AbstractThe upper respiratory tract is the initial site of SARS-CoV-2 infection. Nasal spike-specific secretory immunoglobulin A (sIgA) correlates with protection against Omicron breakthrough infection. We report that intranasal vaccination using human adenovirus serotype 5 (Ad5) vectored Omicron spike in people who previously vaccinated with ancestral vaccine could induce robust neutralizing sIgA in the nasal passage.

摘要上呼吸道是SARS-CoV-2感染的初始部位。鼻刺特异性分泌型免疫球蛋白A（sIgA）与预防Omicron突破性感染相关。我们报告说，使用人类腺病毒血清型5（Ad5）载体的Omicron spike鼻内疫苗接种先前接种祖先疫苗的人可以在鼻道中诱导强烈的中和sIgA。

Nasal sIgA was predominantly present in dimeric and multimeric forms and accounted for nearly 40% of total proteins in nasal mucosal lining fluids (NMLFs). A low-level IgG could also be detected in NMLFs but not IgM, IgD, and IgE. After a complete nasal wash, sIgA in the nasal passage could be replenished rapidly within a few hours.

鼻sIgA主要以二聚体和多聚体形式存在，占鼻粘膜衬里液（NMLF）总蛋白的近40%。在NMLF中也可以检测到低水平的IgG，但不能检测到IgM，IgD和IgE。完全洗鼻后，鼻道中的sIgA可以在几个小时内迅速补充。

A comparison of purified paired serum IgA, serum IgG, and nasal sIgA from the same individuals showed that sIgA was up to 3-logs more potent than serum antibodies in binding to spikes and in neutralizing Omicron subvariants. Serum IgG and IgA failed to neutralize XBB and BA.2.86, while nasal sIgA retained potent neutralization against these newly emerged variants.

来自同一个体的纯化的成对血清IgA，血清IgG和鼻sIgA的比较表明，sIgA在结合尖峰和中和Omicron亚变体方面比血清抗体效力高达3个对数。血清IgG和IgA未能中和XBB和BA.2.86，而鼻sIgA保留了对这些新出现的变体的有效中和作用。

Further analysis showed that sIgA was more effective than IgG or IgA in blocking spike-mediated cell-to-cell transmission and protecting hACE2 mice from XBB challenge. Using a sIgA monoclonal antibody as a reference, we estimated that the total nasal sIgA contains about 2.6–3.9% spike-specific sIgA in NMLFs collected approximately one month after intranasal vaccination.

进一步的分析表明，sIgA在阻断尖峰介导的细胞间传播和保护hACE2小鼠免受XBB攻击方面比IgG或IgA更有效。使用sIgA单克隆抗体作为参考，我们估计鼻内疫苗接种后约一个月收集的NMLF中总鼻sIgA含有约2.6–3.9%的穗特异性sIgA。

Our study provided insights for developing intranasal vaccines that can induce sIgA to build an effective and mutation-resistant first-line immune barrier against constantly emerging variants..

我们的研究为开发鼻内疫苗提供了见解，该疫苗可以诱导sIgA建立针对不断出现的变体的有效且抗突变的一线免疫屏障。。

IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic that has claimed the lives of more than 7.05 million people worldwide since the outbreak in 2019.1 SARS-CoV-2 initially infects epithelial cells in the nasopharynx by using the receptor-binding domain (RBD) of spike protein to interact with the angiotensin-converting enzyme 2 (ACE2) receptor.

引言严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是2019年冠状病毒病（COVID-19）大流行的病原体，自2019年爆发以来，全世界已有750多万人死亡。SARS-CoV-2最初通过使用穗蛋白的受体结合结构域（RBD）与血管紧张素转换酶2（ACE2）受体相互作用来感染鼻咽上皮细胞。

Since the end of 2021, Omicron subvariants have become the dominant circulating strains, capable of immune evasion and rapid transmission. Omicron subvariants preferentially infect the upper respiratory tract, particularly the nasal passage. Intramuscularly administered vaccines can reduce COVID-19 disease severity and mortality, but are ineffective in blocking infection with Omicron variants that first infect and replicate in the upper airway mucosa, especially in the nasal cavity.

