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<p>Neutralizing antibodies are established correlates of protection against SARS-CoV-2, yet T-cell responses are also thought to contribute substantially to limiting disease severity and enhancing durability of protection. To examine whether cellular immunity alone can confer protection, we engineered DNA vaccines encoding modified Spike proteins, including C-terminal truncation (SARS-CoV-2-ΔC, ΔC) and cleavage-site–deleted, linker-inserted (SARS-CoV-2-Linker-ΔT, Linker-ΔT) variants, with or without genetic fusion to MIP3α, which has been shown to enhance targeting of antigen-presenting cells (APC) and preferentially induce T-cell responses. In BALB/c mice, ΔC constructs induced non-neutralizing Spike- and RBD-binding antibodies across variants, as well as robust CD4 + and CD8 + T cell responses, whereas Linker-ΔT elicited strong Th1-skewed cellular immunity in the absence of humoral responses. In K18-hACE2 mice antibody neutralizing activity was not detected by any of the vaccines, and none conferred protection following lethal virus challenge, despite robust specific T-cell cytokine responses. These findings support chemokine-fusion strategies to enhance T cell priming, while indicating that the cellular immunity elicited by this vaccine alone does not confer protection against SARS-CoV-2. Integrating such APC-targeting strategies with structural modifications that preserve pre-fusion neutralizing epitopes may be worthwhile.</p>

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Vaccine-derived T-cell responses are insufficient to generate protective immunity to SARS-CoV-2

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月20日

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  • Soung-Chul Cha,
  • Szymon J. Szymura,
  • Aaron Anderson,
  • Zhenyuan Dong,
  • Anmol Kandel,
  • Elizabeth Oh,
  • Michael Palmer,
  • Kevin Arango,
  • Jibin Zhang,
  • Larry W. Kwak

摘要

Neutralizing antibodies are established correlates of protection against SARS-CoV-2, yet T-cell responses are also thought to contribute substantially to limiting disease severity and enhancing durability of protection. To examine whether cellular immunity alone can confer protection, we engineered DNA vaccines encoding modified Spike proteins, including C-terminal truncation (SARS-CoV-2-ΔC, ΔC) and cleavage-site–deleted, linker-inserted (SARS-CoV-2-Linker-ΔT, Linker-ΔT) variants, with or without genetic fusion to MIP3α, which has been shown to enhance targeting of antigen-presenting cells (APC) and preferentially induce T-cell responses. In BALB/c mice, ΔC constructs induced non-neutralizing Spike- and RBD-binding antibodies across variants, as well as robust CD4 + and CD8 + T cell responses, whereas Linker-ΔT elicited strong Th1-skewed cellular immunity in the absence of humoral responses. In K18-hACE2 mice antibody neutralizing activity was not detected by any of the vaccines, and none conferred protection following lethal virus challenge, despite robust specific T-cell cytokine responses. These findings support chemokine-fusion strategies to enhance T cell priming, while indicating that the cellular immunity elicited by this vaccine alone does not confer protection against SARS-CoV-2. Integrating such APC-targeting strategies with structural modifications that preserve pre-fusion neutralizing epitopes may be worthwhile.