AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) continues its significant health and economic impact globally. Despite the success of spike-protein vaccines in preventing severe disease, long-lasting protection against emerging variants and the prevention of breakthrough infections and transmission remain elusive.

摘要严重急性呼吸综合征冠状病毒2（SARS-CoV-2，COVID-19）继续在全球范围内对健康和经济产生重大影响。尽管刺突蛋白疫苗在预防严重疾病方面取得了成功，但对新出现的变异的持久保护以及预防突破性感染和传播仍然难以捉摸。

We generate an intranasal live-attenuated SARS-CoV-2 vaccine, CDO-7N-1, using codon deoptimization. CDO-7N-1 shows highly attenuated replication and minimal or no lung pathology in vivo over multiple passages. It induces robust mucosal and systemic neutralizing antibody and T-cell subset responses, in mice (female K18-hACE2 and male HFH4-hACE2 mice), hamsters, and macaques triggered by a single immunization.

我们使用密码子去优化产生鼻内减毒SARS-CoV-2活疫苗CDO-7N-1。CDO-7N-1在多次传代中显示出高度减毒的复制和体内最小或无肺部病理。它在小鼠（雌性K18-hACE2和雄性HFH4-hACE2小鼠），仓鼠和由单次免疫触发的猕猴中诱导强烈的粘膜和全身中和抗体和T细胞亚群反应。

Mice and hamsters vaccinated with CDO-7N-1 are protected from challenge with wild-type (WT) SARS-CoV-2 and other variants of concern. Serum from vaccinated animals neutralizes WT SARS-CoV-2, variants of concern (beta and delta), variants of interest (omicron XBB.1.5) and SARS-CoV-1. Antibody responses are sustained and enhanced by repeated immunization or infection with WT SARS-CoV-2.

用CDO-7N-1接种的小鼠和仓鼠免受野生型（WT）SARS-CoV-2和其他令人担忧的变体的攻击。来自接种疫苗的动物的血清中和WT SARS-CoV-2，关注的变体（β和δ），感兴趣的变体（omicron XBB.1.5）和SARS-CoV-1。通过反复免疫或感染WT SARS-CoV-2，抗体反应得以维持和增强。

Immunity against all SARS-CoV-2 proteins by CDO-7N-1 should improve efficacy against future SARS-CoV-2 variants..

CDO-7N-1对所有SARS-CoV-2蛋白的免疫力应能提高对未来SARS-CoV-2变异的疗效。。

IntroductionSevere acute respiratory syndrome virus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19)1,2,3,4, has resulted in over 700 million infections and 7 million deaths worldwide to date5 and continues to be lethal in susceptible individuals. SARS-CoV-2 has a positive-sense, RNA genome with a length of ~30 kb.

引言严重急性呼吸综合征病毒2（SARS-CoV-2）是2019年冠状病毒病（COVID-19）1,2,3,4的致病因子，迄今为止已导致全球7亿多人感染和700万人死亡5，并且在易感人群中仍然致命。SARS-CoV-2具有阳性意义，RNA基因组长度约为30 kb。

The genome has six major open reading frames that encode replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M) and nucleocapsid protein (N). In addition, 11 ORFs encoding accessory proteins are interspersed between structural genes6. The replicase gene encodes a large polyprotein (pp1a/b) that is proteolytically cleaved into 16 nonstructural proteins involved in viral RNA replication.

。此外，编码辅助蛋白的11个ORF散布在结构基因之间6。复制酶基因编码一种大的多蛋白（pp1a/b），该蛋白被蛋白水解切割成16种参与病毒RNA复制的非结构蛋白。

Although, COVID-19 therapeutic strategies have been developed7,8, vaccination is the primary and most effective way to prevent life-threatening COVID-19 disease. Currently available vaccines are typically designed around the spike protein since the receptor-binding domain (RBD) of this protein is the target of most serum-neutralizing antibodies.

虽然COVID-19治疗策略已经开发出来[7,8]，但疫苗接种是预防危及生命的COVID-19疾病的主要和最有效的方法。目前可用的疫苗通常围绕穗蛋白设计，因为该蛋白的受体结合结构域（RBD）是大多数血清中和抗体的靶标。

The protective effects of these vaccines were noticeably successful against alpha, beta, gamma and delta variants of SARS-CoV-2; however, the protection rate from symptomatic disease has declined sharply as new variants with RBD mutations have emerged. For example, the omicron variant and related strains continues to infect and be transmitted in vaccinated and recovered individuals9,10 and mutations in the S protein can decrease the sensitivity to neutralization by antibodies11.

