My laboratory is interested in the regulation of adaptive immunity. We have two major areas of focus
- Development of vaccines for use in neonates
- Regulation of CD4+ and CD8+ T cell responses and following respiratory infection.
Research Highlights
The neonatal immune system is significantly compromised in its ability to mount a protective response, especially following vaccination. This is particularly evident for the influenza vaccine. As a result of its poor effectiveness, the flu vaccine is not licensed for children <6 months of age, leaving them unprotected at a time when they are highly vulnerable to the development of severe disease following infection. Our lab is focused on identifying the roadblocks to effective immunity in newborns and the development of vaccines that can overcome them.
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.
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 School of Medicine
Dr. Martha Alexander-Miller is developing influenza vaccines that will work in young infants.