A core-shell structured COYID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity

Although inoculation of COVID-19 vaccines has rolled out globally,there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries.Here,we report on the development of a highly efficacious mRNA vaccine,SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core-shell structured lipopolyplex(LPP)nanoparticles.SWOT 23 is easy to produce using a large-scale microfluidics-based apparatus.The unique core-shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability,and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration.Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123,represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2,but also a panel of variants including D614G and N501Y variants.In addition,SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge.Taken together,SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.

KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling

IL-6 plays important and pleiotropic roles in infection and inflammatory diseases,and its production needs to be tightly regulated.However,the epigenetic mechanism underlying Il6 gene transcription remains to be fully elucidated.Here,we report that lysine-specific demethylase 2b(KDM2B),which demethylates H3K4me3 and H3K36me2,is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α,IL-1,and IFN-β.Compared to wild-type mice,KDM2B-deficient mice were more resistant to endotoxin shock and colitis,with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera.KDM2B selectively bound the Il6 promoter but did not alter histone demethylation;instead,KDM2B interacted with Brahma-related gene 1(Brg1),the core ATPase subunit of SWI/SNF chromatin remodeling complexes,to facilitate chromatin accessibility of the Il6 promoter.Furthermore,KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription.Thus,our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.