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Intranasal administration of a single dose of a candidate live attenuated vaccine derived from an NSP16-deficient SARS-CoV-2 strain confers sterilizing immunity in animals

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Cellular & Molecular Immunology 2022年第5期19卷 588-601页

作者： Zi-Wei Ye Chon Phin Ong Kaiming Tang Yilan Fan Cuiting Luo Runhong Zhou Peng Luo Yun Cheng Victor Sebastien Gray Pui Wang Hin Chu Jasper Fuk-Woo Chan Kelvin Kai-Wang To Honglin Chen Zhiwei Chen Kwok-Yung Yuen Guang Sheng Ling Shuofeng Yuan Dong-Yan Jin Department of Microbiology Li Ka Shing Faculty of MedicineThe University of Hong Kong102 Pokfulam RoadPokfulamHong KongChina State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong102 Pokfulam RoadPokfulamHong KongChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong Kong21 Sassoon RoadPokfulamHong KongChina

live attenuated vaccines might elicit mucosal and sterilizing immunity against SARS-CoV-2 that the existing mRNA,adenoviral vector and inactivated vaccines fail to induce.Here,we describe a candidate live attenuated vaccine strain of SARS-CoV-2 in which the NSP16 gene,which encodes 2′-O-methyltransferase,is catalytically disrupted by a point mutation.This virus,designated d16,was severely attenuated in hamsters and transgenic mice,causing only asymptomatic and nonpathogenic infection.A single dose of d16 administered intranasally resulted in sterilizing immunity in both the upper and lower respiratory tracts of hamsters,thus preventing viral spread in a contact-based transmission model.It also robustly stimulated humoral and cell-mediated immune responses,thus conferring full protection against lethal challenge with SARS-CoV-2 in a transgenic mouse model.The neutralizing antibodies elicited by d16 effectively cross-reacted with several SARS-CoV-2 variants.Secretory immunoglobulin A was detected in the blood and nasal wash of vaccinated mice.Our work provides proof-of-principle evidence for harnessing NSP16-deficient SARS-CoV-2 for the development of live attenuated vaccines and paves the way for further preclinical studies of d16 as a prototypic vaccine strain,to which new features might be introduced to improve safety,transmissibility,immunogenicity and efficacy.

关键词： live attenuated vaccine NSP16 2'-O-methyltransferase T-cell response Mucosal immunity Sterilizing immunity

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Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long live attenuated vaccine Candidates

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Virologica Sinica 2021年第4期36卷 706-720页

作者： Li-Nan Wang Xiang-Lei Peng Min Xu Yuan-Bo Zheng Yue-Ying Jiao Jie-Mei Yu Yuan-Hui Fu Yan-Peng Zheng Wu-Yang Zhu Zhong-Jun Dong Jin-Sheng He College of Life Sciences and Bioengineering School of ScienceBeijing Jiaotong UniversityBeijing100044China National Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and PreventionBeijing102206China School of Medicine and Institute for Immunology Beijing Key Lab for Immunological Research on Chronic DiseasesTsinghua UniversityBeijing100084China

Human respiratory syncytial virus(RSV)infection is the leading cause of lower respiratory tract illness(LRTI),and no vaccine against LRTI has proven to be safe and effective in infants.Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice.The constructed recombinant plasmids harbored(5′to 3′)a T7 promoter,hammerhead ribozyme,RSV Long strain antigenomic cDNA with cold-passaged(cp)mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain(A2cpts)or further combined with SH gene deletion(A2cptsΔSH),HDV ribozyme(δ),and a T7 terminator.These vectors were subsequently co-transfected with four helper plasmids encoding N,P,L,and M2-1 viral proteins into BHK/T7-9 cells,and the recovered viruses were then passaged in Vero cells.The rescued recombinant RSVs(rRSVs)were named rRSV-Long/A2cp,rRSV-Long/A2cpts,and rRSV-Long/A2cptsΔSH,respectively,and stably passaged in vitro,without reversion to wild type(wt)at sites containing introduced mutations or deletion.Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed temperature-sensitive(ts)phenotype in vitro and in vivo,all rRSVs were significantly attenuated in vivo.Furthermore,BALB/c mice immunized with rRSVs produced Th1-biased immune response,resisted wtRSV infection,and were free from enhanced respiratory disease.We showed that the combination ofΔSH with attenuation(att)mutations of cpts contributed to improving att phenotype,efficacy,and gene stability of rRSV.By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains,we have laid an important foundation for the development of RSV live attenuated vaccines.

