Abstract
The presence of anti-polyethylene glycol (anti-PEG) antibodies can hinder the therapeutic efficacy of PEGylated drugs. With the widespread use of a PEGylated coronavirus disease 2019 (COVID-19) messenger RNA vaccine (Comirnaty), the impact of pre-existing anti-PEG antibodies on vaccine potency has become a point of debate. To investigate this, we established mouse models with pre-existing anti-PEG antibodies and divided them into 3 groups: group 1 with anti-PEG immunoglobulin G + immunoglobulin M concentrations of 0.76 to 27.41 μg/ml, group 2 with concentrations of 31.27 to 99.52 μg/ml, and a naïve group with no detectable anti-PEG antibodies. Results indicated that anti-spike antibody concentrations significantly decreased in group 1 and group 2 after the 2nd vaccine dose compared to those in the naïve group. Spearman's rank correlation analysis demonstrated a negative relationship between anti-spike antibody production and anti-PEG antibody levels at both the 2nd and 3rd doses (2nd dose: ρ = -0.5296, P = 0.0031; 3rd dose: ρ = -0.387, P = 0.0381). Additionally, spike protein concentrations were 31.4-fold and 46.6-fold lower in group 1 and group 2, respectively, compared to those in the naïve group at 8 h postvaccination. The concentration of complement C3a in group 2 was significantly higher than that in the naïve group after the 3rd dose. These findings confirm that pre-existing anti-PEG antibodies diminish vaccine efficacy, alter pharmacokinetics, and elevate complement activation. Therefore, detecting pre-existing anti-PEG antibodies is crucial for optimizing vaccine efficacy, ensuring patient safety, and developing improved therapeutic strategies.