Writing in the August 14th issue of Science Translational Medicine, scientists at the Icahn School of Medicine at Mount Sinai described how exposure to seasonal flu viruses over the course of a lifetime influences a person’s antibody repertoire and adaptive immune responses to subsequent infections. The findings, they said, have significant implications for scientists interested in creating a universal flu vaccine, and that boosting broadly neutralizing antibodies will be essential to its development.
Although it is known that immunological memory developed against previously encountered influenza A viruses (IAVs) affects the outcome of subsequent infections, how such sequential exposures to antigenically variant viruses shape the humoral immune response in humans remains poorly understood, the investigators noted.
Since antigenic shift and drift are the primary mechanisms through which IAVs evolve to evade adaptive immunity, most individuals become infected with flu multiple times through the course of their lives. This constant antigenic drift is the reason that influenza pandemics remain one of the greatest threats to global public health.
To better understand how repeated exposures to influenza affect the immune response to repeated flu infections, Dr. Matthew Miller and his colleagues studied blood sera obtained between 1987 and 2008 from participants in the Framingham Heart Study to analyze the anti-flu antibodies present in the samples.
The investigators found longitudinal increases in neutralizing antibody titers against previously encountered pandemic H2N2, H3N2, and H1N1 IAVs. Antibody titers against seasonal strains encountered later in life also increased longitudinally at a rate similar to that against their pandemic predecessors.
Titers of cross-reactive antibodies specific to the hemagglutinin stalk domain were also investigated because they are influenced by exposure to antigenically diverse IAVs. These titers rose modestly over time, even in the absence of major antigenic shifts. No sustained increase in neutralizing antibody titers against an antigenically more stable virus (human cytomegalovirus) was observed.
The results herein describe a role for antigenic variation in shaping humoral (antibody) responses to flu, and provide a rational basis for the hierarchical nature of antibody titers against IAVs in humans, the investigators said. The authors noted that their findings provide insights regarding the regulation of adaptive immunity and the role played by antigenic variation in shaping the humoral immune responses. Understanding the complex patterns of immunological memory development in human populations should be a focus, they suggest, for those attempting to design more long-lasting and efficacious vaccines.