关键词： Human respiratory syncytial virus(RSV) RSV long strain live attenuated vaccine Safety Protective immunity

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Construction of live attenuated vaccine against Vib- rio alginolyticus and the Evaluation on Its Immuno- protection Effect

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Animal Husbandry and Feed Science 2016年第2期8卷 85-89,93页

作者： Yuan Yonghong Pang Huanying Zhou Zejun Song Dawei Ding Yu Jian Jichang Wu Zaohe Fisheries College of Guangdong Ocean University Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals Key Laboratory of Diseases Controlling for Aquatic Economic Animals of Guangdong Higher Education Institutions Zhanjiang 524088 China Zhongkai University of Agriculture and Engineering Guangzhou 510225 China

Vibrio alginolyticus, a gram-negative bacterium has been described to be one of the most common and economically important aquatic pathogens of fish and shellfish. vaccine immunization is an effective approach preventing V. alginolyticus infection. attenuated vaccine stimulates systemic immune response in the host, but few attenuated vaccine against V. alginolyticus is available. The type III secretion system （T3SS）, an important pathogenic factor of V. alginolyticus, is used by bacterial pathogens to inject effector proteins into the cytoplasm of their host cells. The T3SS forms a structure called needle complex with a multi-ring base that spans the bacteria and a needle-like extension that protrudes several nanometers from the bacterial surface, vscO locates at the ＂needle＂ site of T3SS, playing the role of escorting the molecular chaperone and effector proteins into host cells and further inducing the death of host cells. In this paper, an in-frame deletion mu- tant of vscO was constructed using overlap PCR and homologous recombination technology combining with chloramphenicol （Cm） and sucrose screening. The LDs0 changes of ZJO3AvscO mutant strains compared with the strain ZJ03 were e^amined in grouper （ Epinephelus coioides）. The ZJO3AvscO mutant showed about 150 times decrease in virulence in E. coioides compared with wide type ZJ03. After vaccination with ZJO3AvscO in E. coioides through injection and immersion, the spe- cific antibody titers were markedly higher than that in the saline control group （P 〈 0.05 ）. The titers of injection and immersion group on the forth week reached the maximums at 1：2 048 and 1： 128, respectively. The relative percentage survival （RPS） of injection group was 84%, while that in immersion group was 68%. These results indicate that the ZJO3AvscO of V. alginolyticus has a high immunogenicity, and can be used as live attenuated vaccine. In addition, RPS may be affected by vaccination and infection methods. This study can provide technical support for controlling fish diseases ca

关键词： Vibrio alginolyticus vscO live attenuated vaccine Immunoprotection

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Immunization with a live attenuated H7N9 influenza vaccine protects mice against lethal challenge

Immunization with a live attenuated H7N9 influenza vaccine p...

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第十届全国免疫学学术大会

作者： Yueqiang Duan Penghui Yang Xiaolan Yang Zhongpeng Zhao Hongjing Gu Xiliang Wang Beijing Institute of Microbiology and Epidemiology 302 hospitial