这些疫苗对SARS-CoV-2的α，β，γ和δ变体的保护作用明显成功；然而，随着出现具有RBD突变的新变体，对症状性疾病的保护率急剧下降。例如，omicron变体和相关菌株继续感染并在接种和恢复的个体中传播9,10，S蛋白突变可降低抗体中和的敏感性11。

It is highly concerning that SARS-CoV-2 variants can evade neutralization by antibodies elicited by vaccines based on the S protein of the WT SARS-CoV-2 strain. As such, the design of SARS-CoV-2 vaccines targeting multiple antig.

高度关注的是，SARS-CoV-2变体可以逃避基于WT SARS-CoV-2菌株S蛋白的疫苗引发的抗体的中和。因此，针对多种抗原的SARS-CoV-2疫苗的设计。

Data availability

数据可用性

All datasets are provided in this study. Datasets generated and/or analyzed during the current study are provided with the paper or are appended as supplementary data. Source data are provided with this paper.

本研究提供了所有数据集。在当前研究期间生成和/或分析的数据集随论文提供或作为补充数据附加。本文提供了源数据。

ReferencesChan, J. F. et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395, 514–523 (2020).Article

ReferencesChan，J.F.等人。与2019年新型冠状病毒相关的肺炎家族簇，表明人与人之间的传播：一项家族簇的研究。柳叶刀395514-523（2020）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).Article

Zhou，P。等人。与可能起源于蝙蝠的新冠状病毒相关的肺炎爆发。自然579270-273（2020）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jeong, G. U. et al. Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation. Nat. Commun. 13, 7675 (2022).Article

Jeong，G.U.等人。鼻内接种后通过神经元侵袭产生视网膜炎症的动物模型中SARS-CoV-2的眼向性。国家公社。137675（2022年）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ng, W. H. et al. Comorbidities in SARS-CoV-2 Patients: a Systematic Review and Meta-Analysis. mBio 12, https://doi.org/10.1128/mBio.03647-20 (2021).WHO. Weekly epidemiological update on COVID-19 – 1 September 2023, <https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-september-2023 (2023).Chan, J.

Ng，W.H.等人。SARS-CoV-2患者的合并症：系统评价和荟萃分析。mBio 12，https://doi.org/10.1128/mBio.03647-20（2021年）。谁。2023年9月1日COVID-19的每周流行病学更新<https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-september-2023（2023年）。陈，J。

F. et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg. Microbes Infect. 9, 221–236 (2020).Article .

F、 等人。从访问武汉后的非典型肺炎患者中分离出的2019种新型人类致病性冠状病毒的基因组表征。紧急微生物感染。9221-236（2020）。文章。

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ng, W. H., Tang, P. C. H., Mahalingam, S. & Liu, X. Repurposing of drugs targeting the cytokine storm induced by SARS-CoV-2. Br. J. Pharm. 180, 133–143 (2023).Article

Ng，W.H.，Tang，P.C.H.，Mahalingam，S。＆Liu，X。重新利用靶向SARS-CoV-2诱导的细胞因子风暴的药物。。文章

CAS

中科院

Google Scholar

谷歌学者

Robinson, P. C. et al. COVID-19 therapeutics: challenges and directions for the future. Proc. Natl Acad. Sci. USA 119, e2119893119 (2022).Article

Robinson，P.C.等人，《新型冠状病毒治疗学：未来的挑战和方向》。程序。国家科学院。科学。美国119，e2119893119（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Puhach, O. et al. Infectious viral load in unvaccinated and vaccinated individuals infected with ancestral, Delta or Omicron SARS-CoV-2. Nat. Med 28, 1491–1500 (2022).Article

Puhach，O.等人。未接种疫苗和接种疫苗的个体感染祖先，Delta或Omicron SARS-CoV-2的传染性病毒载量。《自然医学》281491-1500（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Pulliam, J. R. C. et al. Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa. Science 376, eabn4947 (2022).Article

Pulliam，J.R.C.等人，南非出现Omicron后，SARS-CoV-2再感染风险增加。科学376，eabn4947（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021).Article

Gaebler，C。等人。SARS-CoV-2抗体免疫的进化。自然591639-644（2021）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhao, F., Zai, X., Zhang, Z., Xu, J. & Chen, W. Challenges and developments in universal vaccine design against SARS-CoV-2 variants. NPJ Vaccines 7, 167 (2022).Article

Zhao，F.，Zai，X.，Zhang，Z.，Xu，J。＆Chen，W。针对SARS-CoV-2变体的通用疫苗设计的挑战和发展。NPJ疫苗7167（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Garcia-Beltran, W. F. et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell 184, 2372–2383.e2379 (2021).Article

Garcia-Beltran，W.F.等人。多种SARS-CoV-2变体通过疫苗诱导的体液免疫逃避中和。细胞1842372–2383.e2379（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ng, W. H., Liu, X. & Mahalingam, S. Development of vaccines for SARS-CoV-2. F1000Res 9, https://doi.org/10.12688/f1000research.25998.1 (2020).Sheikh-Mohamed, S., Sanders, E. C., Gommerman, J. L. & Tal, M. C. Guardians of the oral and nasopharyngeal galaxy: IgA and protection against SARS-CoV-2 infection.

