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

As the SARS-CoV-2 viruses continue to evolve, mucosal immunity, particularly secretory immunoglobulin A (sIgA), has drawn increasing attention for its role in blocking viral entry at the respiratory mucosa. However, the real-world protective efficacy of mucosal vaccines against rapidly spreading variants such as JN.1 and KP.2 remains largely unverified.

In a recent study published in hLife, researchers from Guangzhou Medical University, led by Dr. Jincun Zhao and Dr. Yanqun Wang, investigated the mucosal and systemic immune responses following administration of a single booster dose of the inhaled adenoviral-vectored vaccine Ad5-XBB.1.5. The study, titled “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”, provides a comprehensive longitudinal analysis of immune responses up to six months post-vaccination.

A cohort of 34 participants was enrolled, with nasal swabs, saliva, and blood samples collected at baseline and on days 7, 14, 28, 90, and 180 following vaccination. The researchers monitored SARS-CoV-2-specific IgA and IgG antibody levels via ELISA, alongside neutralizing antibody titers and T-cell responses.

Results showed that a single mucosal dose of Ad5-XBB.1.5 effectively induced both nasal and plasma IgA responses against the XBB.1.5 spike protein, with IgA levels surpassing IgG at all time points. Peak antibody levels were observed on day 28. Functional assays demonstrated strong mucosal neutralizing activity against wild-type, BA.5, and XBB.1.5 variants, with IgA titers showing a stronger correlation with neutralization capacity than IgG, emphasizing IgA’s dominant role in mucosal protection.

However, the protective effect proved transient. By six months post-vaccination, nasal IgA titers had declined significantly, and most participants experienced mild or asymptomatic breakthrough infections during the JN.1 wave, suggesting that a single dose was insufficient to confer long-lasting protection in real-world conditions.

Further analysis revealed that pre-existing immunity to adenovirus 5 (Ad5) influenced vaccine efficacy. Participants with high baseline Ad5-neutralizing antibodies showed reduced immune responses post-vaccination, while those with low Ad5 immunity demonstrated greater induction of neutralizing antibodies, highlighting the impact of vector immunity on vaccine performance.

In terms of cellular immunity, while CD4⁺ T cell responses remained largely unchanged, antigen-specific CD8⁺ T cells were significantly boosted following vaccination. Cytokine secretion profiles remained stable, and no significant T cell epitope escape was observed across variants.

In summary, this study provides important real-world evidence on the immunogenicity and limitations of the Ad5-XBB.1.5 inhaled mucosal vaccine. While the vaccine effectively induces a rapid mucosal and systemic IgA response, its protective effect against emerging variants like JN.1 appears short-lived. These findings underscore the necessity for improved mucosal vaccine platforms capable of inducing durable immunity, as well as the potential need for periodic boosting to maintain sufficient protection in the upper respiratory tract.

About Author: (Briefly outline the corresponding author's academic achievements and research contributions) (One author only)

Dr. Jincun Zhao is a prominent immunologist and respiratory disease expert at Guangzhou Medical University, widely recognized for his pioneering work on mucosal immunity, T cell responses, and vaccine development against respiratory viruses such as influenza and SARS-CoV-2. His research focuses on understanding the mechanisms of host immune responses at the respiratory mucosal surface, particularly the role of tissue-resident memory T cells and secretory IgA in viral clearance and protection.

Dr. Zhao has led numerous influential studies on the immunopathogenesis of emerging respiratory pathogens, contributing significantly to the design and evaluation of intranasal vaccines. His work has been published in high-impact journals including Cell, Immunity, and The Lancet Infectious Diseases. His research has advanced global understanding of local immune defense mechanisms and informed strategies for next-generation vaccine design.