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Infectious diseases caused by mucosal pathogens significantly increase mortality and morbidity. Thus, the possibility to target these pathogens at their primary entry points can consolidate protective immunity. Regarding SARS-CoV-2 infection, it has been observed that the upper respiratory mucosa is highly affected and that dysregulation of resident microbiota in the gut–lung axis plays a crucial role in determining symptom severity. Thus, understanding the possibility of eliciting various mucosal and adaptive immune responses allows us to effectively design bacterial mucosal vaccine vectors. Such design requires rationally selecting resident bacterial candidates as potential host carriers, evaluating effective carrier proteins for stimulating an immune response, and combining these two to improve antigenic display and immunogenicity. This review investigated mucosal vaccine vectors from 2015 to present, where a few have started to utilize Salmonella and lactic acid bacteria (LAB) to display SARS-CoV-2 Spike S proteins or fragments. Although current literature is still lacking for its studies beyond in vitro or in vivo efficiency, decades of research into these vectors show promising results. Here, we discuss the mucosal immune systems focusing on the gut–lung axis microbiome and offer new insight into the potential use of alpha streptococci in the upper respiratory tract as a vaccine carrier.

Hacking Commensal Bacteria to Consolidate the Adaptive Mucosal Immune Response in the Gut–Lung Axis: Future Possibilities for SARS-CoV-2 Protection