The emergence of severe cases of human influenza A(H7N9) viral infection in China in the spring of 2003 resulted in a global effort to rapidly develop an effective candidate vaccine. In this report, using reverse genetic technology, we generated a cold-adapted(ca), live attenuated monovalent reassortant influenza H7N9 virus(Ah01/AA ca) that contained hemagglutinin(HA) and neuraminidase(NA) genes from a 2013 pandemic A H7N9 isolate, A/Anhui/01/2013 virus(Ah01/H7N9);the remaining six internal gene segments came from the cold-adapted influenza H2N2 A/Ann Arbor/6/60 virus(AA virus). Ah01/AA ca exhibited phenotypes of temperature sensitivity(ts), ca, and attenuation(att). Intranasal immunization of female BALB/c mice with Ah01/AA ca twice at a 2-week interval induced robust humoral, mucosal, and cellmediated immune responses in a dose-dependent manner. Furthermore, the candidate Ah01/AA ca virus was immunogenic and offered partial or complete protection of mice against a lethal challenge by the live 2013 influenza A H7N9(A/Anhui/01/2013). Protection was demonstrated by the inhibition of viral replication and the attenuation of histopathological changes in the challenged mouse lung. Taken together, these data support the evaluation of this Ah01/AA ca candidate vaccine for human use in clinical trials.

关键词： H7N9 live attenuated vaccine cold-adapted

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A live attenuated RHΔompdcΔuprt mutant of Toxoplasma gondii induces strong protective immunity against toxoplasmosis in mice and cats

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Infectious Diseases of Poverty 2023年第3期12卷 51-66页

作者： Yu Shen Bin Zheng Hao Sun Songrui Wu Jiyuan Fan Jianzu Ding Meng Gao Qingming Kong Di Lou Haojie Ding Xunhui Zhuo Shaohong Lu School of Basic Medical Sciences and Forensic Medicine Hangzhou Medical CollegeHangzhouZhejiangChina Engineering Research Center of Novel vaccine of Zhejiang Province Hangzhou Medical CollegeHangzhouChina Key Laboratory of Bio-Tech vaccine of Zhejiang Province Hangzhou Medical CollegeHangzhouChina

Background Toxoplasma gondii is an obligate intracellular apicomplexan parasite and is responsible for zoonotic toxoplasmosis.It is essential to develop an effective anti-T.gondii vaccine for the control of toxoplasmosis,and this study is to explore the immunoprotective effects of a live attenuated vaccine in mice and cats.Methods First,theompdc anduprt genes of T.gondii were deleted through the CRISPR-Cas9 system.Then,the intracellular proliferation and virulence of this mutant strain were evaluated.Subsequently,the immune responses induced by this mutant in mice and cats were detected,including antibody titers,cytokine levels,and subsets of T lymphocytes.Finally,the immunoprotective effects were evaluated by challenge with tachyzoites of different strains in mice or cysts of the ME49 strain in cats.Furthermore,to discover the effective immune element against toxoplasmosis,passive immunizations were carried out.GraphPad Prism software was used to conduct the log-rank(Mantel–Cox)test,Student’st test and one-way ANOVA.Results The RHΔompdcΔuprt were constructed by the CRISPR-Cas9 system.Compared with the wild-type strain,the mutant notably reduced proliferation(P<0.05).In addition,the mutant exhibited virulence attenuation in both murine(BALB/c and BALB/c-nu)and cat models.Notably,limited pathological changes were found in tissues from RHΔompdcΔuprt-injected mice.Furthermore,compared with nonimmunized group,high levels of IgG(IgG1 and IgG2a)antibodies and cytokines(IFN-γ,IL-4,IL-10,IL-2 and IL-12)in mice were detected by the mutant(P<0.05).Remarkably,all RHΔompdcΔuprt-vaccinated mice survived a lethal challenge with RHΔku80 and ME49 and WH6 strains.The immunized sera and splenocytes,especially CD8^(+)T cells,could significantly extend(P<0.05)the survival time of mice challenged with the RHΔku80 strain compared with naïve mice.In addition,compared with nonimmunized cats,cats immunized with the mutant produced high levels of antibodies and cytokines(P<0.05),and notably decreased the shedding numbers of oocysts in fec

关键词： Toxoplasma gondii Orotidine-5’-monophosphate decarboxylase Phosphoribosyltransferase live attenuated vaccine Immunization Mouse Cat

