A novel human Neonatal Tissue Construct (NTC) models age-specific immune responses to Bacille Calmette-Guérin (BCG) vaccine (166.27)

Abstract

Abstract Newborns have a distinct immune system that impairs immune responses to many conventional pediatric vaccines rendering them susceptible to preventable infections. Since birth is a reliable point of healthcare contact worldwide, effective single-dose birth immunization could help reduce global morbidity and mortality. However, vaccine development has been largely ad hoc and empiric. Modeling age-specific human immune responses could help predict safety and efficacy of adjuvants and vaccines targeting the newborn. Using human primary endothelial cells, human extracellular matrix, newborn monocytes and 100% autologous intact plasma we assembled the Neonatal Tissue Construct (NTC). In this tri-dimensional micro-vascular interstitium extravasated CD33+ monocytes autonomously differentiated into HLA-DRhigh CD86high and CCR7+ mature Dendritic Cells (DCs) in response to the live mycobacterial BCG vaccine known to be safe and effective at birth, and to induce effector T cell responses. BCG-pulsed NTC-derived DCs induced autologous naïve CD4+ T cell proliferation and activation (CD45RO+, TNF-α), as efficiently as DCs from an Adult Tissue Construct. While newborn and adult DC:T cell co-cultures secreted IL-2 and TNF-α in response to BCG, only newborn cells demonstrated constitutive IL-4 production and a marked impairment in IFN-γ production. In recapitulating neonatal responses to BCG, the NTC demonstrates its potential as a novel platform to study age-specific vaccine responses.