Ng，W.H.，Liu，X。和Mahalingam，S。SARS-CoV-2疫苗的开发。F1000Res 9，https://doi.org/10.12688/f1000research.25998.1（2020年）。Sheikh Mohamed，S.，Sanders，E.C.，Gommerman，J.L。＆Tal，M.C。口腔和鼻咽星系的守护者：IgA和对SARS-CoV-2感染的保护。

Immunol. Rev. 309, 75–85 (2022).Article .

免疫。第309版，第75-85页（2022年）。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yang, S. L. et al. Comprehensive mapping of SARS-CoV-2 interactions in vivo reveals functional virus-host interactions. Nat. Commun. 12, 5113 (2021).Article

Yang，S.L.等人。体内SARS-CoV-2相互作用的全面定位揭示了功能性病毒-宿主相互作用。国家公社。125113（2021）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Nogales, A. et al. Influenza A virus attenuation by codon deoptimization of the NS gene for vaccine development. J. Virol. 88, 10525–10540 (2014).Article

Nogales，A。等人。通过密码子去优化NS基因以进行疫苗开发来减弱甲型流感病毒。J、 维罗尔。8810525-10540（2014）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gimenez-Roig, J., Nunez-Manchon, E., Alemany, R., Villanueva, E. & Fillat, C. Codon usage and adenovirus fitness: implications for vaccine development. Front Microbiol 12, 633946 (2021).Article

Gimenez-Roig，J.，Nunez-Manchon，E.，Alemany，R.，Villanueva，E。＆Fillat，C。密码子使用和腺病毒适应性：对疫苗开发的影响。前微生物12633946（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lorenzo, M. M., Nogales, A., Chiem, K., Blasco, R. & Martinez-Sobrido, L. Vaccinia virus attenuation by codon deoptimization of the a24r gene for vaccine development. Microbiol Spectr. 10, e0027222 (2022).Article

Lorenzo，M.M.，Nogales，A.，Chiem，K.，Blasco，R。＆Martinez-Sobrido，L.痘苗病毒通过密码子去优化a24r基因来减弱疫苗开发。微生物光谱。10，e0027222（2022）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Konopka-Anstadt, J. L. et al. Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization. NPJ Vaccines 5, 26 (2020).Article

Konopka Anstadt，J.L.等人。使用密码子去优化开发用于根除最终游戏的新型口服脊髓灰质炎病毒疫苗。NPJ疫苗5,26（2020）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rihn, S. J. et al. A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research. PLoS Biol. 19, e3001091 (2021).Article

Rihn，S.J。等人。质粒DNA启动了SARS-CoV-2反向遗传学系统和冠状病毒工具包，用于COVID-19研究。《公共科学图书馆·生物学》。19，e3001091（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Tarres-Freixas, F. et al. Heterogeneous infectivity and pathogenesis of sars-cov-2 variants beta, delta and omicron in transgenic k18-hace2 and wildtype mice.Front. Microbiol. 13, 840757 (2022).Article

。正面。微生物。13840757（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, X. et al. The delta SARS-CoV-2 variant of concern induces distinct pathogenic patterns of respiratory disease in k18-hace2 transgenic mice compared to the ancestral strain from wuhan. mBio 13, e0068322 (2022).Article

。mBio 13，e0068322（2022）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Stammes, M. A. et al. Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates. Trends Mol. Med. 28, 123–142 (2022).Article

Stammes，M.A.等人。SARS-CoV-2暴露的非人灵长类动物肺部疾病的医学成像。趋势分子医学28123-142（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Xia, S., Wang, L., Zhu, Y., Lu, L. & Jiang, S. Origin, virological features, immune evasion and intervention of SARS-CoV-2 Omicron sublineages. Signal Transduct. Target Ther. 7, 241 (2022).Article

Xia，S.，Wang，L.，Zhu，Y.，Lu，L。＆Jiang，S。SARS-CoV-2 Omicron亚系的起源，病毒学特征，免疫逃避和干预。信号传输管。目标Ther。7241（2022年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

WHO. Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic. <https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic (2023).Beatty, A.

谁。《国际卫生条例（2005）》关于新型冠状病毒大流行紧急委员会第十五次会议的声明<https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-（2005）-关于冠状病毒病（covid-19）-大流行的紧急委员会（2023）。。

L. et al. Analysis of COVID-19 vaccine type and adverse effects following vaccination. JAMA Netw. Open 4, e2140364 (2021).Article .

