Global dynamics of vaccine effectiveness and genotype shift in porcine circovirus 2: A cross-temporal analysis.

Background: Porcine circovirus type 2 (PCV2) has caused annual economic losses exceeding US$2 billion to the global swine industry, with mortality rates of 5%-20% in unvaccinated herds. Following the 2006 introduction of PCV2a-based vaccines in 2006, genotype dominance shifted sequentially from PCV2a to PCV2b and from 2010 onward to PCV2d. However, a unified, long-term evaluation of how vaccine uptake influences genotype prevalence and viral evolution remains unavailable. Aim: This study aims to quantify the spatio-temporal relationship between vaccine coverage and genotype shifts, compare genotype-specific vaccine-efficacy decay, and identify capsid-protein sites under positive selection in the post-vaccine era. Methods: Annual genotype frequencies (2000-2025) were extracted from OIE surveillance reports, PCV2 cap-gene sequences were retrieved from GenBank, and vaccine-efficacy figures were compiled from peer-reviewed studies. A reproducible pipeline was used to harmonize these streams into three datasets: genotype prevalence, country-level coverage, and time-indexed efficacy. LOESS smoothing and linear mixed-effects models assessed coverage-prevalence associations. The exponential decay parameters (VE-, k) were estimated via random-effects meta-regression. Codon-level selection was evaluated using MEME on post-vaccination alignments. Results: Vaccine coverage was inversely correlated with PCV2a prevalence (ρ = -0.72, p < 0.001) and positively with PCV2d (ρ = 0.23, p < 0.001). The initial efficacy (VE-) was higher and the decay was slower for PCV2a (95.2%; k = 0.038 month-¹) than for PCV2d (79.4%; k = 0.092 month-¹). Twelve capsid codons exhibited significant positive selection after vaccine rollout, with several overlapping known neutralizing epitopes. Conclusion: PCV2 vaccination exerts selective pressure driving genotype succession. The accelerated waning of protection against emergent genotypes and the emergence of escape-associated mutations at key antigenic sites support the development of multivalent vaccines incorporating PCV2d antigens to sustain long-term herd immunity.