Researchers at the Dana-Farber Cancer Institute in Boston, Massachusetts, and the Centers for Disease Control have identified a germline gene in human memory B cells that appear to resist multiple strains of influenza A virus, and more importantly, that can evolve to protect against changes in the viral strains that become active in any given year.1
Wayne A. Marasco, MD, PhD, and his colleagues isolated broadly neutralizing antibodies (bnAbs) for influenza viruses by culturing and activating 237 H3-reactive memory B cells from peripheral blood mononuclear cells (PBMCs) of 7 healthy donors that were specific to antigens CD19+ and CD27+. The memory B cells chosen already had a high affinity to hemagglutinin (HA), a primary target for the development of vaccines that neutralize several types of group 1 and group 2 influenza A viruses.
The HA (with 18 known subtypes) and neuraminidase (NA) proteins (with 11 subtypes) comprise the 2 type A viruses most frequently linked to human influenza outbreaks. Annual influenza strains are likely to contain unique seasonal variations of these two types, which, combined with antigenic drift—in which HA and/or NA mutations occur over the course of 2-3 seasons—contributes to immunologic failure of vaccines, particularly among the elderly.
The current study, published in Nature Communications, demonstrated neutralization of bnAb 3I14 against the two main types of influenza A virus in mice—group 1 (H1, H2, H5, H6, H8, H9, H11, H12, and H16) and group 2 (H3, H4, H7, H14, and H15)—and further, that it cross competed with binding from group 2 bnAb sutbypes (H3, H4, H7 and H14). Specifically, it showed neutralizing potential against group 2 viruses from H3 and H7 subtypes.
The high binding affinity of bnAbs for multiple type A subtypes, particularly those from group 2, may have important clinical implications for the potential creation of vaccines drawn from memory B cells as opposed to those developed traditionally from long-lived plasma cells that produce neutralizing antibodies in response to original virus.
Because memory B cells re-enter germinal centers, they may evolve to accumulate somatic hypermutations (SHMs) within aging individuals to achieve increasingly broader and more diverse levels of specificity over time. This kind of flexibility sets the stage for a potentially universal vaccine that responds to variations and mutations in viral strains.
Dr Marasco and his colleagues recommended a vaccination development strategy that specifically targets the HA stem pathway, in order to enhance the longevity of memory B cells such as 3114, and to encourage greater expansion of their antiviral activity.
- Fu Y, Zhang Z, Sheehan J, et al. A broadly neutralizing anti-influenza antibody reveals onoing capacity for haemagglutinin-specific memory B cells to evolve. Nat Commun. 2016;7:12780, doi:10.1038/ncomms12780.