Our laboratory seeks to develop vaccines that can protect newborns from life-threatening disease. Our current work focuses on influenza. Infants younger than 6 months of age are particularly vulnerable to the development of severe disease following infection with influenza virus. While effective vaccines are available, they are not approved for infants <6 months of age due to their poor efficacy in this age group. Our laboratory is focused on identifying the roadblocks to effective immunity in newborns and the development of vaccines that can overcome them.
In our quest to achieve this goal, our work evaluates vaccine platforms and adjuvants in the context of newborn and infant immune system in animal models. Past and ongoing work has explored TLR agonists, e.g. R848 and flagellin, as well as MF59-like adjuvants. In addition to identifying platforms and stimulatory signals that can overcome the alterations present in the newborn immune system, we are exploring the potential for universal vaccines to provide protection across multiple strains of influenza virus. While targeting the generation of broadly reactive antibodies by vaccination is highly desirable, we are just beginning to understand the capacity for newborns to produce them or the immunostimulatory signals needed to optimally elicit these antibodies.
Finally, our lab is working to understand how maternal antibody regulates the response to influenza vaccination in newborns. At present, we have a limited understanding of the ways in which maternal antibodies transferred in utero alter the immune response of the infant to vaccination. Understanding the maternal antibody attributes that are important for regulating the newborn response will guide the development of vaccines that generate portent responses in the face of maternal antibodies.
Research Highlights
One of the challenges to identifying effective stimulatory signals for neonate immune responses is the inability to perform studies in human infants. To overcome this limitation, we have employed a nonhuman primate neonate model, which is similar to humans in TLR distribution and function, which are the immune modulators targeted in our experimental vaccines. We have assessed the ability of flagellin, a toll like receptor 5 (TLR5) agonist, mixed with inactivated influenza virus as well as R848, a TLR7/8 agonist, conjugated to the virus to induce protective responses. While both adjuvants increased antibody responses, the R848 containing vaccine was superior to the flagellin containing vaccine as judged by its ability to induce higher antibody after one dose of vaccine. Adjuvanting with R848 also resulted in a significantly increased number of influenza-specific T cells as well as reduced lung pathology following virus challenge.
Our most recent work has focused on mechanistic studies of adjuvant function e.g. the immune cells targeted by the vaccine. We are also developing second generation vaccines. In these studies we have identified an alternative linker for joining R848 to the virus that results in significantly enhanced DC maturation, suggesting it may be superior in vivo. Studies are underway to understand the mechanism of the increased stimulatory capacity of this vaccine.
Vaccination Research at Wake Forest University School of Medicine
Dr. Martha Alexander-Miller is developing influenza vaccines that will work in young infants.