Comprehensive analysis of nasal IgA antibodies induced by intranasal administration of the SARS-CoV-2 spike protein.

Summary

Using monoclonal antibodies derived from intranasally immunized mice, the authors show that multimeric secretory IgA at the nasal mucosa can confer protection against SARS‑CoV‑2 even when the corresponding monomeric IgA is non-neutralizing. Prophylactic intranasal administration of multimeric secretory IgA reduced infection-induced weight loss in hamsters, establishing a mechanistic basis for nasal vaccine efficacy.

Key Findings

• Generated 99 nasal monoclonal IgA clones and 114 nonmucosal IgA/IgG clones from intranasally immunized mice.
• Lineage relationships indicate nonmucosal IgA plasma cells derive from B cells stimulated at the nasal mucosa.
• Multimeric secretory IgA conferred protection even when the corresponding monomeric IgA lacked neutralizing activity; ~70% of nasal IgA repertoire is non-neutralizing as monomers.
• Intranasal prophylaxis with multimeric secretory IgA reduced infection-induced weight loss in a hamster model.

Clinical Implications

Supports intranasal vaccine strategies and suggests that eliciting multimeric secretory IgA may provide mucosal protection even when serum neutralization is modest. Passive mucosal immunoprophylaxis with multimeric sIgA could be explored for high-risk exposure settings.

Limitations

• Preclinical murine and hamster models; human clinical efficacy and durability not assessed.
• Breadth against antigenic variants and safety of repeated intranasal sIgA administration require further study.

Future Directions

Translate to human intranasal vaccine trials focusing on inducing multimeric sIgA; evaluate passive intranasal sIgA as post-exposure prophylaxis; map epitope-specific multimerization effects across variants.