SARS-CoV-2 and its multiple variants continue to spread worldwide, causing respiratory symptoms primarily through mucosal infection. The mucosa serves as the primary barrier against viral entry, in which secretory immunoglobulin A (sIgA) plays a critical role in preventing infection. Here, we engineered and characterized a neutralizing monoclonal antibody ZW2G10 in IgG, monomeric, dimeric, secretory IgA1 and IgA2 formats. All seven forms of ZW2G10 antibodies showed similar thermal stability. Secretory IgA, especially sIgA1, displayed enhanced neutralizing activity against Omicron-lineages BA.2.75, BA.2.76 and BA.4/5 pseudoviruses compared to IgG. Nasal administration of sIgA1 conferred robust protection against BA.2.76 pseudovirus in ACE2 transgenic mice, and its protective efficacy was superior to that of IgG. The crystal structure of Omicron RBD and ZW2G10 Fab complex revealed that ZW2G10 had no clashes with ACE2. Thus, nasal administration of sIgA may serve as a promising tool for the prevention and treatment of Omicron infection.
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