Objectives: Cancer patients are vulnerable to SARS-CoV-2 reinfection due to impaired immunity. We estimated the effectiveness of bivalent COVID-19 vaccination against reinfection in adults with cancer and prior SARS-CoV-2 infection.

Methods: We conducted a nationwide target trial emulation study using the K-CoV-N cohort, including 84,748 adults with cancer and prior SARS-CoV-2 infection (follow-up: Oct 2022-Jun 2023). The clone-censor-weight method with inverse probability of censoring weights compared bivalent vaccination versus none. SARS-CoV-2 reinfection ≥14 days post-vaccination and ≥90 days after prior infection was the primary outcome. Vaccine effectiveness (VE) was estimated via pooled logistic regression (1-HR).

Results: 24.1% received bivalent vaccines. Reinfection risk was 5.2% (bivalent) versus 8.4% (no-bivalent). Overall, VE was 22.2% (95% CI, 15.8%-28.2%). Protection was greater among younger adults, those with prior boosters, and those with more distant prior infections (≥1 year). Significant protection was observed in patients with solid tumors, whereas estimates for hematologic malignancies were attenuated and non-significant.

Conclusions: Bivalent vaccination meaningfully reduced reinfection risk among adults with cancer, extending and strengthening the existing evidence base through a causal inference framework. These findings provide real-world evidence to support their continued role in routine and seasonal immunization strategies while highlighting the need for risk-stratified approaches tailored to immune capacity.