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.