The development and deployment of vaccines against COVID-19 demonstrated major successes in providing immunity and preventing severe disease and death. Yet SARS-CoV-2 evolves and vaccine-induced protection wanes, meaning progress in vaccination strategies is of upmost importance. New vaccines directed at emerging viral strains are being developed while vaccination schemes with booster doses and combinations of different platform-based vaccines are being tested in trials and real-world settings. Despite these diverse approaches, COVID-19 vaccines are only delivered intramuscularly, whereas the nasal mucosa is the primary site of infection with SARS-CoV-2. Preclinical mucosal vaccines with intranasal or oral administration demonstrate promising results regarding mucosal IgA generation and tissue-resident lymphocyte responses against SARS-CoV-2. By mounting an improved local humoral and cell-mediated response, mucosal vaccination could be a safe and effective way to prevent infection, block transmission and contribute to reduce SARS-CoV-2 spread. However, questions and limitations remain: how effectively and reproducibly will vaccines penetrate mucosal barriers? Will vaccine-induced mucosal IgA responses provide sustained protection against infection?

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