Role of Plasmacytoid Dendritic Cells in Humoural and CD8+ T-cell Memory Responses Following BNT162b2 Mrna Vaccination: a Preclinical Mouse Study

Background The Pfizer-BioNTech coronavirus vaccine (BNT162b2) was among the first nanoparticle-based vaccines approved by the World Health Organisation (WHO) and demonstrated 95% efficacy against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Despite its success, the precise immune mechanism behind its effectiveness remains poorly understood. This study investigated the early immune responses occurring in the draining lymph node (dLN) following vaccination. Methods A well-established murine vaccination model was used to investigate the distribution and immunological effects of BNT162b2 in vivo. Vaccine trafficking to the dLN, cellular uptake, and spike protein expression were assessed following immunisation. Single-cell transcriptomic analyses and functional in vivo experiments were performed to identify the immune cell populations involved in orchestrating vaccine-induced responses and to characterise their interactions with adaptive immune cells. Findings BNT162b2 was rapidly transported to the dLN, where it was predominantly captured by leukocytes that subsequently expressed the SARS-CoV-2 spike protein. Among these cells, plasmacytoid dendritic cells (pDCs) emerged as regulators involved in both inflammatory and humoural immune responses. Single-cell transcriptomic profiling revealed active interactions between pDCs and CD8+ T cells. Functional in vivo studies further demonstrated that pDCs promoted CD8+ T-cell activation and expansion, indicating an involvement in shaping adaptive immunity following vaccination. Interpretation These findings identify pDCs as antigen-presenting cells involved in coordinating the immune response to BNT162b2. By regulating both innate and adaptive immune pathways and facilitating CD8+ T-cell activation, pDCs appear to play a functional role in the efficacy of this mRNA vaccine. This study provides additional insights into the immunological processes underlying mRNA vaccine-induced protection and may inform the future design and optimisation of mRNA-based immunotherapies and vaccines. Funding Swiss National Science Foundation, Leonardo Foundation.