Mucosal adenovirus vaccine Ad5-XBB.1.5 boosting elicits nasal IgA and transiently prevents JN.1 wave infection for less than 6 months in real-world settings

Mucosal antibodies are critical for protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by limiting viral replication and transmission. While systemic immunity to SARS-CoV-2 is well-characterized, the durability and protective efficacy of mucosal vaccines, especially during the recent JN.1 wave, are less understood. In this study, we conducted a longitudinal assessment of systemic and nasal immune responses in 34 individuals who had received the inhaled Ad5-XBB.1.5 vaccination at days 0, 7, 14, 28, 90, and 180 post-vaccination, using neutralization assays, immunoglobulin A/G (IgA/IgG) enzyme-linked immunosorbent assay (ELISA), T-cell staining, and Fc-effector function assays. Our results showed that mucosal vaccination preferentially induces IgA responses in both nasal mucosa and systemic circulation, with nasal IgA showing stronger correlation with neutralizing titers than IgG. However, nasal antibody responses declined significantly by 6 months post-vaccination, with most participants experiencing breakthrough infections during the JN.1 wave. Individuals with high pre-existing anti-Ad5 antibodies exhibited reduced vaccine-induced neutralizing responses. The Ad5-XBB.1.5 mucosal vaccine enhanced antigen-specific CD8⁺ T cell responses with a slight increase in Fc-mediated antibody-dependent cellular phagocytosis (ADCP), but failed to induce detectable CD4⁺ T cell responses. Collectively, our findings elucidate the limited durability of mucosal immunity post-vaccination and highlight the need for improved mucosal vaccine strategies that sustain and optimize nasal IgA responses.