SW-0123

Messenger RNA (mRNA) vaccines are promising alternatives to conventional vaccines in many aspects. We previously developed a lipopolyplex (LPP)‐based mRNA vaccine (SW0123) that demonstrated robust immunogenicity and strong protective capacity against severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection in mice and rhesus macaques. However, the immune profiles and mechanisms of pulmonary protection induced by SW0123 remain unclear. Through high‐resolution single‐cell analysis, we found that SW0123 vaccination effectively suppressed SARS‐CoV‐2‐induced inflammatory responses by inhibiting the recruitment of proinflammatory macrophages and increasing the frequency of polymorphonuclear myeloid‐derived suppressor cells. In addition, the apoptotic process in both lung epithelial and endothelial cells was significantly inhibited, which was proposed to be one major mechanism contributing to vaccine‐induced lung protection. Cell−cell interaction in the lung compartment was also altered by vaccination. These data collectively unravel the mechanisms by which the SW0123 protects against lung damage caused by SARS‐CoV‐2 infection.