The respiratory tract is a common portal of entry for pathogens. Respiratory infections represent the third leading cause of death worldwide, killing an estimated 2.5 million in 2019 [1]. The impact of respiratory infections in the global health has recently been well- recognized through the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which brought the world to a standstill, accounting for at least 6.8 million deaths to date [2]. The decades-long effort to develop vaccines to combat respiratory infections such as influenza, respiratory syncytial virus (RSV), and tuberculosis (TB) infections is still encountering challenges 3, 4. Moreover, despite three-quarters of the world population receiving at least one dose of the injectable COVID-19 vaccine, SARS-CoV-2 infection continues to be a global health concern [5]. Mutational changes observed with seasonal variabilities in influenza viruses, and the continued emergence of SARS-CoV-2 variants has necessitated reformulation and boosting with updated vaccines. This challenge primarily stems from the antibody-centric design of these vaccination strategies, aiming to target viral surface antigens that are continuously changing 6, 7, 8, 9. In contrast to humoral immunity, it is now clear that mucosal tissue-resident T cells (TRM) specific for conserved internal structural and nonstructural proteins are vital players in protection against viral infections 10, 11. Additionally, inducing trained immunity in mucosal innate cells can also nonspecifically render protection 8, 12, 13. As such, vaccination strategies that generate adaptive and innate immune memory at the respiratory mucosa may be a viable approach for combating not only current endemic infections but also serve as a foundation for vaccine development against future pandemic respiratory infections.

A multiplicity of factors dictates the vaccine safety, immunogenicity, and efficacy. Collectively, these factors can be defined under the umbrella of ‘vaccination strategies’ that encompass vaccine platform, delivery route, and regimens (the interval between vaccinations, number of vaccinations, and whether homologous vs. heterologous prime-boost vaccination). Thus, electing an appropriate vaccination strategy is critical to achieving the maximal potential of a vaccine. Currently, most licensed vaccines are parenterally injected, via the intramuscular, intradermal, or subcutaneous route. A growing body of literature indicates that parenteral vaccination is highly effective in generating immune responses in the periphery but ineffective at localizing the immunity to the respiratory mucosa, the entry site for most human pathogens 8, 14. Positioning vaccine-induced immunity at mucosal sites is crucial where the infection and transmission occur, and in particular, to respiratory infections such as TB and COVID-19 for which effective host defense requires the participation of innate and adaptive cellular immunity. This notion has led to a shift in the perception of vaccination strategies and steered the field toward developing next-generation vaccines suitable for respiratory mucosal (RM) delivery 14, 15. Indeed, both preclinical and clinical studies have demonstrated the superiority of RM immunization over parenteral immunization in inducing robust and long-lasting immunity encompassing the adaptive and innate arm of immune mechanisms at the mucosa 8, 12, 16•, 17•, 18•, 19••, 20, 21.

Viral-vectored vaccines represent the most effective platform for RM delivery owing to their amenability, safety, intrinsic immunogenicity, and ability to induce multilayer immunity at the respiratory mucosa [22]. The RM delivery of vaccines involves either a nasal or a deep-lung mode of administration, which targets different regions of the respiratory mucosa 23••, 24. However, currently, little is known regarding the immune response profile at the upper and lower respiratory tract (LRT) following intranasal (IN) and deep-lung aerosol (AE) vaccination in humans and how that may impact the efficacy of a vaccine. This article will briefly review the factors instrumental for the establishment of long-lasting RM immunity following RM delivery of viral-vectored vaccines with specific attention given to vaccine biodistribution, type of immune response, and localization of immune responses within the respiratory mucosa following different modes of RM delivery.