NIAID CEIRS | Research Publication Commentary
Currently, the most effective method to prevent influenza is vaccination with a seasonal trivalent or quadrivalent vaccine containing antigens of H1N1, H3N2, and one or two type B strains of influenza. A new vaccine is developed each year to match the season’s circulating influenza strains. Influenza vaccination is less effective in elderly adults than in younger adults, and the molecular mechanisms underlying this difference are unclear. As the majority of influenza-related deaths are in the elderly, it is important to understand why the vaccine is less effective in this population because a more effective vaccine has the potential to save lives. To address this question, Drs. Bali Pulendran (Emory-UGA CEIRS) and Helder Nakaya (now an assistant professor in the School of Pharmaceutical Science at University of São Paulo), along with Dr. Shankar Subramaniam and Thomas Hagan (UCSD), teamed up with a group of international researchers and used a so-called “systems vaccinology approach.” This approach was pioneered by Bali Pulendran’s laboratory and integrates quantitative measurements, genomics, and computational models to search for signatures that predict high immune responses following vaccination. Importantly, their study looks at immune responses across multiple years, with a unique trivalent vaccine used each year. This helped the researchers to differentiate between changes due to annual variation in flu vaccine versus variation in the immune responses of their study populations of elderly adults and young adults.
The authors examined immune responses to seasonal influenza vaccine for five consecutive influenza seasons. Baseline transcriptional signals (prior to vaccination) associated with B and T cell activation were positively correlated with a robust antibody response after vaccination. B and T cells are part of the adaptive immune response that leads to the creation of antibodies. Conversely, signals related to monocytes were associated with a decreased antibody response, particularly genes involved in inflammatory responses. Systems analysis revealed that for individuals with a strong immune response 28 days after vaccination, both the young and the elderly had transcriptional signatures related to the interferon response and activation of dendritic cells, both of which link the innate and adaptive immune responses. These relationships are consistent across age groups and years, demonstrating that molecular signatures can be effective predictors of antibody development following vaccination.
A closer examination of transcriptional signatures revealed important differences between the young and elderly. Younger subjects had higher levels of B cell activation signals following vaccination, while elderly patients had diminished B cell activation signals and stronger signatures related to natural killer cells and monocytes. Weaker B cell signals may help to explain why antibody production following vaccination decreases with age and support the concept that inflammatory pathways activated prior to or following vaccination may be detrimental to antibody production, and reduce the effectiveness of the vaccine.
This longitudinal study provided researchers the opportunity to identify conserved molecular signatures of immunogenicity that revealed important aspects of the poor immune response of the elderly following vaccination. The insights provided by Drs. Pulendran, Subramaniam, and colleagues, and further applications of systems vaccinology, will be critical for the development of next-generation vaccines that better protect the elderly and other vulnerable populations from seasonal influenza.
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