Upper respiratory tract mucosal immunity for SARS-CoV-2 vaccines

Existing SARS-CoV-2 vaccination programmes have several drawbacks: (i) low impact on vaccine breakthrough infections and subsequent transmission in the community (viral replication in vaccinated populations fuels vaccine escape to promote the emergence of new vaccine-resistant SARS-CoV-2 variants); (ii) limited duration of vaccine-mediated protection; and (iii) inefficient vaccine responses in vulnerable individuals at high risk of severe COVID-19, due to compromised host intrinsic antiviral mechanisms.Early control of infection via robust antigen-specific mucosal responses in the upper airways could limit viral dissemination and reduce transmission rates. However, current licensed vaccines and their routes of administration induce mainly systemic, rather than mucosal, immunity.A boosting strategy to induce potent antigen-specific memory responses in the upper respiratory tract mucosa may enhance overall efficacy and durability of vaccine-mediated protection, even in individuals with compromised antiviral mechanisms. SARS-CoV-2 vaccination significantly reduces morbidity and mortality, but has less impact on viral transmission rates, thus aiding viral evolution, and the longevity of vaccine-induced immunity rapidly declines. Immune responses in respiratory tract mucosal tissues are crucial for early control of infection, and can generate long-term antigen-specific protection with prompt recall responses. However, currently approved SARS-CoV-2 vaccines are not amenable to adequate respiratory mucosal delivery, particularly in the upper airways, which could account for the high vaccine breakthrough infection rates and limited duration of vaccine-mediated protection. In view of these drawbacks, we outline a strategy that has the potential to enhance both the efficacy and durability of existing SARS-CoV-2 vaccines, by inducing robust memory responses in the upper respiratory tract (URT) mucosa.