Single-epitope T cell–based vaccine protects against SARS-CoV-2 infection in a preclinical animal model
Takuya Tada, Ju-Yi Peng, Belinda M. Dcosta, Nathaniel R. Landau
Takuya Tada, Ju-Yi Peng, Belinda M. Dcosta, Nathaniel R. Landau
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Research Article COVID-19 Immunology

Single-epitope T cell–based vaccine protects against SARS-CoV-2 infection in a preclinical animal model

Abstract

Currently authorized COVID-19 vaccines induce humoral and cellular responses to epitopes in the SARS-CoV-2 spike protein, though the relative roles of antibodies and T cells in protection are not well understood. To understand the role of vaccine-elicited T cell responses in protection, we established a T cell–only vaccine using a DC-targeted lentiviral vector expressing single CD8+ T cell epitopes of the viral nucleocapsid, spike, and ORF1. Immunization of angiotensin-converting enzyme 2–transgenic mice with ex vivo lentiviral vector–transduced DCs or by direct injection of the vector induced the proliferation of functional antigen-specific CD8+ T cells, resulting in a 3-log decrease in virus load upon live virus challenge that was effective against the ancestral virus and Omicron variants. The Pfizer/BNT162b2 vaccine was also protective in mice, but the antibodies elicited did not cross-react on the Omicron variants, suggesting that the protection was mediated by T cells. The studies suggest that the T cell response plays an important role in vaccine protection. The findings suggest that the incorporation of additional T cell epitopes into current vaccines would increase their effectiveness and broaden protection.

Authors

Takuya Tada, Ju-Yi Peng, Belinda M. Dcosta, Nathaniel R. Landau

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Figure 5

Direct lentivirus injection protects mice from SARS-CoV-2 infection.

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Direct lentivirus injection protects mice from SARS-CoV-2 infection. (A)...
(A) Schematic of direct lentivirus immunization. A total of 5 × 106 IU lentiviral vector encoding CD40L and T cell epitopes N219-227, N105-113, ORF11637-1646, S539-546, and N219-227-S539-546. Lentiviral vectors were injected into hACE2-KI mice IV (n = 6). One week after the first immunization, the mice were re-immunized. One week or 30 days following the second immunization, the mice were challenged with 2 × 104 PFU SARS-CoV-2 WA1/2020. (B) One week (left) or 30 days (right) following the second immunization, SARS-CoV-2 subgenomic viral RNA in the lung was quantified 3 dpi with SARS-CoV-2 WA1/2020. (C) Splenocytes were analyzed for the CD3+, CD8+, CD4+, and SARS-CoV-2–specific TCR+CD8+ T cells by flow cytometry. (D) IFN-γ, TNF-α, perforin, and IL-2 levels in TCR+CD8+ T cells were quantified by flow cytometry. (E) Naive, effector, and central memory T cells were distinguished by CD62L and CD44, then determined the population of naive (CD62LhiCD44lo), effector (CD62LloCD44hi), and central memory cells (CD62LhiCD44hi). The results are summarized in the pie charts on the right. The percentage of naive, effector, and central memory cells of uninfected, unimmunized, and CD40L-immunized mice is shown (top). The percentage of naive, effector, and central memory T cells from CD40L-N105-113–, CD40L-N219-227–, CD40L-ORF11637-1646–, CD40L-S539-546–, and CD40L-N219-227- S539-546–immunized mice (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001) is shown (bottom). Statistical significance was determined by Kruskal-Wallis test with post hoc Dunn’s test. Confidence intervals are shown as the mean ± SD. The experiment was done twice with similar results.