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Current efforts towards safe and effective live attenuated vaccines against African swine fever: challenges and prospects

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Infectious Diseases of Poverty 2021年第6期10卷 83-89页

作者： Tao Wang Rui Luo Yuan Sun Hua‑Ji Qiu State Key Laboratory of Veterinary Biotechnology Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150069China School of Life Science Engineering Foshan UniversityFoshan 528231China

Background: African swine fever (ASF) is a fatal hemorrhagic disease in domestic pigs and wild boar caused by African swine fever virus (ASFV). Since ASF has been introduced into Europe and Asia, the major pig-raising areas, posing a huge threat to the pork industry worldwide. Currently, prevention and control of ASF are basically dependent on strict biosecurity measures and stamping-out policy once ASF occurs.Main text: The major risks of ASF spread are insufficient biosecurity measures and human behaviors. Therefore, a safe and effective vaccine seems to be a reasonable demand for the prevention and control of ASF. Due to the efficacy advantage over other types of vaccines, live attenuated vaccines (LAVs), especially virulence-associated genes deleted vaccines, are likely to be put into emergency and conditional use in restricted areas if ASF is out of control in a country with a huge pig population and pork consumption, like China. However, the safety, efficacy, and genetic stability of current candidate ASF LAVs require comprehensive clinical evaluations prior to country-wide field application. Several critical issues need to be addressed to commercialize an ideal ASF LAV, including a stable cell line for manufacturing vaccines, differentiation of infected from vaccinated animals (DIVA), and cross-protection from different genotypes.Conclusion: A safe and effective DIVA vaccine and an accompanying diagnostic assay will facilitate the prevention, control, and eradication of ASF, which is quite challenging in the near future.

关键词： African swine fever live attenuated vaccine Efficacy Safety Differentiation of infected from vaccinated animals

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Attenuation mechanism of Brucella melitensis M5-10,implications for vaccine development and differential diagnosis

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Frontiers of Agricultural Science and Engineering 2014年第4期1卷 331-340页

作者： Yuanqiang ZHENG Yanchun SHI Chang AN Ruisheng LI Dongjun LIU Yuehua KE Kairong MAO Mingjuan YANG Zeliang CHEN Shorgan BOU National Research Center for Animal Transgenic Biotechnology Inner Mongolia UniversityHohhot 010021China Inner Mongolia Key Laboratory of Molecular Biology Inner Mongolia Medical UniversityHohhot 010058China Animal Laboratory Center 302 Hospital of PLABeijing 100039China Institute of Disease Control and Prevention Academy of Military Medical SciencesBeijing 100071China China Institute of Veterinary Drug Control Center for Veterinary Drug EvaluationMinistry of AgricultureBeijing 100081China College of Medicine Shihezi UniversityShihezi 832003China

Brucellosis is a worldwide zoonosis.Vaccination is the most efficient means to prevent and control brucellosis.The current licensed attenuated vaccines for animal use were developed by sequential passage in nonnatural hosts that decreased virulence in its original hosts.The attenuation mechanism of these strains remains largely unknown.In the present study,we sequenced the genome of Brucella melitensis vaccine strain M5-10.Sequence analysis showed that a large number of genetic changes occurred in the vaccine strains.A total of 2854 genetic polymorphic sites,including 2548 SNP,241 INDEL and 65 MNV were identified.Of the 2074 SNPs in coding regions,1310(63.2%)were non-synonymous SNPs.Gene number,percent and N/S ratios were disproportionally distributed among the cog categories.Genetic polymorphic sites were identified in genes of the virB operon,flagella synthesis,and virulence regulating systems.These data indicate that changes in some cog categories and virulence genes might result in the attenuation.These attenuation mechanisms also have implications for screening and development of new vaccine strains.The genetic changes in the genome represent candidate sites for differential diagnosis between these vaccine strains and other virulence ones.Transcription analysis of virulence genes showed that expression of dnaK,vjbR were reduced in M5-10 strain when compared with that in 16M.A duplex PCR targeting virB6 and dnaK was successfully used to differentiate between M5-10 and the virulent 16M strain.The genome re-sequencing technique represents a strong strategy not only for evaluation of vaccines,but also for development of new vaccines.

