Nasal delivery of secretory IgA confers enhanced neutralizing activity against Omicron variants compared to its IgG...

Severe acute respiratory syndrome coronavirus 2 (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 the ZW2G10 antibody showed similar thermal stability. sIgA, especially sIgA1, displayed enhanced neutralizing activity against Omicron-lineage BA.2.75, BA.2.76 and BA.4/5 pseudoviruses compared to IgG. Nasal administration of sIgA1 conferred robust protection against the BA.2.76 pseudovirus in ACE2 transgenic mice, and its protective efficacy was superior to that of IgG. The crystal structure of Omicron receptor binding domain (RBD) and ZW2G10 antibody fragment (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.