Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents Infection of Omicron lineages

• 成果类型: Article
• 署名作者: Marcotte, Harold; Cao, Yunlong; Zuo, Fanglei; Simonelli, Luca; Sammartino, Jose Camilla; Pedotti, Mattia; Sun, Rui; Cassaniti, Irene; Hagbom, Marie; Piralla, Antonio; Yang, Jinxuan; Du, Likun; Percivalle, Elena; Bertoglio, Federico; Schubert, Maren; Abolhassani, Hassan; Sherina, Natalia; Guerra, Concetta; Borte, Stephan; Rezaei, Nima; Kumagai-Braesch, Makiko; Xue, Yintong; Su, Chen; Yan, Qihong; He, Ping; Groenwall, Caroline; Klareskog, Lars; Calzolai, Luigi; Cavalli, Andrea; Wang, Qiao; Robbiani, Davide F.; Hust, Michael; Shi, Zhengli; Feng, Liqiang; Svensson, Lennart; Chen, Ling; Bao, Linlin; Baldanti, Fausto; Xiao, Junyu; Qin, Chuan; Hammarstrom, Lennart; Yang, Xinglou; Varani, Luca; Xie, Xiaoliang Sunney; Pan-Hammarstrom, Qiang
• 署名单位: Karolinska Institutet; Changping Laboratory; Peking University; Universita della Svizzera Italiana; IRCCS Fondazione San Matteo; Linkoping University; Chinese Academy of Sciences; Kunming Institute of Zoology, CAS; Braunschweig University of Technology; Tehran University of Medical Sciences; Karolinska Institutet; Peking University; Peking University; Chinese Academy of Sciences; Guangzhou Institute of Biomedicine & Health, CAS; State Key Laboratory of Respiratory Disease; Karolinska Institutet; Karolinska University Hospital; Karolinska Institutet; Karolinska University Hospital; European Commission Joint Research Centre; EC JRC ISPRA Site; Fudan University; Chinese Academy of Sciences; Wuhan Institute of Virology, CAS; Karolinska Institutet; Guangzhou Laboratory; Chinese Academy of Medical Sciences - Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; University of Pavia
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9371
• DOI: 10.1073/pnas.2315354120
• 发表日期: 2024-01-16
• 关键词: mucosal immunity; sars-cov-2; antibody; component

摘要

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previ- ously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot suffi- ciently boost the mucosal secretory IgA response in uninfected individuals, particu- larly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgAl antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibod- ies, dimeric and secretory IgAl antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgAl form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secre- tory IgA delivered by nasal administration may potentially be exploited for the treatment Iand prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.