A T cell–based SARS-CoV-2 spike protein vaccine provides protection without antibodies
Juan Shi, Jian Zheng, Xiujuan Zhang, Wanbo Tai, Ryan Compas, Jack Deno, Natalie Jachym, Abhishek K. Verma, Gang Wang, Xiaoqing Guan, Abby E. Odle, Yushun Wan, Fang Li, Stanley Perlman, Liang Qiao, Lanying Du
Juan Shi, Jian Zheng, Xiujuan Zhang, Wanbo Tai, Ryan Compas, Jack Deno, Natalie Jachym, Abhishek K. Verma, Gang Wang, Xiaoqing Guan, Abby E. Odle, Yushun Wan, Fang Li, Stanley Perlman, Liang Qiao, Lanying Du
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Research Article COVID-19 Vaccines

A T cell–based SARS-CoV-2 spike protein vaccine provides protection without antibodies

Abstract

SARS-CoV-2 spike–based vaccines are used to control the COVID-19 pandemic. However, emerging variants have become resistant to antibody neutralization and further mutations may lead to full resistance. We tested whether T cells alone could provide protection without antibodies. We designed a T cell–based vaccine in which SARS-CoV-2 spike sequences were rearranged and attached to ubiquitin. Immunization of mice with the vaccine induced no specific antibodies, but strong specific T cell responses. We challenged mice with SARS-CoV-2 wild-type strain or an Omicron variant after the immunization and monitored survival or viral titers in the lungs. The mice were significantly protected against death and weight loss caused by the SARS-CoV-2 wild-type strain, and the viral titers in the lungs of mice challenged with the SARS-CoV-2 wild-type strain or the Omicron variant were significantly reduced. Importantly, depletion of CD4+ or CD8+ T cells led to significant loss of the protection. Our analyses of spike protein sequences of the variants indicated that fewer than one-third presented by dominant HLA alleles were mutated and that most of the mutated epitopes were in the subunit 1 region. As the subunit 2 region is conservative, the vaccines targeting spike protein are expected to protect against future variants due to the T cell responses.

Authors

Juan Shi, Jian Zheng, Xiujuan Zhang, Wanbo Tai, Ryan Compas, Jack Deno, Natalie Jachym, Abhishek K. Verma, Gang Wang, Xiaoqing Guan, Abby E. Odle, Yushun Wan, Fang Li, Stanley Perlman, Liang Qiao, Lanying Du

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Figure 2

SARS-CoV-2 Ub-S DNA vaccine induced strong T cell responses without antibodies in BALB/c mice.

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SARS-CoV-2 Ub-S DNA vaccine induced strong T cell responses without anti...
Mice were immunized with Ub-S DNA vaccine (plus imiquimod adjuvant), full-length S protein vaccine control (plus Alum + MPL adjuvants), or PBS without adjuvant (background control), and boosted twice with the same immunogens plus the respective adjuvants at 3-week intervals. Ten days after the third dose, splenocytes from the mice were tested for S-specific T cell responses, and sera were tested for IgG antibodies specific for the S, N-terminal domain (NTD), receptor-binding domain (RBD), S1, or S2 of SARS-CoV-2. SARS-CoV-2 S–specific CD8+ (A and B) and CD4+ (C and D) T cells were analyzed by flow cytometry. Splenocytes were stimulated with pooled peptides (final concentration 5 μg/mL) from the SARS-CoV-2 S protein predicted to contain both CTL and T helper cell epitopes, and IFN-γ– and TNF-α–producing CD45+CD8+ T cells and IFN-γ– and TNF-α–producing CD45+CD4+ T cells were stained for respective cell surface and intracellular cytokine markers. (E–I) Serum SARS-CoV-2 S–, NTD–, RBD–, S1–, or S2–specific IgG antibodies were tested by ELISA. The ELISA plates were respectively coated with SARS-CoV-2 full-length S protein or its fragments (1 μg/mL), and antibody (Ab) titers were calculated as the endpoint dilution that remained positively detectable. Data are expressed as mean ± SEM of individual samples (for T cell detection) or quadruplicate wells from pooled sera of mice in each group (n = 5). *P < 0.05, **P < 0.01 by ordinary 1-way ANOVA with Tukey’s multiple-comparison test. Experiments were repeated twice, and similar results were obtained.