Neutralizing capacity failure of inactivated vaccine platforms and the bottleneck created by Omicron immune evasion. Many low- and middle-income countries (LMICs), including China, initially deployed traditional inactivated virus vaccines (e.g., Sinopharm/Sinovac) as the core standard of vaccine governance. However, Omicron sublineages (BF.7 and BA.5.2) that emerged during SARS‑CoV‑2 evolution exhibited extreme antigenic drift, neutralizing the humoral defense induced by inactivated vaccines. The characteristic broad but shallow antibody spectrum of inactivated vaccines was rendered ineffective against the rapid accumulation of receptor‑binding domain (RBD) mutations in Omicron, generating population‑wide immune gaps and precipitating large‑scale breakthrough infections—a critical public‑health bottleneck and a blind spot in real‑world data (RWD).

Large‑scale heterologous booster cohort analysis: A retrospective epidemiologic study conducted during the Omicron surge in Macao assembled a high‑resolution real‑world omics and clinical matrix from 4,879 residents collected immediately after the late‑2022 Omicron wave. Among the total cohort, 83.2 % (n = 4,052) had completed a primary series with Sinopharm, and of these, 20 % (n = 827) received a heterologous mRNA booster from a different platform. Logistic regression and ordinary least squares (OLS) models were employed to filter environmental noise and track infection kinetics for each vaccine combination.

Demonstration of ~60 % risk reduction based on odds ratios (OR) and mathematical integrity of clinical endpoints. After fully adjusting for confounders, the heterologous mRNA booster group exhibited an odds ratio of 0.421 for confirmed COVID‑19 infection relative to a homologous three‑dose inactivated regimen, corresponding to an approximate 60 % reduction in relative infection risk. Moreover, among the few breakthrough cases, the heterologous regimen reduced the odds of fever manifestation to 0.290 (71 % reduction) via accelerated cellular immunity, and shortened the duration of viral positivity by an average of 0.931 days, confirming robust clinical benefit.

Implications for global health‑governance standards and variant‑responsive booster guidelines. This real‑world dataset provides compelling evidence that countries relying on inactivated vaccines should shift from additional inactivated doses to a heterologous switch to mRNA platforms. The inter‑platform interaction metrics serve as a predictive filter for population‑level immunity collapse thresholds upon emergence of new variants. By quantifying polyclonal immune efficacy at the population level through real‑world clinical scoring, the dataset can act as a master reference for forecasting global demand for next‑generation variant‑adapted mRNA vaccines and compressing national regulatory timelines.