五十、 等。新型冠状病毒肺炎疫苗类型和接种后不良反应的分析。JAMA网络。开放4，e2140364（2021）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, Y. et al. A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions. Nat. Commun. 13, 4337 (2022).Article

Liu，Y。等人。具有辅助蛋白缺失的减毒SARS-CoV-2活疫苗候选物。国家公社。134337（2022年）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, Y. et al. Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy. Proc. Natl Acad. Sci. USA 118, e2102775118 (2021).Article

Wang，Y。等人。可扩展的SARS-CoV-2减毒活疫苗候选物证明了临床前的安全性和有效性。程序。国家科学院。科学。美国118，e2102775118（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sanchez-Felipe, L. et al. A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate. Nature 590, 320–325 (2021).Article

Sanchez-Felipe，L。等人。单剂量减毒YF17D载体SARS-CoV-2候选疫苗。自然590320-325（2021）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Zhu, F. et al. Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Respir. Med 10, 749–760 (2022).Article

Zhu，F.等人。基于减毒活流感病毒载体的成人鼻内SARS-CoV-2疫苗的安全性和免疫原性：随机，双盲，安慰剂对照，1期和2期试验。柳叶刀呼吸。医学杂志10749-760（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Tang, P. C. H., Ng, W. H., King, N. J. C. & Mahalingam, S. Can live-attenuated SARS-CoV-2 vaccine contribute to stopping the pandemic? PLoS Pathog. 18, e1010821 (2022).Article

Tang，P.C.H.，Ng，W.H.，King，N.J.C。和Mahalingam，S。减毒SARS-CoV-2活疫苗能否有助于阻止大流行？PLoS Pathog。18，e1010821（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ramesh, S. et al. Emerging SARS-CoV-2 variants: a review of its mutations, its implications and vaccine efficacy. Vaccines (Basel) 9, https://doi.org/10.3390/vaccines9101195 (2021).Tarke, A. et al. Impact of SARS-CoV-2 variants on the total CD4(+) and CD8(+) T cell reactivity in infected or vaccinated individuals.

Ramesh，S。等人。新出现的SARS-CoV-2变体：其突变，其意义和疫苗功效的综述。疫苗（巴塞尔）9，https://doi.org/10.3390/vaccines9101195（2021年）。。

Cell Rep. Med 2, 100355 (2021).Article .

Cell Rep.Med 2100355（2021）。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Goldblatt, D., Alter, G., Crotty, S. & Plotkin, S. A. Correlates of protection against SARS-CoV-2 infection and COVID-19 disease. Immunol. Rev. 310, 6–26 (2022).Article

Goldblatt，D.，Alter，G.，Crotty，S。＆Plotkin，S.A。与SARS-CoV-2感染和COVID-19疾病的保护相关。免疫。第310版，第6-26页（2022年）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Abu-Raddad, L. J. et al. Effect of mRNA vaccine boosters against SARS-CoV-2 omicron infection in qatar. N. Engl. J. Med 386, 1804–1816 (2022).Article

Abu Raddad，L.J.等人。卡塔尔针对SARS-CoV-2 omicron感染的mRNA疫苗增强剂的效果。N、 英语。J、 Med 3861804–1816（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Andrews, N. et al. Covid-19 vaccine effectiveness against the omicron (B.1.1.529) variant. N. Engl. J. Med 386, 1532–1546 (2022).Article

Andrews，N.等人，针对omicron（B.1.1.529）变体的新型冠状病毒肺炎疫苗的有效性。N、 英语。J、 。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Park, J. H. & Lee, H. K. Delivery Routes for COVID-19 Vaccines. Vaccines (Basel) 9, https://doi.org/10.3390/vaccines9050524 (2021).Tang, J. et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci. Immunol. 7, eadd4853 (2022).Article

Park，J.H。和Lee，H.K。新型冠状病毒疫苗的递送途径。疫苗（巴塞尔）9，https://doi.org/10.3390/vaccines9050524（2021年）。Tang，J。等人。mRNA疫苗接种后对SARS-CoV-2的呼吸道粘膜免疫。科学。免疫。。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Meinhardt, J. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat. Neurosci. 24, 168–175 (2021).Article

Meinhardt，J。等人。嗅觉跨粘膜SARS-CoV-2入侵是COVID-19个体中枢神经系统进入的港口。自然神经科学。24168-175（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Chen, S. et al. The role of B cells in COVID-19 infection and vaccination. Front Immunol. 13, 988536 (2022).Article

Chen，S。等人。B细胞在COVID-19感染和疫苗接种中的作用。前免疫。13988536（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lv, J., Wu, H., Xu, J. & Liu, J. Immunogenicity and safety of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine: a systematic review. Infect. Dis. Poverty 11, 53 (2022).Article

Lv，J.，Wu，H.，Xu，J。＆Liu，J。使用腺病毒载体和mRNA COVID-19疫苗的异源与同源初次加强方案的免疫原性和安全性：系统评价。感染。Dis。贫困11，53（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sapkota, B. et al. Heterologous prime-boost strategies for COVID-19 vaccines. J. Travel Med. 29, https://doi.org/10.1093/jtm/taab191 (2022)Bates, T. A. et al. Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants.

