Abstract
BACKGROUND: Current COVID-19 vaccines primarily target the Spike protein of defined virus variants, offering limited protection against emerging variants in immunocompetent individuals. Similarly, protective immunity following natural SARS-CoV-2 infection is variable and of short duration, raising concerns about immunocompromised individuals' vaccination strategies. METHODS: This prospective multicenter study examined 66 sera from 59 immunocompromised and 451 sera from 215 immunocompetent individuals from different pandemic periods. We establish and validate a live virus-based neutralization assay to determine the virus-inactivating potential against ancestral and current SARS-CoV-2 isolates. RESULTS: Our virus-based neutralization assay demonstrated superior performance over surrogate neutralization assays. We found strong but transient immunity after complete vaccination schemes, with single doses providing minimum neutralization, regardless of vaccine type. Combining vaccination-induced immunity with SARS-CoV-2 infection before or after vaccination yielded higher neutralizing titers than vaccination or infection alone, consistent across both study groups. Additional doses after a full vaccination course restored neutralization levels. CONCLUSIONS: Potentially protective SARS-CoV-2 neutralization is reliably induced in immunocompromised individuals by prior attenuation of immunosuppression. First-generation vaccines protect against various SARS-CoV-2 variants in immunocompetent individuals, with effective cross-neutralization demonstrated up to the Delta variant but largely absent for later Omicron variants. Continuous vaccine updates are necessary to address emerging SARS-CoV-2 variants.