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Longitudinal proteome-wide antibody profiling in Marburg virus survivors identifies wing domain immunogen for vaccine
Surender Khurana1, Gabrielle Grubbs2, Supriya Ravichandran2
1Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, 20993, USA. Surender.Khurana@fda.hhs.gov.
Abstract:
Limited knowledge exists on the quality of polyclonal antibody responses generated following Marburg virus (MARV) infection and its evolution in survivors. In this study, we evaluate MARV proteome-wide antibody repertoire longitudinally in convalescent phase approximately every six months for five years following MARV infection in ten human survivors. Differential kinetics were observed for IgM vs IgG vs IgA epitope diversity, antibody binding, antibody affinity maturation and Fc-receptor interaction to MARV proteins. Durability of MARV-neutralizing antibodies is low in survivors. MARV infection induces a diverse epitope repertoire with predominance against GP, VP40, VP30 and VP24 that persisted up to 5 years post-exposure. However, the IgM and IgA repertoire declines over time. Within MARV-GP, IgG recognize antigenic sites predominantly in the amino-terminus, wing domain and GP2-heptad repeat. Interestingly, MARV infection generates robust durable FcɣRI, FcɣRIIA and FcɣRIIIA IgG-Fc receptor interactions. Immunization with immunodominant MARV epitopes reveals conserved wing region between GP1 and GP2, induces neutralizing antibodies against MARV. These findings demonstrate that MARV infection generates a diverse, long-lasting, non-neutralizing, IgG antibody repertoire that perturbs disease by FcɣR activity. This information, along with discovery of neutralizing immunogen in wing domain, could aid in development of effective therapeutics and vaccines against Marburg virus.
Insights
Marburg virus (MARV) infection elicits a durable, non-neutralizing IgG antibody response targeting viral proteins for up to five years. However, neutralizing antibody levels decline, highlighting potential therapeutic targets.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Limited understanding of antibody responses post-Marburg virus (MARV) infection.
- Need to characterize the long-term antibody repertoire in MARV survivors.
Purpose of the Study:
- To longitudinally evaluate the MARV proteome-wide antibody repertoire in human survivors for five years.
- To analyze antibody kinetics, affinity maturation, and Fc-receptor interactions.
Main Methods:
- Longitudinal sample collection from ten MARV survivors every six months for five years.
- Assessment of IgM, IgG, and IgA epitope diversity, binding, affinity, and Fc-receptor interactions against MARV proteins.
Main Results:
- MARV infection induces a diverse, long-lasting IgG antibody repertoire against GP, VP40, VP30, and VP24 proteins persisting for five years.
- MARV-neutralizing antibody durability is low; IgM and IgA repertoires decline over time.
- Robust and durable IgG-Fc receptor interactions (FcɣRI, FcɣRIIA, FcɣRIIIA) were observed.
Conclusions:
- MARV infection generates a diverse, long-lasting, non-neutralizing IgG antibody repertoire that impacts disease via Fc-receptor activity.
- The conserved wing region of MARV-GP is a potential target for developing neutralizing antibodies, aiding therapeutics and vaccine development.