Sapkota，B。等人。COVID-19疫苗的异源初次加强策略。J、 旅行医学29，https://doi.org/10.1093/jtm/taab191（2022）Bates，T.A.等人在SARS-CoV-2感染之前或之后接种疫苗导致强烈的体液反应和有效中和变体的抗体。

Sci. Immunol. 7, eabn8014 (2022).Article .

科学。免疫。7，eabn8014（2022）。文章。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Bates, T. A. et al. Antibody response and variant cross-neutralization after SARS-CoV-2 breakthrough infection. JAMA 327, 179–181 (2022).Article

Bates，T.A.等人。SARS-CoV-2突破性感染后的抗体反应和变异交叉中和。JAMA 327179-181（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Guo, L. et al. SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study. Lancet Microbe 3, e348–e356 (2022).Article

郭，L。等。SARS-CoV-2特异性抗体和感染后1年从COVID-19恢复的人的T细胞反应：一项纵向队列研究。柳叶刀微生物3，e348-e356（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, X. et al. Infectious clones produce SARS-CoV-2 that causes severe pulmonary disease in infected K18-human ACE2 mice. mBio 12, https://doi.org/10.1128/mBio.00819-21 (2021).Hou, Y. J. et al. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science 370, 1464–1468 (2020).Article .

Liu，X。等人。传染性克隆产生SARS-CoV-2，在感染的K18人ACE2小鼠中引起严重的肺部疾病。mBio 12，https://doi.org/10.1128/mBio.00819-21（2021年）。Hou，Y。J。等人。SARS-CoV-2 D614G变体在体外表现出有效的复制和体内传播。科学3701464-1468（2020）。文章。

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Martinez, D. R. et al. A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice. bioRxiv https://doi.org/10.1101/2021.04.27.441655 (2021).Munoz-Fontela, C. et al. Animal models for COVID-19. Nature 586, 509–515 (2020).Article

Martinez，D.R.等人。一种广泛中和的抗体可以预防小鼠中的SARS-CoV，突现前bat-CoV和SARS-CoV-2变异。生物十四https://doi.org/10.1101/2021.04.27.441655（2021年）。Munoz-Fontela，C。等人。新型冠状病毒肺炎的动物模型。《自然》586509-515（2020）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Arce, V. M. & Costoya, J. A. SARS-CoV-2 infection in K18-ACE2 transgenic mice replicates human pulmonary disease in COVID-19. Cell Mol. Immunol. 18, 513–514 (2021).Article

Arce，V.M。＆Costoya，J.A。K18-ACE2转基因小鼠中的SARS-CoV-2感染在COVID-19中复制人类肺部疾病。细胞分子免疫。18513-514（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jiang, R. D. et al. Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensin-converting enzyme 2. Cell 182, 50–58.e58 (2020).Article

Jiang，R.D.等人。SARS-CoV-2在表达人血管紧张素转换酶2的转基因小鼠中的发病机制。。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ashhurst, T. M., Cox, D. A., Smith, A. L. & King, N. J. C. Analysis of the murine bone marrow hematopoietic system using mass and flow cytometry. Methods Mol. Biol. 1989, 159–192 (2019).Article

Ashhurst，T.M.，Cox，D.A.，Smith，A.L。＆King，N.J.C。使用质量和流式细胞术分析小鼠骨髓造血系统。方法分子生物学。1989159-192（2019）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Ashhurst, T. M. et al. Integration, exploration, and analysis of high-dimensional single-cell cytometry data using Spectre. Cytom. A 101, 237–253 (2022).Article

Ashhurst，T.M.等人。使用Spectre对高维单细胞细胞计数数据进行整合，探索和分析。Cytom公司。A 101237-253（2022）。文章

CAS

中科院

Google Scholar

谷歌学者

Van Gassen, S. et al. FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Cytom. A 87, 636–645 (2015).Article

Van Gassen，S。等人。FlowSOM：使用自组织图可视化和解释细胞计数数据。Cytom公司。。文章

Google Scholar

谷歌学者

Linderman, G. C., Rachh, M., Hoskins, J. G., Steinerberger, S. & Kluger, Y. Fast interpolation-based t-SNE for improved visualization of single-cell RNA-seq data. Nat. Methods 16, 243–245 (2019).Article

