Quantifying the vaccine-induced humoral immune response to spike-receptor binding domain as a surrogate for neutralization testing following mRNA-1273 (Spikevax) vaccination against COVID-19
Authors: Kirste Imke , Hortsch Sayuri , Grunert Veit Peter , Legault Holly , Maglinao Maha , Eichenlaub Udo , Kashlan Basel , Pajon Rolando , Jochum Simon 
Published: March 2022

AbstractBackgroundThere is a need for automated, high throughput assays to quantify immune response after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study assessed the combined utility of the Roche assays, Elecsys® Anti-SARS-CoV-2 S (ACOV2S) and Elecsys Anti-SARS-CoV-2 (ACOV2N) using samples from the 2019-nCoV vaccine (mRNA-1273, Spikevax™) phase 2 trial (NCT04405076).MethodsSamples from 593 healthy participants in two age cohorts (18–54 years and ≥55 years), who received two injections with either placebo (n=198) or mRNA-1273 at a dose of either 50 μg (n=197) or 100 μg (n=198), were collected at Days 1 (first vaccination), 15, 29 (second vaccination), 43 and 57. ACOV2S results were used to assess the humoral response to vaccination in different clinical trial subgroups and were compared to a live virus microneutralization assay. Sample panels from patients with evidence of previous or concomitant infection (as identified using ACOV2N) or with an inconsistent antibody response pattern were analyzed separately.ResultsReceptor-binding domain (RBD)-specific antibodies were readily detectable by ACOV2S for the vast majority of participants (174/189 [50 μg dose group] and 178/192 [100 μg]) at the first time point of assessment, with non-converters predominantly older in age. Complete seroconversion for all participants was observed at the subsequent timepoint (Day 29) and before administration of the second dose of vaccine. Two weeks after the first vaccine dose (Day 15), geometric mean concentration (GMC) of antibody levels were 1.37-fold higher in the 100 μg compared with the 50 μg dose group; this difference reduced to 1.09-fold two weeks after the second dose (Day 43). In both the 50 μg and 100 μg dose groups, a more pronounced response was observed in the younger versus the older age group on Day 15 (2.49-fold and 3.94-fold higher GMC, respectively) and Day 43 (1.35-fold and 1.50-fold higher GMC). Few subjects had a previous or concomitant natural SARS-CoV-2-infection (n=8). Vaccination of pre-infected individuals boosted the immune response to very high ACOV2S results compared to infection-naïve vaccine recipients. ACOV2S measurements were strongly correlated with those from the live microneutralization assay (Pearson’s r=0.779; p<0.0001) and good qualitative agreement was achieved (100% positive and 91.8% negative percentage agreement; 90.0% positive and 100% negative predictive value).ConclusionThe results from this study confirmed that ACOV2S is a highly valuable assay for the tracking of vaccine-related immune responses. Combined application with ACOV2N enables serologic monitoring for breakthrough infection or stratification of previous natively-infected individuals. The adaptive measuring range and high resolution of ACOV2S allows for the early identification of seroconversion as well as for resolution of very high titers and detection of longitudinal differences between age and dose groups. Additionally, good correlation of ACOV2S with live virus microneutralization indicates the utility of ACOV2S as a reliable estimate of neutralization capacity in routine diagnostic settings.