Origin and maturation of protective memory B cell responses against pathogenic viruses in natural infections and upon vaccination.

National Institute Of Allergy And Infectious Diseases

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Abstract

The human immune system generates a diverse repertoire of pathogen-binding proteins called antibodies secreted by terminally differentiated short- and long-lived plasma cells as well as antigen-experienced B cells which constitute a pool of memory B cells that can further mature upon re-engagement in recall responses. Virus neutralizing antibodies are the correlate of protection for many licensed vaccines. While diversity in the antibody repertoire is essential to respond to infections, it can also lead to differential engagement of B cell subpopulations with repercussions on the function of the de novo and recall response. The phenomenon of antigenic sin has been documented for influenza and the severity of potential antibody-dependent enhancement of infectivity in sequential flavivirus infections is currently a controversial topic of concern. Recent studies also suggest that the impact of cross-reactive pre-existing immunity may play a previously underappreciated role in B cell recruitment for viral antigenic epitopes that include a glycan component. Moreover, despite extensive investigations and considerable progress, highly mutating viruses still present considerable challenges to the development of effective (e.g. HCV and HIV-1) or durable vaccines (e.g. influenza virus), as they can quickly escape control from neutralizing antibodies. In these cases, vaccine formulations that comprise multiple immunogens, administered either concomitantly or sequentially, are likely needed to elicit adequately affinity matured broadly neutralizing antibodies. Therefore, furthering our understanding of the ontogeny and maturation of memory B cell responses in the contexts of natural infection and vaccination is essential to inform successful immunogen design strategies and better understand the development of humoral immunity during natural infections. The activity of the TIBU is centered on studying the ontogeny and maturation of protective memory B cell responses in multiple virus models to identify novel and generalizable criteria pertaining B cell maturation. In this context, a special area of interest of the TIBU pertains the origins and role of IgM-positive memory B cells, using flaviviruses as a model.