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Thus, the inflammatory milieu induced by the LNPs could be partially responsible for reported side effects of mRNA-LNP-based SARS-CoV-2 vaccines in humans and are possibly contributory to their reported high potency for eliciting antibody responses. Using complementary techniques, we show that in mice intradermal, intramuscular, or intranasal delivery of LNPs used in preclinical studies triggers inflammation characterized by leukocytic infiltration, activation of different inflammatory pathways, and secretion of a diverse pool of inflammatory cytokines and chemokines.
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Therefore, in this study, we took a systematic approach, focusing our attention on the injection site and analyzing the inflammatory reactions caused by the LNPs used for preclinical vaccine studies ( Awasthi et al., 2019 Laczkó et al., 2020 Lederer et al., 2020 Pardi et al., 2017, Pardi et al., 2018a, Pardi et al., 2018b).
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Still, no studies have been undertaken to characterize the immediate innate inflammatory reactions induced by this vaccine platform that could potentially cause the local and systemic side effects. These side effects, however, are more in line with acute inflammatory responses induced by the vaccine. Under the presumption that this vaccine platform is noninflammatory, some of the clinicians and public health communicators interpreted these reported acute side effects as the vaccine being potent and generating an adaptive immune response. The human clinical trials of the Pfizer/BioNTech and Moderna vaccines have reported side effects such as pain, swelling, fever, and sleepiness ( Jackson et al., 2020 Sahin et al., 2020 Walsh et al., 2020). However, the potential inflammatory nature of these LNPs was not assessed ( Alameh et al., 2020 Pardi et al., 2018a). A preclinical study showed that nucleoside-modified mRNA complexed with Acuitas Therapeutics' LNPs containing proprietary ionizable lipid has adjuvant activity ( Pardi et al., 2018a). The ionizable lipids were developed to decrease the highly inflammatory and cytotoxic effects of some of the permanently charged cationic lipids ( Kulkarni et al., 2018). The cationic/ionizable lipids are included to allow the complexing of the negatively charged mRNA molecules and enable the exit of the mRNA from the endosome to the cytosol for translation ( Samaridou et al., 2020). The phospholipids and cholesterol have structural and stabilizing roles, whereas the PEGylated lipids support prolonged circulation. The LNPs consist of a mixture of phospholipids, cholesterol, PEGylated lipids, and cationic or ionizable lipids. The LNP was chosen as a carrier vehicle to protect the mRNA from degradation and aid intracellular delivery and endosomal escape. These vaccines' mRNA component is nucleoside modified to decrease potential innate immune recognition ( Karikó et al., 2005 Karikó et al., 2008). The nucleoside-modified mRNA-LNP vaccine platform used by Pfizer/BioNTech and Moderna in their SARS-CoV-2 vaccines has been widely tested in preclinical studies, and its effectiveness in supporting Tfh cells and protective humoral immune responses matches or surpasses other vaccines ( Alameh et al., 2020). Thus, the mRNA-LNP platforms' potency in supporting the induction of adaptive immune responses and the observed side effects may stem from the LNPs' highly inflammatory nature. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate, with mechanism unresolved. Intradermal and intramuscular injection of these LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. Here we present evidence that Acuitas' LNPs used in preclinical nucleoside-modified mRNA vaccine studies are highly inflammatory in mice.
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Flowjo 10 platform drivers#
However, the drivers of the reported side effects remain poorly defined. Clinical trials and ongoing vaccinations present with varying degrees of protection levels and side effects. Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against COVID-19.