Linderman，G.C.，Rachh，M.，Hoskins，J.G.，Steinerberger，S。＆Kluger，Y。基于快速插值的t-SNE，用于改进单细胞RNA-seq数据的可视化。自然方法16243-245（2019）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Matsuyama, S. et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc. Natl Acad. Sci. USA 117, 7001–7003 (2020).Article

。程序。国家科学院。科学。美国1177001–7003（2020）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lau, E. H. et al. Long-term persistence of SARS-CoV-2 neutralizing antibody responses after infection and estimates of the duration of protection. EClinicalMedicine 41, 101174 (2021).Article

Lau，E.H.等人。感染后SARS-CoV-2中和抗体反应的长期持续性和保护持续时间的估计。EClinicalMedicine 41101174（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsThis study was supported by Indian Immunologicals Ltd. S.M. is the recipient of an NHMRC Senior Research Fellowship (APP1154347). W.H.N. is a recipient of a Griffith University Postgraduate Scholarship. We would like to thank Drs Julian Druce and Leon Caly from the Victorian Infectious Diseases Reference Laboratory (VIDRL) for providing SARS-CoV-2 variant strains.

下载参考文献致谢本研究得到了印度免疫学有限公司的支持。S.M.是NHMRC高级研究奖学金（APP1154347）的获得者。W、 H.N.是格里菲斯大学研究生奖学金的获得者。我们要感谢维多利亚传染病参考实验室（VIDRL）的朱利安·德鲁塞（JulianDruce）博士和莱昂·卡利（LeonCaly）博士提供SARS-CoV-2变异株。

We also appreciate Dr Aroon Supramaniam and Professor Nigel McMillan (both from Griffith University) for kindly cultivating stocks of the omicron variant and providing the virus for our studies. Griffith University contracted COMMISSARIAT A L’ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES (CEA), Center for Immunology of Viral, Autoimmune, Hematological, and Bacterial Diseases to perform the non-human primate study (research agreement Ref CEA: CJ 2020-0398).

我们还感谢Aroon Supramaniam博士和Nigel McMillan教授（均来自格里菲斯大学）友善地培育了omicron变体的种群，并为我们的研究提供了病毒。。

We would specifically like to acknowledge CEA staff Drs. Roger Le Grand, Helene Letscher, Marlin Romain, and Quentin Pascal, along with other CEA staff members, for their contributions to the non-human primate data in this study. We would like to acknowledge the contributions of the animal facility staff members from Griffith University.

我们特别感谢CEA工作人员Roger Le Grand博士，Helene Letscher博士，Marlin Romain博士和Quentin Pascal博士以及其他CEA工作人员对本研究中非人灵长类动物数据的贡献。我们要感谢格里菲斯大学动物设施工作人员的贡献。

BioRender was used to generate supplementary Fig. 2c and 3a, supplementary Fig. 14a and e and supplementary Fig. 19-23 in this study.Author informationAuthors and AffiliationsEmerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, AustraliaXiang Liu, Wern Hann Ng, Joseph Freitas, Adam Taylor, Ali Zaid, Ujjwal Dua, Nicholas J.

。作者信息作者和所属机构Menzies Health Institute Queensland，Griffith University，Gold Coast，QLD，AustraliaXiang Liu，Wern Hann Ng，Joseph Freitas，Adam Taylor，Ali Zaid，Ujjwal Dua，Nicholas J。

C. King & Suresh MahalingamGlobal Virus Network (GVN) Centre of Excellence in Arboviruses, Griffith University, Gold Coast, QLD, AustraliaXiang Liu, Wern Hann Ng, Joseph Freitas, .

C、 King＆Suresh MahalingamGlobal Virus Network（GVN）虫媒病毒卓越中心，格里菲斯大学，昆士兰州黄金海岸，澳大利亚刘翔，Wern Hann Ng，Joseph Freitas。

PubMed Google ScholarWern Hann NgView author publicationsYou can also search for this author in

PubMed Google ScholarWern Hann NgView作者出版物您也可以在

PubMed Google ScholarEva ZusinaiteView author publicationsYou can also search for this author in

PubMed Google ScholarEva Zusinateview作者出版物您也可以在

PubMed Google ScholarJoseph FreitasView author publicationsYou can also search for this author in

PubMed谷歌学者Joseph FreitasView作者出版物您也可以在

PubMed Google ScholarAdam TaylorView author publicationsYou can also search for this author in

PubMed Google ScholarVenugopal YerraguntaView author publicationsYou can also search for this author in

PubMed Google ScholarVenugopal YerraguntaView作者出版物您也可以在

PubMed Google ScholarShukra Madhaha AavulaView author publicationsYou can also search for this author in

PubMed Google ScholarShukra Madhaha AavulaView作者出版物您也可以在

PubMed Google ScholarSambaiah GorriparthiView author publicationsYou can also search for this author in

