The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fundamentally transformed global public health paradigms. As we navigate the endemic phase of COVID-19, understanding the complex dynamics of immunity against continuously evolving viral variants remains critical for maintaining population-level protection and informing evidence-based vaccination policies [1].

SARS-CoV-2 immunity can be acquired through three distinct pathways: vaccine-induced immunity, natural infection-induced immunity, and hybrid immunity resulting from both vaccination and infection [2]. Each pathway confers unique protective characteristics with varying effectiveness, breadth, and durability. Vaccine-induced immunity has proven highly effective in reducing COVID-19 severity, hospitalizations, and deaths across diverse populations [[3], [4], [5], [6], [7]]. However, immune waning and viral evolution continuously reshape the protective landscape, necessitating updated vaccination strategies [[8], [9]].

Hybrid immunity, resulting from both vaccination and natural infection, typically provides the most robust and durable protection [[10], [11], [12]]. However, emerging evidence suggests that the temporal sequence of these immune exposures critically determines the ultimate protective benefit, with vaccination-first approaches showing superior outcomes compared to infection-first scenarios [[13], [14], [15]].

In Hong Kong, the COVID-19 Vaccination Programme launched on February 26, 2021. Initially, the program offered two primary vaccine options: BNT162b2, an mRNA-based vaccine developed by Pfizer-BioNTech, and CoronaVac (Sinovac Biotech), an inactivated virus vaccine. By the time of this analysis (November 2022), a bivalent mRNA vaccine (Bivalent Omicron BA.4/BA.5 BNT162b2) was also available. While the original formulations demonstrated substantial initial effectiveness, the emergence of immune-evasive variants, particularly the Omicron lineage and its subvariants, has challenged the durability and breadth of protection [[16], [17], [18]].

The COVID-19 pandemic has generated unprecedented real-world data on vaccination effectiveness, immune responses, and optimal strategies for population protection against emerging respiratory pathogens. The experience with SARS-CoV-2 variants, particularly the Omicron lineage, has provided valuable insights for developing evidence-based vaccination strategies that could inform rapid response approaches for future pandemic threats. The Omicron subvariants, particularly BA.4/5, have demonstrated enhanced transmissibility and partial immune escape, leading to increased breakthrough infection rates even among vaccinated populations [19].

The Omicron BA.4/5 experience offers an opportunity to address fundamental questions relevant to future pandemic preparedness: How effective are heterologous vaccination strategies when primary vaccines lose effectiveness against new variants? What is the real-world performance of variant-adapted vaccines compared to original formulations?

Vaccination timing has particular public health significance. Some individuals and communities have advocated for natural immunity strategies involving intentional exposure to infection. Such approaches assume that infection-acquired immunity provides equal or superior protection compared to vaccination, an assumption requiring rigorous scientific evaluation. Understanding the comparative effectiveness of vaccination-first versus infection-first pathways is essential for evidence-based public health messaging and policy development [20].

In this study, we define heterologous vaccination as switching between different vaccine platform types (e.g., from inactivated whole-virus vaccines to mRNA vaccines), as distinct from switching between different manufacturers of the same vaccine platform (e.g., between different mRNA vaccines). This distinction is critical because immune responses differ substantially across vaccine platforms due to differences in antigen presentation, adjuvant systems, and mechanisms of immune activation.

This study aims to extract actionable insights from Hong Kong's BA.4/5 experience that could inform future pandemic vaccination strategies. Our analysis leveraged Hong Kong's unique position as a well-defined population with universal healthcare access, comprehensive testing infrastructure, and detailed vaccination records—creating an ideal setting for generating pandemic preparedness insights. We focus specifically on individuals with waned immunity, those whose last vaccination or infection occurred more than six months prior, to determine optimal booster strategies for this vulnerable population. Through comprehensive analysis of cohorts stratified by primary vaccination series, booster type, prior infection history, and critically, the temporal sequence of vaccination and infection events, we provide crucial evidence to inform public health policies.

Our analysis investigates whether switching vaccine types or using variant-adapted boosters offers superior protection, how the temporal sequence of vaccination and infection influences subsequent immune responses, and whether vaccination before infection provides measurably better protection than infection-first scenarios. The demonstrated benefits of heterologous boosting and vaccination timing are essential for refining future vaccination campaigns to ensure sustained population-level protection while providing strong evidence to support early vaccination strategies over approaches that rely on or tolerate initial infection as a pathway to immunity.