面向新冠肺炎疫情防控需求的应用基础研究

严重急性呼吸综合征冠状病毒2(Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2)全球大流行导致的新冠肺炎疫情仍在持续,不断进化的变异毒株谱系具有较强的免疫逃逸和突破性感染能力,一系列新冠肺炎后遗症陆续被发现,并可能在未来对人类社会造成严重的医疗负担。我国面临“外防输入、内防反弹”的巨大抗疫压力,不仅需要全面统筹疫情防控和经济社会发展,还需要积极为将来全面放开出入境限制做好科技储备。建立完备的疫情防控体系和群体免疫屏障,研究和发展抗疫产品和科学技术,进一步减少重症和死亡,是保障人民生命健康、打赢抗疫“拉锯战”的法宝。厦门大学国家传染病诊断试剂与疫苗工程技术研究中心团队长期以来在国家自然科学基金项目的支持下,形成了坚实的感染性疾病研究积累,建立了系统的生物医药研究平台,锻造了一支朝气蓬勃的科研创新团队;面对复杂的疫情发展态势,围绕“诊断、预防、治疗”三方面的防控产品需求,在SARS-CoV-2检测技术体系、鼻喷流感病毒载体新冠疫苗和重组蛋白新冠疫苗、广谱中和抗体与小分子药物筛选、重症肺炎动物模型和致病机制等方面取得了一系列研究进展,为我国疫情防控和公共卫生事业提供了重要的科技支撑。

A live attenuated virus-based intranasal COVID-19 vaccine provides rapid,prolonged,and broad protection against SARS-CoV-2

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2);however,they are limited with respect to eliciting local immunity in the respiratory tract,which is the primary infection site for SARS-CoV-2.To overcome the limitations of intramuscular vaccines,we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain(RBD)of the spike protein of SARSCoV-2,named CA4-d NS1-n CoV-RBD(d NS1-RBD).A preclinical study showed that in hamsters challenged 1d after single-dose vaccination or 9 months after booster vaccination,d NS1-RBD largely mitigated lung pathology,with no loss of body weight.Moreover,such cellular immunity is relatively unimpaired for the most concerning SARS-Co V-2 variants,especially for the latest Omicron variant.In addition,this vaccine also provides cross-protection against H1N1 and H5N1 influenza viruses.The protective immune mechanism of d NS1-RBD could be attributed to the innate immune response in the nasal epithelium,local RBD-specific T cell response in the lung,and RBD-specific Ig A and Ig G response.Thus,this study demonstrates that the intranasally delivered d NS1-RBD vaccine candidate may offer an important addition to the fight against the ongoing coronavirus disease 2019 pandemic and influenza infection,compensating limitations of current intramuscular vaccines.

Gender associates with both susceptibility to infection and pathogenesis of SARS-CoV-2 in Syrian hamster

Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2.Remarkably,high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss,weakness,piloerection,hunched back and abdominal respiration,as well as severe pneumonia,pulmonary edema,consolidation,and fibrosis.In contrast with the males,the female hamsters showed much lower shedding viral titers,moderate symptoms,and relatively mild lung pathogenesis.The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.

Dexamethasone ameliorates severe pneumonia but slightly enhances viral replication in the lungs of SARS-CoV-2-infected Syrian hamsters

The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than 230 million cases and over four million deaths worldwide.Furthermore,multiple emerging SARS-CoV-2 variants have shown enhanced infectivity,transmissibility,pathogenicity and ability to escape neutralization by vaccine-induced humoral immunity[1].The antibody resistance of SARS-CoV-2 variants constitutes a challenge for current vaccines and therapeutic antibodies.No specific antiviral is currently available for coronavirus in humans[2].Although remdesivir was approved by the FDA for the treatment of SARS-CoV-2 infection,the therapeutic effect is limited,particularly for critical cases with severe pneumonia.

Female sex hormone, progesterone, ameliorates the severity of SARS-CoV-2-caused pneumonia in the Syrian hamster model

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has infected more than 260 million people worldwide and causes coronavirus disease 2019(COVID-19)with clinical spectrum ranging from mild to severe pneumonia.Recent clinical trials and experimental animal studies demonstrated that the severity of COVID-19 is lower in the females than in males.

Persisting lung pathogenesis and minimum residual virus in hamster after acute COVID-19

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has infected more than 200 million people,causing coronavirus disease 2019(COVID-19)worldwide.Lungs are the primary target organ of SARS-CoV-2 infection.The mild COVID-19 cases develop symptoms of fever,fatigue,muscle weakness,chest pain,headache and cough(Chen et al.,2020;Wang et al.,2020;Zhu et al.,2020),while severe COIVD-19 cases might have pneumonia,breathing difficulties,multiple organ failure and death(Chen et al.,2020;Wang et al.,2020;Zhu et al.,2020).Both the clinicians and researchers have largely focused on the acute phase of COVID-19,but the long-term health consequences of the COVID-19 patients after clinical recovery remain less investigated.Several clinical cohorts demonstrated that some patients discharged from hospital still experience symptoms including fatigue,muscle weakness,chest pain,cough and breathing difficulties(Carfi et al.,2020;Lim et al.,2020;Huang et al.,2021).Moreover,severely impaired pulmonary diffusion capacities and abnormal chest imaging manifestations were observed in some convalescent patients(Huang et al.,2021).Surprisingly,residual virus(An et al.,2020;Yao et al.,2020;Kim et al.,2021)were detected in some convalescent patients.

Infection,pathology and interferon treatment of the SARS-CoV-2 Omicron BA.1 variant in juvenile,adult and aged Syrian hamsters

The new predominant circulating SARS-CoV-2 variant,Omicron,can robustly escape current vaccines and neutralizing antibodies.Although Omicron has been reported to have milder replication and disease manifestations than some earlier variants,its pathogenicity in different age groups has not been well elucidated.Here,we report that the SARS-CoV-2 Omicron BA.1 sublineage causes elevated infection and lung pathogenesis in juvenile and aged hamsters,with more body weight loss,respiratory tract viral burden,and lung injury in these hamsters than in adult hamsters.Juvenile hamsters show a reduced interferon response against Omicron BA.1 infection,whereas aged hamsters show excessive proinflammatory cytokine expression,delayed viral clearance,and aggravated lung injury.Early inhaled IFN-α2b treatment suppresses Omicron BA.1 infection and lung pathogenesis in juvenile and adult hamsters.Overall,the data suggest that the diverse patterns of the innate immune response affect the disease outcomes of Omicron BA.1 infection in different age groups.

Liver chimeric mice with tupaia hepatocyte transplantation as an animal model for hepatitis B virus infection and antiviral therapy

The human liver chimeric mouse is a milestone animal model for hepatitis B virus(HBV)infection.Such mice with primary human hepatocyte(PHH)transplantation are adequate to support chronic HBV infection for several weeks and to evaluate antiviral drugs.However,the drawbacks of PHHs include lack of available donors,poor expansion in vitro and ethical issues that limit the application of human liver chimeric mice,necessitating the search for alternatives.Here,we transplanted primary tupaia hepatocytes(PTHs)into the livers of immunodeficient mice and achieved high liver chimerism within six weeks.These tupaia liver chimeric mice are adequate to support chronic infection of the four common HBV genotypes A,B,C and D for 36 weeks,as well as evaluate of antiviral drugs,including hepatitis B immune globulin(HBIG),monoclonal antibody and nucleoside analogues(NAs),for preventative therapy and treatment post infection.In conclusion,the tupaia liver chimeric mouse model provides a convenient,efficient and stable animal model for chronic HBV infection and long-term drug evaluation.