Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire

Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T cell responses as well as protection against lethal SARS-CoV-2 challenge in human ACE2 transgenic mice. In HLA-A2.1 transgenic mice, the RdRp vaccine elicits CD8+ T cell responses against HLA-A*02:01-restricted epitopes recognized by human donor T cells. These results highlight RdRp as a candidate antigen for COVID-19 vaccines. The findings also offer insights into crafting effective multivalent mRNA vaccines to broaden CD8+ T cell responses against SARS-CoV-2 and potentially other viruses with pandemic potential.

Authors

Institutions

Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-11-26
DOI
https://doi.org/10.1073/pnas.2406332121
Citations
4
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
1.56

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire

Amanda L. Creech, Ting Wu, Caius G. Radu, Miyako Noguchi et al.
4 citations
Proceedings of the National Academy of Sciences
SARS-CoV-2 and COVID-19 Research
1.56
article

Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire

Amanda L. Creech, Ting Wu, Caius G. Radu, Miyako Noguchi, Khalid Rashid, Giselle Burton Sojo, Lucio Comai, Arjit Vijey Jeyachandran, Ying K. Tam, Evan R. Abt, Pavlo A. Nesterenko, Norbert Pardi, Alex K. Lam, Vaithilingaraja Arumugaswami, Jill Henley, Wendy Tran, Owen N. Witte, Zhiyuan Mao, Donghui Cheng, Pu-Lin Teng, Jami McLaughlin
article en
4 citations

Abstract

Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T cell responses as well as protection against lethal SARS-CoV-2 challenge in human ACE2 transgenic mice. In HLA-A2.1 transgenic mice, the RdRp vaccine elicits CD8+ T cell responses against HLA-A*02:01-restricted epitopes recognized by human donor T cells. These results highlight RdRp as a candidate antigen for COVID-19 vaccines. The findings also offer insights into crafting effective multivalent mRNA vaccines to broaden CD8+ T cell responses against SARS-CoV-2 and potentially other viruses with pandemic potential.

Proceedings of the National Academy of SciencesVol. 121(49)
University of Southern California (US), University of California, Los Angeles (US), Black AIDS Institute (US), Parker Institute for Cancer Immunotherapy (US), Acuitas Therapeutics (Canada) (CA), Broad Center (US), University of Pennsylvania (US)
W. M. Keck Foundation, California HIV/AIDS Research Program, National Institutes of Health, University of California, Los Angeles, National Cancer Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
Good health and well-being
Openalex Percentile: Top 16%
SARS-CoV-2 and COVID-19 Research
1.56
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.