Background Although SARS-CoV-2 neutralising antibodies protect against severe COVID-19, whether circulating IgG titres reflect underlying host capacity to neutralise wild type (WT) and variants of concern (VOC) and what IgG threshold reflects sufficient neutralising capacity remains unclear. Methods In plasma from individuals in the All Ireland Infectious Diseases Cohort, we measured anti receptor binding domain (RBD) IgG and neutralising capacity by a micro-neutralisation assay, which determined the maximum plasma dilution to maintain 50% inhibition of replication (NT50) of live SARS-CoV-2, using WT and VOC (Beta and Omicron). We examined 3 groups sampled at 3 time periods: unvaccinated, prior infected (group 1, WT dominated), primary (2 dose) vaccinated (group 2) and group 3 with hybrid immunity (booster vaccine and Omicron infection). Although an NT50 ≥100 IU is considered sufficient protection in vaccine trials, as some VOC induce up to 6-fold reduction in NT50, we used NT50 ≥ 1000 IU as a cut off for WT neutralisation that would retain neutralisation against VOC. We used ROC curves to explore sensitivity and specificity and Youden Index to determine the RBD threshold associated with WT NT50 < 1000 IU. We validated the accuracy of this RBD threshold to predict NT50 < 100 IU against Beta and Omicron in groups 2 and 3 respectively. Results We included 255 participants across the 3 groups (table 1). In all groups, RBD highly correlated with WT NT50 (rho 0.81, 0.76 and 0.77 in groups 1, 2 and 3, all p< 0.001). In group 1 Youden’s Index determined RBD < 456 BAU/ml to best predict WT NT50 < 1000 IU (sensitivity 77% (95% CI 69, 84%), specificity 100% (95% CI 82, 100%)). All 99 samples with RBD < 456 BAU/ml had WT NT50 < 1000 IU; positive predictive value (PPV) 100%, (95% CI 95, 100%), and overall accuracy 80% (95% CI 73, 86%). When validated in groups 2 and 3, RBD < 456 BAU/ml retained good accuracy at predicting underlying neutralisation against VOC (group 2, accuracy 80% (95% CI 67, 90%) in predicting NT50 < 100 IU against Beta, and in group 3, overall accuracy of 87% (95% CI 77, 94%) to determine an NT50 of < 100 IU against Omicron.Table 1Participant Characteristics Conclusion Host RBD titres closely correlate with NT50. An RBD threshold of < 456 BAU/ml accurately predicts a clinically relevant neutralising capacity against both WT and common VOC. Disclosures Oliver A. Cornely, MD PhD, DZIF: Advisor/Consultant|DZIF: Board Member|DZIF: Grant/Research Support|DZIF: Honoraria|DZIF: Stocks/Bonds