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

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: These results support the development of a CD40-vaccine platform capable of eliciting long-lasting T-cell immunity.

Funding: This work was supported by Inserm, Université Paris-Est Créteil, and the Investissements d'Avenir program, Vaccine Research Institute (VRI), managed by the ANR.