3种平台Delta-Omicron嵌合RBD二聚体新型冠状病毒疫苗的免疫原性头对头比较

新型冠状病毒(新冠病毒)在全球范围内流行,对公共卫生和人民生命健康造成了巨大威胁,新冠病毒疫苗的研发和使用对预防疾病和控制疫情起到了关键作用.基于包括重组蛋白亚单位、病毒载体、mRNA脂纳米颗粒在内的多种技术平台开发的疫苗都获得了使用.然而,由于抗原设计的差异、免疫剂量和注射间隔的差别,不同疫苗平台之间的免疫效果无法直接比较.因此,本研究以Delta-Omicron嵌合RBD二聚体为免疫原,对广泛使用的3个疫苗平台(重组蛋白亚单位疫苗、腺病毒载体疫苗和mRNA疫苗)进行了免疫原性头对头比较,通过小鼠模型比较了它们同源接种和序贯接种所诱导的体液免疫和细胞免疫反应的差异.结果显示,小鼠在免疫同源的两剂疫苗后,m RNA疫苗诱导的结合抗体和中和抗体滴度都最高,其次分别是重组蛋白亚单位疫苗和腺病毒载体疫苗;异源加强免疫的结果显示,不管是以重组蛋白亚单位疫苗、腺病毒载体疫苗或者mRNA疫苗初免,以mRNA疫苗作为第2针加强免疫均能诱导更强的体液免疫反应.此外,在疫苗激发的细胞免疫方面,mRNA疫苗诱导了较强的CD4^(+)T细胞反应,腺病毒载体疫苗诱导了较强的CD8^(+)T细胞反应,而亚单位疫苗刺激的细胞免疫反应以CD4^(+)T细胞为主,但在强度上较弱.本研究具有重要的应用价值,为未来新一代的新冠病毒疫苗研发和接种策略提供了指导.

Durable and enhanced immunity against SARS-CoV-2 elicited by manganese nanoadjuvant formulated subunit vaccine

Dear editor,Vaccines are the most efficient and effective means to prevent infectious diseases,but improving the long-term protective efficacy is still a major challenge in contemporary vaccine development.1 The waning immunity varies depending on the diversification of the pathogen and the number of booster doses.1 Strategies to overcome this warrant is using adjuvants that amplify the immune response,and drive the production of memory B and T cells or long-lived plasma cells that recognize the pathogen for durable protection.2–4 Although existing adjuvants have achieved promising results,research on generating durable protective immunity is lacking in promoting vaccine development and staying ahead of global pandemics such as coronavirus disease 2019(COVID-19).The precisely designed nanoadjuvants can enhance lymph node targeting and increase antigenpresenting cell(APCs)uptake,achieving the co-delivery of adjuvants and antigens and activating innate and adaptive immune responses.5 Previously,we reported a manganese nanoadjuvant(MnARK)and receptor-binding domain(RBD)monomer antigen formulated nanovaccine.6 MnARK transported antigens to lymph nodes,activated the STING pathway,elicited strong neutralizing abilities and increased immune memory T cell percentage against the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).6 Regarding the long-term protection potential of MnARK for subunit vaccine development,we further explored the durable immune regulation abilities of MnARK to a SARS-CoV-2 RBD dimer antigen,which has been used in an approved COVID-19 subunit vaccine ZF2001 with aluminum adjuvant(alum).7,8 TEM result revealed that RBD dimer could interact with BSA on MnARK surface and epitope can be well preserved(Supplementary Fig.1a).The size and zeta potential of MnARK-RBD dimer nanovaccine was~58 nm and-14 mV,respectively(Supplementary Fig.1b,c).

