Age differentially impacts the efficacy of booster vaccination against severe COVID-19 caused by Omicron: Enhanced vulnerability to immune imprinting in the elderly mediated by immunosenescence

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Emerging viral variants reduce vaccine efficacy via immune imprinting, and immunosenescence elevates severe COVID-19 risk in older adults. These dual challenges highlight the urgent need for targeted research on age-specific vaccination strategies. However, how aging impacts the vaccine's efficacy against severe COVID-19 in this population remains incompletely understood. Here, we conducted a retrospective cohort study of 765 hospitalized BA.5 variant-infected patients (233 elderly, 532 young adults) and observed significant age-dependent differences in the protective efficacy of the wild-type inactivated vaccine against severe COVID-19. In young adults, vaccine effectiveness showed a dose-dependent pattern: booster vaccination was associated with substantial protection against severe disease (vaccine effectiveness = 79.1%; 95% CI: 26.1–94.1), which remained robust after propensity score matching. In contrast, protection was attenuated in the elderly (interaction P = 0.039), and Vaccine effectiveness did not reach statistical significance after adjustment or matching. Humoral profiling revealed greater susceptibility to immune imprinting in the elderly, reflected by lower BA.5/wild-type neutralizing antibody ratios ( P = 0.001) and preferential recall of ancestral strain-specific responses. Metabolomic analysis identified age-associated accumulation of taurochenodeoxycholic acid (TCDCA), which inversely correlated with BA.5-specific immune responses. In a mouse RBD immunization model, exogenous TCDCA administration reduced BA.5-specific IgG titers and T follicular helper cell frequencies. The study confirms that age significantly affects vaccine efficacy against severe COVID-19, with older adults more vulnerable to immune imprinting. Future research should prioritize the development of personalized vaccines for the elderly, and metabolic reprogramming to modulate immunosenescence emerges as a promising strategy.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.