自2021年底以来，Omicron亚型已成为主要的循环菌株，能够免疫逃避和快速传播。Omicron亚变体优先感染上呼吸道，特别是鼻道。肌肉注射疫苗可以降低COVID-19疾病的严重程度和死亡率，但对于阻断首先在上呼吸道粘膜（尤其是鼻腔）感染和复制的Omicron变体的感染无效。

It is reported that one month after the fourth dose of mRNA vaccine, vaccine efficacy against symptomatic Omicron infection was 11–30%. Most of these Omicron infected individuals have a high viral load in the nasopharyngeal tract and can therefore be highly contagious.2,3People who had multiple doses of vaccination plus a previous infection developed the so-called “hybrid immunity”, and were best protected against future symptomatic Omicron infection than people who only received mRNA vaccines.2 Anti-RBD IgA in saliva with neutralizing activities can be detected in SARS-CoV-2-infected patients.4 Spike-specific mucosal sIgA can be detected in the nasal swabs of individuals who recovered from a SARS-CoV-2 infection.5 After recovery from a previous SARS-CoV-2 infection, people with a lower level of SARS-CoV-2-specific sIgA in the nasal passage have a higher ris.

据报道，第四剂mRNA疫苗接种后一个月，针对症状性Omicron感染的疫苗效力为11-30%。这些Omicron感染者中的大多数在鼻咽道中具有高病毒载量，因此具有高度传染性。2,3多次接种疫苗加上先前感染的人产生了所谓的“混合免疫力”，并且比仅接受mRNA疫苗的人更好地防止了未来的症状性Omicron感染。2在SARS-CoV-2感染的患者中可以检测到唾液中具有中和活性的抗RBD IgA。4在从SARS-CoV-2感染中恢复的个体的鼻拭子中可以检测到尖峰特异性粘膜sIgA。5从先前的SARS-CoV-2感染中恢复后，SARS-CoV-2感染水平较低的人鼻道中的2特异性sIgA具有较高的ris。

Data availability

数据可用性

All data generated or analyzed during this study are available from the corresponding authors upon reasonable request.

本研究期间生成或分析的所有数据均可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsWe are grateful to Yichu Liu, Zhixia Li for their technical assistance in this study. The study was supported by the National Natural Science Foundation (92269201), Youth Innovation Promotion Association of CAS (2022361), Grants from Guangzhou National Laboratory (GZNL2024A01012, GZNL2023A01009), State Key Laboratory of Respiratory Disease (SKLRD-Z-202106, SKLRD-Z-202328), and Science and Technology Projects in Guangzhou (SL2022A04J00604).Author informationAuthor notesThese authors contributed equally: Si Chen, Zhengyuan Zhang, Qian Wang, Qi YangAuthors and AffiliationsGuangzhou Institute of Infectious Disease, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, ChinaSi Chen, Feng Li & Ling ChenGuangzhou National Laboratory, Guangzhou, ChinaSi Chen, Qian Wang, Qi Yang, Jielin Tang, Ping He, Hengchun Li, Yijun Deng, Baoqing Sun, Nanshan Zhong, Xinwen Chen & Ling ChenState Key Laboratory of Respiratory Disease, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaZhengyuan Zhang, Li Yin, Lishan Ning, Weiqi Deng, Linjing Shi, Zijian Liu, Hemeng Bu, Yaohui Zhu, Wenming Liu, Linbing Qu, Liqiang Feng, Xiaoli Xiong, Pingchao Li & Ling ChenUniversity of Chinese Academy of Sciences, Beijing, ChinaZhengyuan Zhang, Li Yin, Lishan Ning, Weiqi Deng, Linjing Shi, Zijian Liu, Hemeng Bu & Yaohui ZhuState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaQian Wang, Baoqing Sun, Nanshan Zhong, Xinwen Chen & Ling ChenXiamen United Institute of Respiratory Health, Xiamen, Chi.

下载参考文献致谢我们感谢刘一楚，李志霞在本研究中提供的技术援助。该研究得到了国家自然科学基金（92269201），中国科学院青年创新促进会（2022361），广州国家实验室（GZNL2024A01012，GZNL2023A01009），呼吸系统疾病国家重点实验室（SKLRD-Z-202106，SKLRD-Z-202328）和广州科技项目（SL2022A04J00604）的资助。作者信息作者注意到，这些作者做出了同样的贡献：陈思晨，张正元，钱旺，祁阳作者和附属机构广州医科大学广州市第八人民医院广州传染病研究所陈思晨，冯丽和凌凌陈光州国家实验室，广州，陈思晨，钱旺，祁阳，唐杰林，何平，李恒春，邓益军，孙宝清，钟南山，陈新文和凌晨中国科学院广州生物医学与健康研究所细胞谱系研究中心呼吸系统疾病国家重点实验室，广州，张正元，李寅，李山宁，邓伟奇，石林静，刘自健，布荷梦，朱耀辉，刘文明，瞿林兵，冯立强，熊晓丽，李平超，中国科学院北京大学，张正元，李寅，李山宁，邓伟奇，石林静，刘自健，广州医科大学第一附属医院广州呼吸健康研究所国家呼吸疾病临床研究中心呼吸系统疾病国家重点实验室，广州，中国广州，王倩，孙宝清，钟南山，陈新文，陈玲厦门呼吸健康联合研究所，厦门，池。

