Optimizing COVID-19 vaccination strategies for high-risk populations: potential and challenges of combining heterologous boosting with respiratory mucosal delivery.

Despite the decline of the global peak of COVID-19, SARS-CoV-2 continues to circulate, evolve, and undergo immune escape, posing persistent threats, particularly to older adults, individuals with comorbidities, and immunocompromised populations. Although existing vaccination strategies have substantially reduced the risks of severe disease, hospitalization, and death, their ability to block infection and transmission remains limited, and protection wanes over time. Current heterologous booster strategies still rely largely on combinations of different parenteral vaccine platforms. Although these regimens can enhance systemic humoral and cellular immunity, they are insufficient to robustly induce upper respiratory mucosal immunity, thereby limiting their role in early infection control and interruption of transmission. Because respiratory mucosal vaccines target the natural entry site of SARS-CoV-2, they have the potential to induce secretory IgA, tissue-resident memory immune cells, and local immune memory, offering distinct advantages in compensating for the shortcomings of conventional heterologous boosting. Combining heterologous boosting with respiratory mucosal delivery may further enhance the control of viral infection, early replication, and subsequent transmission while preserving systemic immunity, thereby providing more comprehensive immune protection for high-risk populations. However, this strategy still faces challenges related to mucosal barriers, delivery efficiency, adjuvant safety, manufacturing scale-up, and incomplete clinical evaluation frameworks. Future high-quality studies focusing on high-risk populations are needed to clarify its value in preventing infection, protecting against severe disease, and providing long-term protection.