Vaccination with COVID-19 mRNA vaccines generates robust antibody responses, but the impact of prior infection on the quality of these responses, particularly immunoglobulin G (IgG) subclass profiles remain unclear. A longitudinal study was conducted to compare humoral immune responses in SARS-CoV-2 infection-naïve and pre-immune (previously infected) individuals following a two-dose mRNA vaccine primary series and a booster dose. Anti-spike receptor-binding domain (RBD) IgG levels, neutralizing antibody titers against the vaccine-matched (Wuhan-Hu-1) virus and the Omicron BA.1 variant, and IgG1-IgG4 subclass distributions over time were measured. After two doses, pre-immune participants had higher anti-RBD IgG (2-fold, < .001) and neutralization titers than naïve participants (GMT±SD; 6407 ± 4 vs 5706 ± 3.5). Notably, 89.7% of pre-immune versus 28.1% of naïve sera neutralized Omicron BA.1 ( < .0001). However, a third (booster) raised antibody levels in naïve participants to a statistically similar titer to pre-immune participants ( > .05). The booster vaccination also markedly enhanced the titers of cross-neutralizing antibodies against Omicron BA.1 in both vaccine groups. This increased the proportion of responders from 31.8% to 95.5% in naïve participants. Booster vaccinations induced significant IgG4 titers in naïve ( < .0001), but not in pre-immune participants ( > .05) compared to primary series of vaccination levels. Both vaccinated naïve participants and pre-immune vaccinated participants had a breakthrough infection within one year following the booster vaccination (36.4% vs 25%, > .05 respectively). We report that the presence of IgG4 antibodies, specifically in naïve individuals, did not alter in vitro virus neutralizing response against ancestral WH-1 and Omicron BA.1 variant, with comparable breakthrough infection rates. p p p p p p
