This large-scale cohort study conducted in Hong Kong examined the time-varying protective effects of various COVID-19 vaccines and dosing regimens against the Omicron BA.1/BA.2 variants. An innovative pharmacokinetic/pharmacodynamic model was employed to estimate the trajectory of vaccine effectiveness over time. Results indicated that the maximum protection for a single dose reached 0.120 for CoronaVac and 0.171 for Comirnaty. The peak protective effectiveness for the second and third doses were observed at 0.348 and 0.522, respectively. In a 4-dose regimen, CoronaVac demonstrated a maximum protective effectiveness of 0.548, stabilizing at 0.487, while Comirnaty achieved a maximum effectiveness of 0.784, stabilizing at 0.714 six months after the administration of the last dose. The vaccine effectiveness exhibited a rising and then declining pattern, peaking approximately 1-2 months post-vaccination. Understanding waning immunity is crucial for optimizing vaccination strategies and policies as viral evolution continues. This real-world study captured changing dynamics that may differ from clinical trials with limited follow-up, providing essential evidence to guide the optimization of vaccination efforts. Ongoing monitoring of vaccine effectiveness remains critical as the viral landscape evolves.

Objectives: This study aims to investigate the time-varying protective effects of various COVID-19 vaccines and dosing regimens against infections caused by the Omicron BA.1/BA.2 in Hong Kong.

Methods: This territory-wide cohort study from Hong Kong combined vaccination records, confirmed COVID-19 cases, and census data from January 2022 to May 2022 to comprehensively analyze the time-varying protective effects of different COVID-19 vaccines and dosing regimens against Omicron BA.1 and BA.2 infections. A 4-parameter pharmacokinetic/pharmacodynamic model was used to estimate the trajectory of vaccine effectiveness over time.

Results: Among 6.2 million adults, the maximum protective effectiveness for a single vaccine dose reached 0.120 for CoronaVac and 0.171 for Comirnaty. For the second and third doses, peak effectiveness were observed at 0.348 for CoronaVac and 0.522 for Comirnaty. Notably, a 4-dose regimen resulted in maximum protections of 0.548 for CoronaVac and 0.785 for Comirnaty, which stabilized at 0.487 and 0.714, respectively, six months following the last doses. The vaccine effectiveness exhibited a rising then declining pattern, peaking around 1-2 months post-vaccination, underscoring the importance of ongoing vaccination strategies.

Conclusions: Understanding the waning of vaccine protection over time is critical for informing optimal vaccination strategies, booster schedules, and public health policies. This real-world study can capture changing dynamics that may differ from clinical trials which have more limited follow-up periods, and can provide crucial evidence to guide optimization of vaccination strategies. Ongoing monitoring of vaccine effectiveness remains crucial as the viral evolution continues.

Keywords: Andersen-gill model; Comirnaty; CoronaVac; Omicron; Protective effectiveness; SARS-CoV-2.

Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.