Regulation of the HA stem nanoparticle vaccine response by antigen duration

The immune system of young infants exhibits profound alterations compared to that of older children and adults. Notable among these are lower responses to TLR engagement, reduced dendritic cell maturation, reduced Tfh responses, and a strong Th2 bias. While proposed to be beneficial for establishment of the microbiome and preventing untoward inflammatory responses, these alterations hamper the ability to respond to vaccines. As a result, infants are poor at mounting protective antibody responses following vaccination with standard seasonal influenza vaccines. Consequently, these vaccines are not approved for infants under 6 months of age. An ideal vaccine for young infants would require only a single vaccination to elicit high levels of protective antibody. In our efforts to more fully understand the infant immune response and achieve high levels of protective antibody with a primary vaccine regimen, we explored a prolonged antigen delivery approach. We found that this resulted in significantly increased levels of antibody in infant mice following administration of a nanoparticle vaccine containing only the stem region. Infants vaccinated with a bolus dose of this vaccine had barely detectable antibody at 14 days following vaccination. In striking contrast, infants vaccinated with the prolonged approach elicited a strong stem-specific antibody at d14 that was similar in level to that of adult animals. Notably, there was minimal difference in the bolus versus prolonged approach in adult mice. Together, these data form the foundation for the proposed studies, which seek to understand at a mechanistic level how antigen duration and vaccine construct modulate the infant B and T cell response. At the conclusion of these studies, we will have gained novel insights into the regulation of the infant influenza-specific immune response. These findings have important implications for the rational design of novel vaccine approaches that can be used in this at-risk population.