has not been characterized. While cost-effectiveness analyses have demonstrated that administration of both products is not cost-effective or indicated for most infants, it is likely that some infants may receive both products inadvertently, and still others may benefit from both. These include infants born to women who may not have mounted adequate antibody response to vaccination (e.g. due to immunocompromise, prematurity, or insufficient time from vaccination to delivery) or who may have had impaired antibody transfer across the placenta (e.g. due to placental pathology). It also includes high-risk infants (e.g. with prematurity or chronic lung disease) who may benefit from an interval dose of nirsevimab to protect in the setting of waning antibodies and off- season RSV circulation. Thus, understanding the safety and serology of administration of both products vs. either product alone is of clinical and public health importance. These knowledge gaps underly the objectives for this study. DMID 23-0006 ETEC “A Phase 2b, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy of Intramuscularly Administered CssBA+dmLT against Moderate-severe Diarrhea in a Controlled Human Infection Model with Enterotoxigenic Escherichia coli (ETEC) Strain B7A in Healthy Adults” Summary/Abstract Enterotoxigenic Escherichia coli (ETEC) is an important cause of bacterial diarrhea resulting in significant morbidity and mortality, especially in children under 5 years of age living in low-and middle-income countries (LMIC) and travelers visiting LMICs. Annually, ETEC is estimated to cause approximately 220 million diarrheal episodes globally, with about 75 million of those episodes occurring in children <5 years of age, resulting in more than 40,000 deaths. Asymptomatic ETEC infection, or repeated episodes of diarrhea with various pathogens including ETEC, have been correlated with malnutrition, stunted growth, and impaired cognitive development. The pathogenicity of ETEC is associated with the production of colonization factors (CFs) heat-labile (LT) and heat-stable (ST) toxins. Coli surface antigen 6 (CS6) is a widely expressed ETEC CF that mediates bacterial attachment to the small intestinal epithelium. Blocking CF adherence is thus thought to be an effective means to prevent infection. This has resulted in a CF/enterotoxin-targeted approach as the primary strategy for many of the current ETEC vaccines in development. In an open-label Phase I clinical trial, the current prototype CS6-based subunit vaccine (CssBA) was safe and well-tolerated with vaccine-related adverse events (AEs) consisting predominately of short- lived vaccine site reactions. Based on the safety and robust immunogenicity of CssBA, we now will evaluate the efficacy of this vaccine using a controlled human infection model (CHIM).