关键词： Brucella live attenuated vaccine attenuation differential diagnosis

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HUMAN PAPILLOMAVIRUS TYPE 16 L1 PROTEIN CAN BE EXPRESSED IN live attenuated SHIGELLA FLEXNERI 5A STRAIN SH42

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Journal of Pharmaceutical Analysis 2005年第1期17卷 57-61页

作者：屈新中杨筱凤郑瑾王凯司履生王一理 Department of Obesteric and Gynecology First Hospital of Xi'an Jiaotong University Xi'an 710061China Institute for Cancer Research School of Life and TechnologyXi anJiaotong UniversityXi an710061China

Objective attenuated strains of Shigella are attractive live vaccine candidates for eliciting mucosal immune responses which is a suitable carrier for the prophylactic human papillomaviruses (HPV) vaccine development, To examine the potential of a live Shigella based prophylactic HPV vaccine, HPV16L1should be expressed in attenuated shigella strain. Methods A Shigella large invasive plasmid (icsA/virG) based prokaryotic expression plasmid pHS3199 was constructed. HPV16L1 gene was inserted into plasmid pHS3199 to form pHS3199-HPV16 L1 construct, and pHS3199-hpv16L1 was electroporated into a live attenuated shigella strain sh42. The expression of HPV16L1 protein was demonstrated by Western blotting with monoclonal antibody to HPV16L1, The genetic stability of recombinant strain sh42-HPV16 L1 was monitored by consecutive passage culture. Invasive ability of sh42-HPV16L1 was evaluated by Hela cell infection assay. Results HPV16 L1 protein can be expressed in recombinant strain sh42-HPV16 L1, and the protein stably expressed over 140 generations. The invasive ability of sh42-HPV16L1 was diminished dramatically compared to its parent strain, but not abolished completely. Conclusion HPV16L1 protein was constitutively expressed in the attenuated strain of shigella flexneri sh42, and maintained partial invasive ability. Our strategy may represent a promising vaccine candidate against genital HPV16 infection.

关键词： human papillomaviruse type 16 live attenuated vaccine cervical cancer

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Study on the protective efficacy of SA14-14-2 attenuated Japanese encephalitis against different JE virus new isolates in China

Study on the protective efficacy of SA14-14-2 attenuated Jap...

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2010年中国药学大会暨第十届中国药师周

作者： Xinyu Liu~a,Yongxin Yu~a,Maoguang Li~a,Guodong Liang~b,Huanyu Wang~b,Lili Jia~a and Guanmu Dong~aa.Department of first viral vaccine ,National Institute for the Control of Pharmaceutical and Biological Products,Beijing,100050,China b. State Key Laboratory for Infectious Disease Prevention and Control,Institute for Viral Disease Control and Prevention,Chinese Center for Disease Control and Prevention,Beijing,100052,China

In China, many JE virus strains of genotype Ⅰ are isolated recent years while strains of genotype Ⅲ are still circulating. In order to understand the immunogenicity of vaccines to these new isolates of genotype Ⅰ, we perform this research. In vaccination-challenge protection test of mice, JE live attenuated vaccine （LAV）（≥234 pfu） and inactivated purified vaccine （IPV）（dilution 1:5） can protect effectively to all the tested strains including genotype Ⅰ strains by i.p. challenge. When challenged by i.c. routes, most of the virus strains can be protected （≥60%） by the LAV, and ≤40% by the IPV. This results indicated that JE vaccines used in China can still protect the prevalent strains in China and the LAV appeared stronger protection than that produced by IPV.

关键词： Japanese encephalitis virus live attenuated vaccine New isolates efficacy

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