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 4

Vaccine-induced protection from infection is mediated by CD8+ T cells.

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Vaccine-induced protection from infection is mediated by CD8+ T cells. (...
(A) The cytolytic and antiviral activity of different cell types induced by vaccination was analyzed by the diagrammed experimental scheme. Mice were immunized twice with 1 × 106 DCs transduced with CD40L or CD40L-N219-227 vector. At 7 days after second immunization, splenic CD8+ T cell, CD4+ T cell, DC, and B cell populations were isolated on magnetic beads. A portion of the cells was analyzed in an in vitro cytolytic assay in which the cells were mixed with the CFSE-labeled SARS-CoV-2–infected naive lung cells of hACE2-KI mice and the number of lysed cells was quantified by flow cytometry. A portion of each population was reinfused into recipient mice (n = 5), which were challenged 5 days later with SARS-CoV-2 WA1/2020. (B) Seven days after the second immunization, the fraction of antigen-specific CD8+ and CD4+ T cells in splenocytes was quantified by flow cytometry using tetramers for the N219-227 epitopes. (C) Cytolytic activity of the CD4+ T cells, CD8+ T cells, DCs, and B cells of control CD40L alone and CD40L-N219-227 vector–immunized mice was analyzed with the assay diagrammed in A using SARS-CoV-2–infected primary mouse lung epithelial cell targets. (D) Splenic CD8+ T cell, CD4+ T cell, DC, and B cell populations from immunized mice were reinfused into recipient mice (n = 5). At 5 days postinjection, mice were challenged with SARS-CoV-2 WA1/2020. Subgenomic viral RNA in the lungs of the mice was quantified 3 dpi. Statistical significance was determined by Kruskal-Wallis test with post hoc Dunn’s test. Confidence intervals are shown as the mean ± SD. (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.) The experiment was done twice with similar results.