Abstract The decline in neutralizing antibody (nAb) titers and vaccine efficacy /effectiveness (VE) for SARS-CoV-2 vaccines has been observed over time and when confronted with emerging variants, two factors that are hard to distinguish. Despite substantial drop in nAb titers against Omicron, VE remains high for severe cases and fatalities, raising questions about the utility of detected nAbs as a correlate of protection for COVID-19 vaccines for varying disease severity. Here, we conducted a systematic comparison of waning dynamics of nAb and VE over time and against variants with varying levels of disease severity. Using Bayesian linear regression models, we found that antigenically-shifted variants, like Omicron, could potentially lead to greater reductions in nAb titers and primary VE against mild infections than associated immunity waning observed over a 180-day period. By comparing model predicted nAb titers and VE on the same time scales, we found that VE against severe and fatal outcomes remained above 75% even when nAb titers reached the detectable limit of assays, despite strong correlations with nAb titers (spearman correlations ≥0.7) across variants over time. This finding suggested detectable nAb titers are not always sensitive enough to fully predict protection against severe disease and death from SARS-CoV-2.