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. The activity of the TIU is centered on studying the ontogeny, maturation and plasticity of protective memory B cell responses in multiple virus models. We use these studies as a rational launchpad toward translation to develop biologics and small molecules against relevant human pathogens. To do this, we use multiple virus models, which include Dengue, Zika, hepatitis C, HIV-1, and influenza viruses. For Hepatitis C virus (HCV), we use information from immune responses to target sites of HCV vulnerability with small molecules whereas for Dengue and Zika flaviviruses we are pursuing multiple related lines of investigation. Virus neutralizing antibodies are protective against numerous viral infections but, while diversity in the antibody repertoire is essential to effective antiviral responses, the engagement of pre-existing B cells stimulated by prior infections with sufficiently similar but distinct pathogens 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 (ADE) in sequential flavivirus infections. In this context, flaviviruses pose an extremely interesting case study with real world repercussions because Zika virus and four serotypes of Dengue virus share the same arthropod vector, are genetically similar and circulate in the same endemic areas. These characteristics put the issue of pre-existing immunity, with its potential for both protective and detrimental effects, at the center of biomedical research in this area (Hardy et al. PLoS Neg Trop Med 2025). Our program aims at defining the impact of sequential heterotypic flavivirus infections on the breadth and cross-reactivity of memory B cells, devising mechanisms to mitigate ADE and/or reduce the burden of disease, and translating our findings into practical interventions via the development of biologics. For Zika, congenital Zika syndrome poses the greatest disease burden and threat to human health. It has been estimated that congenital transmission of ZIKV causes microcephaly and other birth defects in up to 14% of infants born to ZIKV-infected pregnancies. Persistent IgM responses have been documented but only partially characterized in flavivirus infections. We had previously described a ZIKV ultrapotent neutralizing monoclonal antibody of the IgM isotype. Based on this prototype antibody, we are now investigating the development and use of IgM-derived biologics in the prevention of vertical transmission during pregnancy. The program also includes further investigation on the origins and plasticity of IgM-positive memory B cells and the function of IgM responses in both Zika and Dengue infections. Antigenic sin can also play a role in the context of sequential immunization regimens or repeated vaccinations. Sequential multivalent immunizations are being investigated to counter diversity in rapidly mutating viruses, such as HIV. However, the effect of changing immunogen formats on the elicited humoral memory responses is not routinely assessed. In DeLuca et al. (Commun Med, 2025) we demonstrate that a change in immunogen format during an HIV sequential immunization regimen resulted in divergent B cell responses that vastly failed to engage pre-expanded cross-reactive memory responses. These results implicate that a change in immunogen format may cause off-target B cell engagement, but also that B cell repriming is possible despite pre-existing immunity. In line with our analytical, technical and logistical capabilities applicable to the high-throughput evaluation of clinical trials, the TIU is also involved in the assessment of immunogenicity of an NIH-led universal influenza vaccine candidate.