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    The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously 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 sufficiently boost the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgA1 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 antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 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 secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.

    Citation

    Harold Marcotte, Yunlong Cao, Fanglei Zuo, Luca Simonelli, Josè Camilla Sammartino, Mattia Pedotti, Rui Sun, Irene Cassaniti, Marie Hagbom, Antonio Piralla, Jinxuan Yang, Likun Du, Elena Percivalle, Federico Bertoglio, Maren Schubert, Hassan Abolhassani, Natalia Sherina, Concetta Guerra, Stephan Borte, Nima Rezaei, Makiko Kumagai-Braesch, Yintong Xue, Chen Su, Qihong Yan, Ping He, Caroline Grönwall, Lars Klareskog, Luigi Calzolai, Andrea Cavalli, Qiao Wang, Davide F Robbiani, Michael Hust, Zhengli Shi, Liqiang Feng, Lennart Svensson, Ling Chen, Linlin Bao, Fausto Baldanti, Junyu Xiao, Chuan Qin, Lennart Hammarström, Xinglou Yang, Luca Varani, Xiaoliang Sunney Xie, Qiang Pan-Hammarström. Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages. Proceedings of the National Academy of Sciences of the United States of America. 2024 Jan 16;121(3):e2315354120

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    PMID: 38194459

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