Development of vaccine approaches to elicit broadly protective influenza-specific immune responses in infants

Influenza virus infection of neonates can lead to life-threatening disease. The rate of LRTI-associated
hospitalizations is >4 times higher in children less than 1 year of age compared to those between 1 and 4
years and infants younger than 6 months of age are particularly vulnerable to the development of severe
disease. Current influenza vaccines on the market are not approved for infants <6 months of age as a result of
their limited effectiveness in this age group. Overcoming this poor responsiveness will require development of
vaccines with greater immunogenicity in this population. Another important area of investigation is the ability of
infants to respond to universal vaccines designed to provide protection across multiple strains of influenza.
While targeting production of these antibodies by vaccination is highly desirable, our understanding of how
effectively newborns can produce them or the accessory signals that can optimally elicit these antibodies is
unknown. The ultimate goal of the studies proposed in this application is to identify a vaccine approach for
influenza that is safe and broadly protective when delivered to neonates. To evaluate potential strategies, we
will use our established African green monkey (AGM) nonhuman primate neonate model. Using this model we
previously found that conjugation of the TLR7/8 agonist R848 to inactivated influenza promotes significant
increases in virus-specific IgG and IFNγ-producing T cell responses, providing rationale for the continued
exploration of this adjuvant in neonates. We will utilize R848 together with heterologous boost or an HA stem
construct as approaches to elicit broadly reactive antibody. As part of our analyses we will evaluate the role of
Tfh responses in modulating broadly reactive antibody quantity and quality. The results of these studies will
provide mechanistic as well as practical information that may lead to the improved design of vaccines that will
be efficacious in the vulnerable neonate population.

Grant Number: 5R01AI146059-04
NIH Institute/Center: NIH
Principal Investigator: Martha Alexander-Miller