Is cellular immunity the future key for deciphering and monitoring COVID-19 vaccines efficacy?

Although the efficacy of the second COVID-19 vaccine booster for preventing mild Omicron infections remains uncertain in the general healthy population, we cannot feasibly continue to boost antibody responses forever. Several studies reveal that it is now challenging to identify threshold values of anti-SARS-CoV-2 neutralizing antibodies (measured with current immunoassays) displaying sufficient protect against highly mutated variants, including those belonging to the Omicron lineage, so that infection will likely occur regardless of the amount of neutralizing antibodies. The constant monitoring of anti-SARS-CoV-2 antibodies levels with “obsolete” immunoassays may turn to be unsuccessful, or even misleading, since it may instill a false sense of reassurance to people with extremely high antibodies titers who, instead, may only be marginally protected against COVID-19 illness. Contrarily, major efforts should be focused to construct efficient assays aimed at deciphering and monitoring ex vivo cellular immunity, since this approach may be more robust to withstanding SARS-CoV-2 antigen drift and reflecting ex vivo vulnerability to COVID-19. Some of these assays have already become commercially available, even if their real performance remains undetermined, thus paving the way to additional research on this matter.