SARS-CoV-2 vaccination during pregnancy enhances hippocampal neurogenesis and working memory in offspring through IFN-gamma and CX3CR1-dependent mechanisms

Abstract The worldwide Coronavirus disease 2019 (COVID-19) pandemic affects the world, and prenatal COVID-19 infection is associated with severe adverse outcomes. Thus, both for safety and immunogenicity, the COVID-19 vaccination is strongly recommended for pregnant women. Specifically, this study examines how maternal COVID-19 vaccination affects postnatal physical development, neurogenesis, and behavior in pups. We successfully detected a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody in the plasma of vaccinated dams and their pups when inactivated COVID-19 vaccine (Vero Cell) was administered at gestational day 14.5. At the age of 1 month, pups from pregnant mice receiving the SARS-CoV-2 vaccine displayed increased proliferation, neuroblasts, neuronal stem cells, and mature neurons in the dentate gyrus (DG) and enhanced working memory. Luminex multiplex assay showed that elevated levels of hippocampal cytokines/chemokines, including interferon-γ (IFN-γ) and CX3C motif chemokine ligand 1 (CX3CL1), which are crucial for neurogenesis and memory function. Mechanistically, using conditional knockout technology, we identify microglial IFN-γ receptor 1 (IFNγR1) and CX3C motif chemokine receptor 1 (CX3CR1), as crucial intercellular participants, in the neuronal developmental process via regulating microglial activation and microglial chemotaxis, respectively. We propose that maternal SARS-CoV-2 vaccination appears to enhance hippocampal neurogenesis and working memory in offspring underlying the mechanism of microglia-proliferating neuron interaction.