Elicitation of neutralizing antibodies and IgG4 subclass switching following booster vaccination with ancestral COVID-19 mRNA vaccines does not reduce breakthrough infections

Aug 14, 2025Human vaccines & immunotherapeutics

Booster shots with original COVID-19 mRNA vaccines increase neutralizing antibodies and IgG4 but do not lower breakthrough infections

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Abstract

Pre-immune individuals had 2-fold higher anti-RBD IgG levels than naïve individuals after two doses of mRNA vaccines.

Pre-immune participants exhibited higher neutralization titers against the Wuhan-Hu-1 virus and Omicron BA.1 variant compared to naïve participants.
A booster dose raised antibody levels in naïve participants to similar titers as in pre-immune participants.
Booster vaccinations significantly increased cross-neutralizing antibodies against Omicron BA.1, raising the responder proportion in naïve participants from 31.8% to 95.5%.
Naïve individuals showed significant increases in IgG4 titers after the booster, while pre-immune participants did not.
Both groups experienced breakthrough infections within one year post-booster, with rates of 36.4% in naïve and 25% in pre-immune individuals.

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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

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Elicitation of neutralizing antibodies and IgG4 subclass switching following booster vaccination with ancestral COVID-19 mRNA vaccines does not reduce breakthrough infections

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