Safety and immunogenicity of COVID-19 vaccine ZF2001 in Chinese aged 60 years and older

The coronavirus disease 2019(COVID-19)pandemic remains a significant global health challenge.Older adults are the population at high risk of developing severe COVID-19 or death[1–3].To date,dozens of vaccines for prototype severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)have received emergency use authorization or conditional marketing approval in many countries[4].ZF2001,a protein subunit vaccine comprising two copies of tandem receptor-binding domain(RBD)from prototype SARS-CoV-2(HB-02 strain)[5,6],has demonstrated safety and immunogenicity in populations aged 3–17 and 18–59 after three doses of vaccination[7,8].Moreover,it has shown good efficacy in the prevention of symptomatic COVID-19 caused by infections from the alpha,kappa,and delta variants after a six-month follow-up for adults beyond 18 years of age in a phase 3 trial[9].ZF2001 was safe and well-tolerated in a large cohort of adults(R18 years of age),and the incidence of adverse events was lower among the participants 60 years of age or older than among those aged 18–59[9].However,its durability and immunogenicity in individuals 60 years of age and older have not been reported and need further investigation.Here,we reported the phase 1 trial of ZF2001 in adults aged 60 or older in China to determine the safety,tolerability,and immunogenicity of ZF2001 in older populations after short(1 month)-and long(6 months)-term follow-up.Moreover,we conducted a post-hoc analysis of serum samples to assess their neutralization capacity against omicron variants.

Rapid evaluation of heterologous chimeric RBD-dimer mRNA vaccine for currently-epidemic Omicron sub-variants as booster shot after inactivated vaccine

With continuous mutations of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines,especially as booster jabs after high-level vaccination coverage of inactivated vaccines in China and many other countries.Previously,we developed a coronavirus disease 2019(COVID-19)protein subunit vaccine ZF2001?based on the tandem homo-prototype receptor-binding domain(RBD)-dimer of the SARS-CoV-2 spike protein.We upgraded the antigen into a hetero-chimeric prototype(PT)-Beta or Delta-BA.1 RBD-dimer to broaden the cross-protection efficacy and prove its efficiency with protein subunit and mRNA vaccine platforms.Herein,we further explored the hetero-chimeric RBD-dimer mRNA vaccines and evaluated their broad-spectrum activities as booster jabs following two doses of inactivated vaccine(Ⅳ)in mice.Our data demonstrated that the chi-meric vaccines significantly boosted neutralizing antibody levels and specific T-cell responses against the vari-ants,and PT-Beta was superior to Delta-BA.1 RBD as a booster in mice,shedding light on the antigen design for the next-generation COVID-19 vaccines.

呼吸道病毒感染的肺部黏膜免疫应答研究

流感病毒和新型冠状病毒(SARS-CoV-2)是近年来频繁引发呼吸道疾病的主要病原,其引起的黏膜免疫应答对于病毒的控制和清除至关重要.目前对于SARS-CoV-2感染后肺部黏膜免疫应答的具体调控机制及其与流感感染的区别尚不清楚我们通过原位杂交-多重免疫荧光染色技术及空间转录组学揭示了流感病毒和SARS-CoV-2感染过程中局部免疫应答的动态变化过程,并发现相比于流感病毒感染,SARS-CoV-2感染早期肺部黏膜会更加快速地形成诱导性支气管相关淋巴组织(iBALT)结构并活化B1细胞产生较高水平IgM和IgA,可能在抗病毒感染及iBALT的形成中发挥重要作用.同时,SARS-CoV-2及表达其S蛋白的假病毒感染均能够促进小鼠和人的B1细胞的活化.将表达S蛋白的腺病毒疫苗AdC7-S对小鼠进行免疫后,可以成功诱导出包含B1细胞的iBALT,并在病毒感染中发挥保护作用.本研究揭示了呼吸道病毒引起的肺脏黏膜免疫动态应答过程,并阐明了SARS-CoV-2感染早期B1细胞的活化特点及免疫保护作用,为揭示新发呼吸道传染病的保护性应答机制及疫苗设计提供了理论基础.

