T cell control of SARS-CoV-2: When, which, and where?

In search of a pan-coronavirus vaccine: next-generation vaccine design and immune mechanisms

“…Another difficulty associated with vaccination against viruses targeting the upper respiratory tract is the generation of long-lasting mucosal immunity. Mechanistic studies in animal models suggest that mucosal targeting is likely to offer better protection against respiratory infections [ 43 ], but methods for inducing mucosal immunity are in the earliest stages of testing. The route of vaccine administration could be critical, with intranasal, aerosolized, subinguinal and oral approaches being tested; however, immunogenicity may be hampered owing to the natural immune barriers present at these sites.…”

“…The route of administration can have a profound impact on the localization of the immunity generated [ 43 – 45 ]. Alternative routes of administration are being investigated in the context of coronavirus vaccines with the aim of inducing strong mucosal immunity at the site of viral infection and replication to improve vaccine efficacy.…”

“…Next-generation mucosally targeted vaccines may be able to draw T and B cells from the blood and lymphatics into the mucosa, prime de novo responses locally, or even boost immunity generated by previous infections of the airways. It has previously been suggested that mucosal immunity tends to be short-lived and that vaccines targeted to the mucosa may be less immunogenic at these sites [ 43 ], which are limitations that need to be overcome for efficacious mucosal-targeted vaccines.…”

“…Cross-viral species recognition by coronavirus-reactive T cells has been well described, with SARS-CoV-2-reactive T cells being reported in samples taken before SARS-CoV-2 circulated in humans. Preexisting SARS-CoV-2 cross-reactive T cells have been widely identified and are detected in up to three-quarters of individuals using sensitive assays and in vitro expansion [ 43 , 67 , 88 – 91 ]. Importantly, preexisting T cells have been shown to not only be cross-reactive to SARS-CoV-2 sequence peptides in vitro but also respond in vivo and have been associated with early control of viral infection, limited disease and stronger responses to vaccination [ 62 , 68 , 92 , 93 ].…”

“…Although enriched in proteins with higher levels of total conservation, there are examples of conserved immunogenic epitopes in most, if not all, viral proteins [ 43 , 99 , 100 ]. The RNA-dependent RNA polymerase (NSP12) and helicase (NSP13) of the replication-transcription complex (RTC) are the most conserved proteins when considering the rate of change at each amino acid site (homologies or nucleic acid diversity) over the course of the SARS-CoV-2 pandemic or conservation in sequence across HCoVs and the coronavirus family [ 62 ].…”