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

• 成果类型: Article
• 署名作者: Abt, Evan R.; Lam, Alex K.; Noguchi, Miyako; Rashid, Khalid; Mclaughlin, Jami; Teng, Pu - Lin; Tran, Wendy; Cheng, Donghui; Nesterenko, Pavlo A.; Mao, Zhiyuan; Creech, Amanda L.; Sojo, Giselle Burton; Jeyachandran, Arjit Vijey; Tam, Ying K.; Henley, Jill E.; Comai, Lucio; Pardi, Norbert; Arumugaswami, Vaithilingaraja; Witte, Owen N.; Radu, Caius G.; Wu, Ting- Ting
• 署名单位: University of California System; University of California Los Angeles; University of Southern California; University of Pennsylvania; UCLA Jonsson Comprehensive Cancer Center; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11100
• DOI: 10.1073/pnas.2406332121
• 发表日期: 2024-12-03
• 关键词: lipid nanoparticles; immune-response; mice

摘要

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.