Inside-out assembly of viral antigens for the enhanced vaccination

Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens,but neglect that pathogens evolve to evade the immune system rather than to provoke it.In the case of enveloped RNA viruses,it is the natural dissemination of nucleocapsid protein(NP,core antigen)and surface antigen that delays NP exposure to immune surveillance.Here,we report a multi-layered aluminum hydroxide-stabilized emulsion(MASE)to dictate the delivery sequence of the antigens.In this manner,the receptor-binding domain(RBD,surface antigen)of the spike protein was trapped inside the nanocavity,while NP was absorbed on the outside of the droplets,enabling the burst release of NP before RBD.Compared with the natural packaging strategy,the inside-out strategy induced potent type I interferon-mediated innate immune responses and triggered an immune-potentiated environment in advance,which subsequently boosted CD40+DC activations and the engagement of the lymph nodes.In both H1N1 influenza and SARS-CoV-2 vaccines,rMASE significantly increased antigen-specific antibody secretion,memory T cell engagement,and Th1-biased immune response,which diminished viral loads after lethal challenge.By simply reversing the delivery sequence of the surface antigen and core antigen,the inside-out strategy may offer major implications for enhanced vaccinations against the enveloped RNA virus.

A protective human antibody against respiratory syncytial virus by targeting a prefusion epitope across sites IV and V of the viral fusion glycoprotein

Respiratory syncytial virus(RSV)is one of the leading pathogens that cause lower respiratory tract infections in infants and the elderly.Passive immunoprophylaxis with monoclonal antibody(mAb)has been approved to prevent morbidity and mortality from RSV infection in infants.Here we report the isolation of two neutralizing mAbs against RSV from convalescent children by prefusion form of fusion(F)glycoprotein as bait.One mAb RV11 exhibited good potency in neutralization of RSV strains from both A and B subtypes in cell-based assay,and protected mice from RSV infection in vivo.An RV11 escape mutant was identified,which contains an S443P mutation in F protein.Crystal structure showed the RV11 bound to a conserved prefusion epitope across the antigenic sites IV and V of the F glycoprotein.RV11 showed a strong synergistic effect when combined with two RSV antivirals,an F-targeting small molecular inhibitor ziresovir and a siteØneutralizing mAb D25(the parental mAb for nirsevimab).The study extended our knowledge to the neutralizing and protective epitopes of RSV,and the mAb RV11 deserves further development for clinical translation.

Avian influenza A(H7N9)virus:from low pathogenic to highly pathogenic

OriginalTranslation The avian influenza A(H7N9)virus is a zoonotic virus that is closely associated with live poultry markets.It has caused infections in humans in China since 2013.Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017.H7N9 with low-pathogenicity dominated in the first four waves,whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave,causing wide concern.Specialists and officials from China and other countries responded quickly,controlled the epidemic well thus far,and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts.Here,we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease.It was summarized and discussed from the perspectives of molecular epidemiology,clinical features,virulence and pathogenesis,receptor binding,T-cell responses,monoclonal antibody development,vaccine development,and disease burden.These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses,such as SARS-CoV-2.

A neutralizing-protective supersite of human monoclonal antibodies for yellow fever virus

The yellow fever virus(YFV)is a life-threatening human pathogen.Owing to the lack of available therapeutics,non-vaccinated individuals are at risk.Here,we isolated eight human monoclonal antibodies that neutralize YFV infection.Five recognized overlapping epitopes and exhibited potent neutralizing activity.Two(YD6 and YD73)were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model.Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre-and post-fusion states,suggesting viral inhibition by a“double-lock”mechanism.The recognition determinants for YD6 and YD73 are clustered at the premembrane(prM)-binding site.Notably,antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization,suggesting a vulnerable supersite of YFV.We provide two promising candidates for immunotherapy against YFV,and the supersite represents an ideal target for epitope-based vaccine design.

CASCIRE surveillance network and work on avian influenza viruses

Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2.2H5N1 subtype highly pathogenic avian influenza virus(HPAIV)first caused severe outbreak in wild birds in Qinghai Lake(Liu et al.,2005).