SUMMARY
RNA-based vaccines against SARS-CoV-2 are critical to limiting COVID-19 severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. We used single-cell technologies to identify and characterized antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 in longitudinal samples from a cohort of healthy donors. Mass cytometry and machine learning pinpointed a novel expanding, population of antigen-specific non-canonical memory CD4+ and CD8+ T cells. B cell sequencing suggested progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlated with eventual SARS-CoV-2 IgG and a donor lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms reveal an antigen-specific cellular basis of RNA vaccine-based immunity.
ONE SENTENCE SUMMARY Single-cell profiling reveals the cellular basis of the antigen-specific response to the BNT162b2 SARS-CoV-2 RNA vaccine.
Competing Interest Statement
EMW receives research funding from Boehringer-Ingelheim and is a member of their myositis ILD advisory board. ARS and ISG are co-founders of AbSeek Bio. RHC is an inventor on patents related to other SARS-CoV-2 antibodies. JEC has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines and is Founder of IDBiologics. JEC has received sponsored research agreements from Takeda Vaccines, IDBiologics and AstraZeneca. JMI was a co-founder and a board member of Cytobank Inc. and has engaged in sponsored research with Incyte Corp, Janssen, Pharmacyclics. JCR is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics, a scientific advisory board member and stockholder of Caribou Biosciences, a member of the scientific advisory board of Nirogy Therapeutics, has consulted for Merck, Pfizer, and Mitobridge within the past three years, and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. No other author reports a competing interest.
- ABBREVIATIONS
- BCL6
- B-cell lymphoma 6 protein
- BCR
- B cell receptor
- COVID-19
- Coronavirus disease 2019
- cTfh
- Circulating T follicular helper
- CyTOF
- Cytometry by Time-of-Flight mass spectrometry
- CYTOC
- Cytochrome C
- dsRNA
- Double stranded ribonucleic acid
- FACS
- Fluorescence activated cell sorting
- ICOS
- Inducible T cell costimulator
- LIBRA-seq
- Linking B cell receptor to antigen specificity through sequencing
- MEM
- Marker Enrichment Modeling
- mRNA
- Messenger ribonucleic acid
- SARS-CoV-2
- Systemic acute respiratory syndrome coronavirus 2
- S protein
- Spike protein
- TLR
- Toll-like receptor
- T-REX
- Tracking responders expanding
- VSV
- Vesicular stomatitis virus