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PubMed Google ScholarXinwen ChenView author publicationsYou can also search for this author in

PubMed谷歌学者陈新文查看作者出版物您也可以在

PubMed Google ScholarLing ChenView author publicationsYou can also search for this author in

PubMed Google ScholarLing ChenView作者出版物您也可以在

PubMed Google ScholarContributionsSi Chen, Zhengyuan Zhang, and Li Yin purified serum IgA, serum IgG, and nasal sIgA. Qian Wang, Yijun Deng, and Hengchun Li performed pseudovirus neutralization assays. Qian Wang and Yijun Deng conducted MSD and ELISA analyses. Si Chen, Zhengyuan Zhang, Li Yin, and Wenming Liu performed western blot and size exclusion chromatography assays.

PubMed谷歌学术贡献Si Chen，Zhengyuan Zhang和Li Yin纯化了血清IgA，血清IgG和鼻sIgA。Qian Wang，Yijun Deng和Hengchun Li进行了假病毒中和试验。。Si Chen，Zhengyuan Zhang，Li Yin和Wemming Liu进行了蛋白质印迹和尺寸排阻色谱分析。

Qian Wang, Zhengyuan Zhang, Zijian Liu, Linjing Shi, Li Yin, Weiqi Deng, Hemeng Bu, and Yaohui Zhu collected human samples. Qi Yang and Jielin Tang performed an authentic virus neutralization assay. Qi Yang, Jielin Tang, and Qian Wang performed a mouse challenge study and analysis of lung virus load.

王倩，张正元，刘子建，石林静，李寅，邓伟奇，布何梦和朱耀辉收集了人类样本。Qi Yang和Jielin Tang进行了真正的病毒中和试验。Qi Yang，Jielin Tang和Qian Wang进行了小鼠攻击研究和肺病毒载量分析。

Zhilong Chen, Lishan Ning, and Ping He provided spike proteins and preparation of monoclonal antibodies. Liqiang Feng, Linbing Qu, Baoqing Sun, Xiaoli Xiong, and Nanshan Zhong reviewed the manuscript. Si Chen, Pingchao Li, Feng Li, Xinwen Chen, and Ling Chen wrote the paper with all co-authors. All authors have read and approved the article.Corresponding authorsCorrespondence to.

陈志龙，宁立山和何平提供了穗蛋白和单克隆抗体的制备。冯立强，瞿林兵，孙宝清，熊晓丽和钟南山审阅了手稿。Si Chen，Pingchao Li，Feng Li，Xinwen Chen和Ling Chen与所有合著者一起撰写了这篇论文。所有作者都阅读并批准了这篇文章。通讯作者通讯。

Pingchao Li, Xinwen Chen or Ling Chen.Ethics declarations

李平超，陈新文或陈玲。道德宣言

Competing interests

相互竞争的利益

Ling Chen serves as scientific advisor for Guangzhou nBiomed Ltd, which provided NB2155 (Ad5-S-Omicron BA.1) for this study. The remaining authors declare no competing interests.

陈玲是广州nBiomed有限公司的科学顾问，该公司为本研究提供了NB2155（Ad5-S-Omicron BA。1）。其余作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleChen, S., Zhang, Z., Wang, Q. et al. Intranasal adenovirus-vectored Omicron vaccine induced nasal immunoglobulin A has superior neutralizing potency than serum antibodies.

转载和许可本文引用本文Chen，S.，Zhang，Z.，Wang，Q。等人。鼻内腺病毒载体的Omicron疫苗诱导的鼻免疫球蛋白A具有比血清抗体更好的中和效力。

Sig Transduct Target Ther 9, 190 (2024). https://doi.org/10.1038/s41392-024-01906-0Download citationReceived: 20 February 2024Revised: 03 June 2024Accepted: 22 June 2024Published: 22 July 2024DOI: https://doi.org/10.1038/s41392-024-01906-0Share 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.

Sig Transduct Target Ther 9190（2024）。https://doi.org/10.1038/s41392-024-01906-0Download引文收到日期：2024年2月20日修订日期：2024年6月3日接受日期：2024年6月22日发布日期：2024年7月22日OI：https://doi.org/10.1038/s41392-024-01906-0Share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。

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