Subunit protein CD40.SARS.CoV2 vaccine induces SARS-CoV-2-specific stem cell-like memory CD8+ T cells

• Published in: EBioMedicine 2025-01, Vol.111, p.105479, Article 105479
• Main Authors: Nguema, Laury, Picard, Florence, El Hajj, Marwa, Dupaty, Léa, Fenwick, Craig, Cardinaud, Sylvain, Wiedemann, Aurélie, Pantaleo, Giuseppe, Zurawski, Sandra, Centlivre, Mireille, Zurawski, Gerard, Lévy, Yves, Godot, Véronique
• Format: Article
• Language: English
• Subjects: COVID-19; Life Sciences; Long-lasting T-cell immunity; Pre-clinical models; SARS-CoV-2; Vaccine
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2024.105479

Ideally, vaccination should induce protective long-lived humoral and cellular immunity. Current licensed COVID-19 mRNA vaccines focused on the spike (S) region induce neutralizing antibodies that rapidly wane. Herein, we show that a subunit vaccine (CD40.CoV2) targeting spike and nucleocapsid antigens to CD40-expressing cells elicits broad specific human (hu)Th1 CD4+ and CD8+ T cells in humanized mice. CD40.CoV2 vaccination selectively enriched long-lived spike- and nucleocapsid-specific CD8+ progenitors with stem-cell-like memory (Tscm) properties, whereas mRNA BNT162b2 induced effector memory CD8+ T cells. CD8+ Tscm cells produced IFNγ and TNF upon antigenic restimulation and showed a high proliferation rate. We demonstrate that CD40 activation is specifically required for the generation of huCD8+ Tscm cells. These results support the development of a CD40-vaccine platform capable of eliciting long-lasting T-cell immunity. This work was supported by Inserm, Université Paris-Est Créteil, and the Investissements d’Avenir program, Vaccine Research Institute (VRI), managed by the ANR.