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

Investigators

Linked publications & trials

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 effective antiviral responses, the engagement of pre-existing B cells stimulated by a prior infection can lead to the expansion of suboptimal responses both in the settings of natural infection and upon vaccination. This phenomenon is known as antigenic sin. Antigenic sin has been documented for influenza and it has been evoked as the underlying cause of antibody-dependent enhancement of infectivity in sequential flavivirus infections (e.g., Zika and Dengue viruses). Our prior studies (Williams et al. Cell. 2021 May 27; 128(11):2955) also identified the possibility for glycan-binding antibodies to cross-react with different viruses. Antigenic sin can also play a role in the context of sequential immunization regimens or repeated vaccinations. 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, SARS-CoV-2), 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. In the context of vaccination, the format in which immunogens are presented may also influence the balance between recall and de novo responses. Therefore, furthering our understanding of the ontogeny and maturation of memory B cell responses in the contexts of natural infection and vaccination and the role of cross-reactivity in shaping the memory B cell response are essential to inform successful immunogen design strategies and better understand the natural development of humoral immunity. The activity of the TIU 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. A special area of interest of the TIU pertains the origins, role and plasticity of IgM-positive marginal zone B cells in protection from viral infections, including flaviviruses, for which persistent IgM responses have been documented.