PhenoAge acceleration predicts antibody persistence and breakthrough infection after SARS-CoV-2 vaccination and infection.

BACKGROUND

The durability of anti-SARS-CoV-2 antibodies after vaccination or infection varies among individuals, and the role of biological aging remains unclear. This study investigated the impact of PhenoAge acceleration on antibody responses and the risk of breakthrough infection.

METHODS

We analyzed serum concentration of antibodies against the receptor-binding domain of the SARS-CoV-2 S protein and calculated PhenoAge/PhenoAgeAccel using nine clinical biomarkers in 93 participants, including COVID-19-infected and vaccinated individuals, with follow-up every 3 months.

RESULTS

Receiving ≥ 3 vaccine doses was associated with high antibody levels (OR: 4.36, p = 0.001), but natural infection was the strongest predictor (OR: 124.79, p < 0.001). Antibody titers > 2500 IU/mL protected against breakthrough infection (HR: 0.04, p = 0.0368). Despite ≥ 3 vaccine doses, individuals with titers ≤ 2500 IU/mL had increased risk (HR: 34.25, p = 0.0155). PhenoAge acceleration was associated with higher infection risk (HR: 4.75, p = 0.042).

CONCLUSION

Booster vaccination and natural infection are key to sustaining high antibody levels. Accelerated biological aging may increase infection risk. High antibody levels are essential to prevent breakthrough SARS-CoV-2 infection, and vaccine doses alone are insufficient without an adequate antibody response.