PubMed Google ScholarSambaiah GorriparthiView作者出版物您也可以在

PubMed Google ScholarSanthakumar PonsekaranView author publicationsYou can also search for this author in

PubMed Google ScholarSanthakumar PonsekaranView作者出版物您也可以在

PubMed Google ScholarRama Lakshmi BondaView author publicationsYou can also search for this author in

PubMed Google ScholarRama Lakshmi BondaView作者出版物您也可以在

PubMed Google ScholarPriyanka ManiView author publicationsYou can also search for this author in

PubMed Google ScholarPriyanka ManiView作者出版物您也可以在

PubMed Google ScholarSridevi V. NimmagaddaView author publicationsYou can also search for this author in

PubMed Google ScholarSridevi V.NimmagaddaView作者出版物您也可以在

PubMed Google ScholarSainan WangView author publicationsYou can also search for this author in

PubMed Google ScholarSainan WangView作者出版物您也可以在

PubMed Google ScholarLaura Sandra LelloView author publicationsYou can also search for this author in

PubMed Google ScholarLaura Sandra LelloView作者出版物您也可以在

PubMed Google ScholarAli ZaidView author publicationsYou can also search for this author in

PubMed Google ScholarAli ZaidView作者出版物您也可以在

PubMed Google ScholarUjjwal DuaView author publicationsYou can also search for this author in

PubMed Google ScholarUjjwal DuaView作者出版物您也可以在

PubMed Google ScholarSharon A. Taft-BenzView author publicationsYou can also search for this author in

PubMed Google ScholarElizabeth AndersonView author publicationsYou can also search for this author in

PubMed Google ScholarElizabeth AndersonView作者出版物您也可以在

PubMed Google ScholarVictoria K. BaxterView author publicationsYou can also search for this author in

PubMed Google ScholarVictoria K.BaxterView作者出版物您也可以在

PubMed Google ScholarSanjay SarkarView author publicationsYou can also search for this author in

PubMed Google ScholarSanjay SarkarView作者出版物您也可以在

PubMed Google ScholarZheng L. LingView author publicationsYou can also search for this author in

PubMed Google ScholarZheng L.LingView作者出版物您也可以在

PubMed Google ScholarThomas M. AshhurstView author publicationsYou can also search for this author in

PubMed Google ScholarThomas M.AshhurstView作者出版物您也可以在

PubMed Google ScholarSamuel M. S. ChengView author publicationsYou can also search for this author in

PubMed Google ScholarSamuel M.S.ChengView作者出版物您也可以在

PubMed Google ScholarPriyabrata PattnaikView author publicationsYou can also search for this author in

PubMed Google ScholarPriyabrata PattnaikView作者出版物您也可以在

PubMed Google ScholarAnand Kumar KanakasapapathyView author publicationsYou can also search for this author in

PubMed Google Scholarand Kumar KanakasapapathyView作者出版物您也可以在

PubMed Google ScholarRalph S. BaricView author publicationsYou can also search for this author in

PubMed Google Scholaralph S.BaricView作者出版物您也可以在

PubMed Google ScholarFelicity J. BurtView author publicationsYou can also search for this author in

PubMed Google ScholarFelicity J.BurtView作者出版物您也可以在

PubMed Google ScholarMalik PeirisView author publicationsYou can also search for this author in

PubMed Google ScholarMalik PeirisView作者出版物您也可以在

PubMed Google ScholarMark T. HeiseView author publicationsYou can also search for this author in

PubMed Google ScholarMark T.HeiseView作者出版物您也可以在

PubMed Google ScholarNicholas J. C. KingView author publicationsYou can also search for this author in

PubMed Google ScholarNicholas J.C.KingView作者出版物您也可以在

PubMed Google ScholarAndres MeritsView author publicationsYou can also search for this author in

PubMed Google Scholaranders MeritsView作者出版物您也可以在

PubMed Google ScholarRajendra LingalaView author publicationsYou can also search for this author in

PubMed Google Scholarajendra LingalaView作者出版物您也可以在

PubMed Google ScholarSuresh MahalingamView author publicationsYou can also search for this author in

PubMed Google ScholarSuresh MahalingamView作者出版物您也可以在

PubMed Google ScholarContributionsS.M. and R.L. conceived this study. S.M., R.L., A.M., U.D., P.P., A.K.K., and M.T.H. supervised this study. S.M., X.L., M.T.H., A.M., R.L., and N.J.C.K. designed experiments. W.H.N., X.L., E.Z., J.F., A.Z., A.T., S.W., L.S.L., V.Y., S.M.A., S.G., S.P., R.L.B., P.M., S.A.T-B., E.A., V.K.B., S.S., Z.L.L., and T.M.A.

