This figure, color-coded according to avidity level, presents the median avidity values (with interquartile ranges) measured using 6M Urea. SARS-CoV-2 strains should translate to better protection from ever-evolving strains. Higher avidities may help explain how the vaccines protective effects persist despite waning antibody titers after each vaccine dose. == Supplementary Information == The online version contains supplementary material available at 10.1007/s11357-024-01215-y. Keywords:Avidity, Affinity maturation, Nursing home residents, Healthcare workers, COVID-19, Bivalent boosters, Omicron, BNT162b2 mRNA vaccine == Introduction == Vaccine-induced immunity has mitigated Coronavirus disease 2019 (COVID-19), reducing morbidity and mortality to more modest rates, most dramatically for the frail nursing home (NH) population [1,2]. Follow-up studies have demonstrated a significant decline in humoral immunity over the months following vaccination, making the case for booster doses [3,4]. Despite the significant immunologic and clinical benefits associated with the boosters [58], the emergence of the Omicron variant resulted in a dramatic increase in infections, even among vaccinees who completed the primary and booster series, and notably in frail and vulnerable NH populations [9]. Establishing definitive immunologic correlates of protection in the face of rapidly Nrp1 developing variants has remained elusive, yet increased binding and neutralizing antibody titers are associated with protection against symptomatic SARS-CoV-2 infections [10,11]. The SARS-CoV-2 virus spike protein (S) facilitates entry into cells via the receptor-binding domain (RBD) by binding to the human angiotensin-converting enzyme 2 (ACE-2) receptor [12]. The avidity of RBD binding would be predicted to Taranabant translate to the quality of protection, and offer a better measure than just antibody quantification for assessing vaccine-induced immunity and determining correlates of effective protection. Antibody avidity is the total binding strength of an antibody to its specific epitope and is a consequence of the overall maturation of the humoral response Taranabant [1315]. It progressively increases after antigenic stimulation by infection or vaccination and occurs due to affinity maturation [1618]. Avidity can thus help distinguish recent from more remote infections, as acute infections produce low avidity antibodies that typically mature progressively over time [19,20]. Like other seasonal coronaviruses, SARS-CoV-2 infection produces antibodies with low and intermediate avidity titers that plateau early [21,22]. In contrast, repeated doses of the BNT162b2 mRNA vaccination produced highly avid antibodies that bound more variants in convalescent and infection-naive subjects highlighting the qualitative benefit of repeat vaccinations [2325]. While neutralizing antibodies helps assess antibodies qualitatively, we know little about the effective binding strength of these antibodies over time. As vaccine-induced antibodies wane quantitatively, it is thus critical to assess the effect of this longitudinal decline on the strength of their binding abilities. We have previously reported on the kinetics of binding and neutralization antibodies in this cohort of NH residents (NHRs) and healthcare workers (HCWs) [2629]. Here, we extend our study of this cohort to examine the kinetics of avidity maturation as a surrogate for effective antibody binding, from the initial BNT162b2 mRNA primary vaccination series through the administration of the booster doses among NHRs and HCWs. == Methods == == Participants’ demographics and sampling == Study approval was obtained from the WCG institutional review board. All participants or their legally authorized representatives provided informed consent. NHRs and HCWs were sampled from 3 community NHs and one state Veterans Home. Additionally, HCWs that included hospital and laboratory staff were recruited from the Cleveland Department of Veterans Taranabant Affairs Medical Center and Case Western Reserve University. All sites administered the BNT162b2 mRNA vaccine primary series in December 2020 and January 2021 followed by a second dose 3 weeks later during the emergency use authorization period, then a monovalent first booster dose (3rd dose) 6 months or longer after their primary series and a second monovalent booster (4th dose) 6 months or longer after the 1st booster and then a bivalent booster (5th dose). Not all participants received every booster dose. Participants were deemed to have a prior infection if they had a known history of SARS-CoV-2.