The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice

Hepatitis A virus(HAV)live-attenuated vaccine H2 strain has been approved for clinical use for decades with ideal safety profiles in nonhuman primate models and humans.Recently,type Ⅰ interferon(IFN)receptor-deficient mice were shown to be susceptible to HAV infection.Herein,we sought to determine the infection and replication dynamics of the H2 in Ifnar^(-/-)mice that lack type Ⅰ IFN receptor.Following intravenous injection,the H2 failed to cause obvious clinical symptoms in Ifnar^(-/-)mice,and no significant upregulation in serum alanine aminotransferase(ALT)levels was observed.Notably,the histopathological examination showed that there were significant focal infiltrations of lymphocytes and neutrophils in the portal area,but no focal necrosis was observed in liver tissues.Viral RNAs sustained in the liver,and the infectious virus could be recovered from the liver tissue until 42 days post-infection.More importantly,H2 infection induced obvious viremia and persistent viral shedding in feces.In addition,robust HAV-specific humoral immune responses were induced in Ifnar^(-/-)mice.Overall,our study revealed the safety profile of H2 in Ifnar^(-/-)mice,which not only helps understand the attenuation mechanism of H2,but also expands the application of the Ifnar^(-/-)mouse model for HAV studies.

Long-term stability and protection efficacy of the RBD-targeting COVID-19 mRNA vaccine in nonhuman primates

Messenger RNA(mRNA)vaccine technology has shown its power in preventing the ongoing COVID-19 pandemic.Two mRNA vaccines targeting the full-length S protein of SARS-CoV-2 have been authorized for emergency use.Recently,we have developed a lipid nanoparticle-encapsulated mRNA(mRNA-LNP)encoding the receptor-binding domain(RBD)of SARS-CoV-2(termed ARCoV),which confers complete protection in mouse model.Herein,we further characterized the protection efficacy of ARCoV in nonhuman primates and the Iong-term stability under normal refrigerator temperature.Intramuscular immunization of two doses of ARCoV elicited robust neutralizing antibodies as well as cellular response against SARS-CoV-2 in cynomolgus macaques.More importantly,ARCoV vaccination in macaques significantly protected animals from acute lung lesions caused by SARS-CoV-2,and viral replication in lungs and secretion in nasal swabs were completely cleared in all animals immunized with low or high doses of ARCoV.No evidenee of antibody-dependent enhancement of infection was observed throughout the study.Finally,extensive stability assays showed that ARCoV can be stored at 2-8℃ for at least 6 months without decrease of immunogenicity.All these promising results strongly support the ongoing clinical trial.