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Author Spotlight: A Pseudotype Virus System for Assessing Omicron Subvariants and Neutralizing Antibodies in SARS-CoV-2 Research
Published on: September 8, 2023
Antigen presentation dynamics shape the antibody response to variants like SARS-CoV-2 Omicron after multiple
Leerang Yang1, Matthew Van Beek1, Zijun Wang2
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
The Omicron variant of SARS-CoV-2 is not effectively neutralized by most antibodies elicited by two doses of mRNA vaccines, but a third dose increases anti-Omicron neutralizing antibodies. We reveal mechanisms underlying this observation by combining computational modeling with data from vaccinated humans. After the first dose, limited antigen availability in germinal centers (GCs) results in a response dominated by B cells that target immunodominant epitopes that are mutated in an Omicron-like variant. After the second dose, these memory cells expand and differentiate into plasma cells that secrete antibodies that are thus ineffective for such variants. However, these pre-existing antigen-specific antibodies transport antigen efficiently to secondary GCs. They also partially mask immunodominant epitopes. Enhanced antigen availability and epitope masking in secondary GCs together result in generation of memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.
Insights
A third mRNA vaccine dose boosts neutralizing antibodies against the Omicron variant by generating memory B cells targeting less mutated epitopes. This enhances protection against SARS-CoV-2 variants.
Area of Science:
- Immunology
- Virology
- Computational Biology
Background:
- Two mRNA vaccine doses elicit antibodies poorly effective against SARS-CoV-2 Omicron variant.
- A third dose significantly enhances neutralizing antibody responses against Omicron.
Purpose of the Study:
- To elucidate the immunological mechanisms behind the increased neutralizing antibody response after a third mRNA vaccine dose.
- To understand how B cell responses adapt to SARS-CoV-2 variants like Omicron.
Main Methods:
- Combined computational modeling with immunological data from vaccinated humans.
- Analyzed B cell responses, germinal center dynamics, and antibody neutralization.
Main Results:
- Limited antigen in germinal centers after two doses favors B cells targeting immunodominant epitopes mutated in Omicron.
- Pre-existing antibodies from prior doses facilitate antigen transport and epitope masking in secondary germinal centers.
- This leads to the generation of memory B cells targeting subdominant, less mutated epitopes.
Conclusions:
- The third mRNA vaccine dose expands memory B cells targeting subdominant epitopes, boosting anti-Omicron neutralizing antibodies.
- This mechanism explains enhanced protection against SARS-CoV-2 variants after booster vaccination.
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