Abstract
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.
Data availability
The dataset used and analyzed in the present study is available from the corresponding authors upon reasonable request.
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S.C. and L.W.K. designed the project, oversaw the experiments, and wrote the manuscript. S.C., S.J.S., and L.W.K. contributed to the design of the vaccine construct. S.J.S. and A.A. cloned the vaccine and conducted an analysis of the sequencing data. A.A., E.O., and S.C. optimized the mouse injection protocol and carried out the immunization of the mice. Z.D. developed and optimized assays for the production of SARS-CoV-2 pseudovirus and its neutralization. M.P. and K.A. prepared and organized all mouse samples and conducted the analysis of the antibody response to the S protein. S.S., Z.D., and A.A. performed FACS and subsequently analyzed the data. Z.D., J.B., S.J.S., and A.A. conducted the data analysis and contributed to the manuscript revision.
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Cha, SC., Szymura, S.J., Anderson, A. et al. Vaccine-derived T-cell responses are insufficient to generate protective immunity to SARS-CoV-2. Sci Rep (2026). https://doi.org/10.1038/s41598-026-44391-x
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DOI: https://doi.org/10.1038/s41598-026-44391-x
