From injection to inhalation: A STING‐activating mucosal adjuvant reprograms vaccination

The respiratory mucosa of the nasal cavity and conducting airways is a major portal of entry for respiratory viruses and an important site for vaccine-induced protection.Local immunity acts at the earliest stage of infection, when viral replication remains largely confined to the respiratory epithelium. 1 Secretory immunoglobulin A (sIgA) is a key component of mucosal adaptive immunity and can block viral attachment to host receptors and limit entry into epithelial cells.Tissue-resident memory T (T RM ) cells can respond rapidly within the respiratory tract and help eliminate infected cells without relying on the recruitment of circulating lymphocytes.These responses are difficult to establish after intramuscular vaccination.2,3 Intramuscular vaccines induce strong systemic antibody and T-cell responses and reduce the risk of severe respiratory infection.However, their protection in the upper respiratory tract is often weaker and less durable.This limitation has renewed interest in mucosal vaccination.4,5 Effective mucosal vaccines remain difficult to develop.Although several mucosal COVID-19 vaccines based on adenoviral or influenza virus vectors have been authorized in some countries for aerosol inhalation or intranasal administration, approved protein-subunit mucosal vaccines remain rare.Respiratory mucosal subunit vaccines face three main challenges.First, protein antigens must diffuse through the mucus layer and then be transported across, or sampled at, the epithelial barrier to reach antigen-presenting cells (APCs) in the underlying lamina propria.During this process, they must also resist proteolytic degradation and rapid mucociliary clearance.Second, soluble protein antigens are often weakly immunogenic at mucosal surfaces and, without sufficient innate immune stimulation, may induce weak responses or mucosal tolerance.Third, approved adjuvanted protein-based mucosal vaccines remain rare and no broadly established adjuvant platform is currently available for intranasal protein-subunit vaccination (Figure 1).6,7 An effective mucosal adjuvant must therefore promote rapid antigen uptake and presentation while limiting