The lack of an animal model for human norovirus (HuNoV) has hindered the development of therapeutic strategies. This study demonstrated that a commonly used cholesterol-lowering statin medication, simvastatin, which increases HuNoV replication in an in vitro replicon system, also enhances HuNoV infectivity in the gnotobiotic (Gn) pig model. In contrast, oral treatment with interferon (IFN)-α reduces HuNoV infectivity. Young piglets, all with A or H1 histo-blood group antigens on enterocytes, were treated orally with 8 mg/kg/day of simvastatin; 5 days later, the pigs were inoculated orally with a GII.4 HuNoV (HS194/2009/US strain) and then treated with simvastatin for 5 more days. Simvastatin induced significantly earlier onset and longer duration of HuNoV fecal shedding in treated pigs, frequently with higher fecal viral titers. Simvastatin impaired poly (I:C)-induced IFN-α expression in macrophages or dendritic cells, possibly due to lowered toll-like receptor (TLR) 3 expression; however, the mechanisms were not related to interferon regulatory factor 3 or nuclear factor kappa B signaling pathway. Thus, the enhanced, earlier infectivity of HuNoV in simvastatin-treated pigs coincided with the inhibitory effect of simvastatin on innate immunity. In contrast to the increased HuNoV shedding that simvastatin induced, viral shedding during the treatment period was reduced or curtailed in the HuNoV-inoculated pigs pre-treated/treated with human IFN-α. Our findings are the first to indicate that IFN-α has potential as antiviral therapy against HuNoV. Based on these intriguing and novel findings using the Gn pig model, we confirmed that HuNoV infectivity is altered by treatment with simvastatin or IFN-α. Collectively, these findings indicate that Gn pigs are a useful model to test immunomodulators or efficacy of antivirals against HuNoV.

SARS-CoV-2, the causative agent of COVID-191, features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein1–6. Neutralizing antibodies that block RBD-ACE2 interaction are candidates for the development of targeted therapeutics7–17. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (KD = 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.42 μg mL−1). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log10. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak.

Norovirus is a major cause of acute gastroenteritis in humans. A norovirus outbreak occurred in Ohio in

Aim: To identify the safety, immunogenicity, and protective efficacy of COVID-19 vaccines in children and adolescents. Methods: We conducted a systematic review of published studies and ongoing clinical studies related to the safety, immunogenicity, and efficacy of COVID-19 vaccine in children or adolescents (aged < 18 years). Databases including PubMed, Web of Science, WHO COVID-19 database, and China National Knowledge Infrastructure (CNKI) were searched on 23 July 2021. International Clinical Trials Registry Platform (ICTRP) was also searched to identify ongoing studies. Results: Eight published studies with a total of 2852 children and adolescents and 28 ongoing clinical studies were included. Of the eight published studies, two were RCTs, two case series, and four case reports. The investigated COVID-19 vaccines had good safety profiles in children and adolescents. Injection site pain, fatigue, headache, and chest pain were the most common adverse events. A limited number of cases of myocarditis and pericarditis were reported. The RCTs showed that the immune response to BNT162b2 in adolescents aged 12–15 years was non-inferior to that in young people aged 16–25 years, while with 3 μg CoronaVac injection the immune response was stronger than with 1.5 μg. The efficacy of BNT162b2 was 100% (95% CI: 75.3 to 100), based on one RCT. Of the 28 ongoing clinical studies, twenty-three were interventional studies. The interventional studies were being conducted in fifteen countries, among them, China (10, 43.5%) and United States(9, 39.1%) had the highest number of ongoing trials. BNT162b2 was the most commonly studied vaccine in the ongoing trials. Conclusion: Two COVID-19 vaccines have potential protective effects in children and adolescents, but awareness is needed to monitor possible adverse effects after injection. Clinical studies of the COVID-19 vaccination in children and adolescents with longer follow-up time, larger sample size, and a greater variety of vaccines are still urgently needed.