Conserved CD8 T cell vaccines without B cell epitopes drive robust protection against SARS-CoV-2 that is enhanced by intranasal boost
- Genghao Chen
- Thao Nguyen
- Lindsay G. A. McKay
- Sravya Sowdamini Nakka
- Pan Hu
- Julia McBride
- Anthony C. Liang
- Rachel Olson
- James J. Moon
- Andrew D. Luster
- Anthony Griffiths
- Stephen J. Elledge
2025-11-21
The emergence of SARS-CoV-2 variants has challenged the current spike protein–focused COVID-19 vaccine strategy due to neutralizing antibody escape and waning antibody-mediated immunity. In contrast, T cell–mediated immunity targeting conserved epitopes may offer broad and long-lasting protection. However, whether T cells alone can provide sufficient protection remains unclear. Here, we identified both Omicron BA.1–specific and ancestral (Wuhan)–conserved CD8 T cell epitopes in the SARS-CoV-2 spike protein and evaluated them as carrier-protein fusion vaccines in mouse models. Subcutaneous immunizations with two CD8 epitope peptides substantially lowered lung viral load and conferred protection against low-dose viral challenge, but not against high-dose challenge. Notably, intranasal boosting—with or without adjuvant—enhanced lung resident memory T cell responses and conferred potent, durable protection against high-dose infection. These findings emphasize the importance of mucosal vaccination to boost protective T cell immunity against SARS-CoV-2 and support the potential of T cell–based vaccines targeting conserved epitopes for broad immunity against SARS-CoV-2 and other respiratory viral threats.