PubMed谷歌学术贡献。M、 R.L.构思了这项研究。S、 M.，R.L.，A.M.，U.D.，P.P.，A.K.K。和M.T.H.监督了这项研究。S、 M.，X.L.，M.T.H.，A.M.，R.L。和N.J.C.K.设计的实验。W、 H.N.，X.L.，E.Z.，J.F.，A.Z.，A.T.，S.W.，L.S.L.，V.Y.，S.M.A.，S.G.，S.P.，R.L.B.，P.M.，S.A.T-B.，E.A.，V.K.B.，S.S.，Z.L.L.，和T.M.A。

performed experiments. X.L., E.Z., V.Y., S.M.A., S.G., S.P., R.L.B., P.M., S.V.M., S.A.T-B., E.A., V.K.B., S.S., Z.L.L., and T.M.A. analyzed data. R.B., M.T.H., and N.J.C.K. provided essential reagents. S.M., W.H.N., F.B., and X.L. wrote the manuscript. All authors reviewed and edited the manuscript.Corresponding authorCorrespondence to.

进行了实验。十、 L.，E.Z.，V.Y.，S.M.A.，S.G.，S.P.，R.L.B.，P.M.，S.V.M.，S.A.T-B.，E.A.，V.K.B.，S.S.，Z.L.L。和T.M.A.分析数据。R、 B.，M.T.H。和N.J.C.K.提供了必需的试剂。S、 M.，W.H.N.，F.B。和X.L.撰写了手稿。所有作者都审阅并编辑了手稿。对应作者对应。

Suresh Mahalingam.Ethics declarations

Suresh Mahalingam。道德宣言

Competing interests

相互竞争的利益

Suresh Mahalingam, Xiang Liu, and Andres Merits are inventors of the live-attenuated SARS-CoV-2 vaccine CDO-7N-1, which has been licensed to Indian Immunologicals Ltd for further development. The study was funded by Indian Immunologicals Ltd. Venugopal Yerragunta, Shukra Madhaha Aavula, Sambaiah Gorriparthi, Santhakumar Ponsekaran, Rama Lakshmi Bonda, Priyanka Mani, Sridevi V.

Suresh Mahalingam，Xiang Liu和Andres Mertives是减毒SARS-CoV-2活疫苗CDO-7N-1的发明者，该疫苗已获得印度Immunomicals Ltd的进一步开发许可。这项研究由印度免疫学有限公司资助。Venugopal Yerragunta，Shukra Madhaha Aavula，Sambaiah Gorriparthi，Santhakumar Ponsekaran，Rama Lakshmi Bonda，Priyanka Mani，Sridevi V。

Nimmagadda, Priyabrata Pattnaik, Anand Kumar Kanakasapapathy, and Rajendra Lingala are employees of Indian Immunologicals Ltd. The remaining authors declare no competing interests..

Nimmagadda，Priyabrata Pattnaik，Anand Kumar Kanakasapathy和Rajendra Lingala是印度免疫学有限公司的员工。其余作者声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature Communications thanks Kai Dallmeier, Shibo Jiang, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢Kai Dallmeier，Shibo Jiang和其他匿名审稿人对这项工作的同行评审做出的贡献。同行评审文件可用。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationPeer Review FileReporting SummarySource dataSource DataRights and permissions

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息同行评审文件报告摘要源数据源数据权限

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

开放获取本文是根据知识共享署名非商业性NoDerivatives 4.0国际许可证授权的，该许可证允许以任何媒介或格式进行任何非商业性使用，共享，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出您是否修改了许可材料。

You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

根据本许可证，您无权共享源自本文或其部分的改编材料。本文中的图像或其他第三方材料包含在文章的知识共享许可证中，除非该材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不受法律法规的许可或超出许可用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by-nc-nd/4.0/..

Reprints and permissionsAbout this articleCite this articleLiu, X., Ng, W.H., Zusinaite, E. et al. A single-dose intranasal live-attenuated codon deoptimized vaccine provides broad protection against SARS-CoV-2 and its variants.

转载和许可本文引用本文Liu，X.，Ng，W.H.，Zusinaite，E。等人。单剂量鼻内减毒活密码子去优化疫苗提供了针对SARS-CoV-2及其变体的广泛保护。

Nat Commun 15, 7225 (2024). https://doi.org/10.1038/s41467-024-51535-yDownload citationReceived: 06 May 2024Accepted: 07 August 2024Published: 26 August 2024DOI: https://doi.org/10.1038/s41467-024-51535-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157225（2024）。https://doi.org/10.1038/s41467-024-51535-yDownload引文接收日期：2024年5月6日接受日期：2024年8月7日发布日期：2024年8月26日OI：https://doi.org/10.1038/s41467-024-51535-yShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供

CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

评论通过提交评论，您同意遵守我们的条款和社区指南。如果您发现有虐待行为或不符合我们的条款或准则，请将其标记为不合适。