Estimating Waning of Vaccine Effectiveness: a Simulation Study

TL;DR

This study evaluates statistical methods for estimating vaccine effectiveness waning over time, highlighting the limitations of existing models and proposing an improved Cox model extension with time-vaccine interaction for better accuracy.

Contribution

The paper introduces an optimized Cox proportional hazards model with a time-vaccine interaction term to more accurately estimate rapid intra-seasonal vaccine effectiveness waning.

Findings

Partitioning time and including interaction terms improves VE waning estimates.

Scaled Schoenfeld residuals are unreliable for capturing rapid waning.

Optimized partitioning scheme enhances model performance.

Abstract

Developing accurate and reliable methods to estimate vaccine protection is a key goal in immunology and public health. While several statistical methods have been proposed, their potential inaccuracy in capturing fast intra-seasonal waning of vaccine-induced protection needs to be rigorously investigated. To compare statistical methods for vaccine effectiveness (VE) estimation, we generated simulated data using a multiscale agent-based model of an epidemic with an acute viral infection and differing extents of VE waning. We extended the previously proposed framework for VE measures based on the observational data richness to assess changes of vaccine-induced protection with time. While VE measures based on hard-to-collect information (e.g. exact timing of exposures) were accurate, usually VE studies rely on time-to-infection data and the Cox proportional hazard model. We found that its extension utilizing scaled Schoenfeld residuals, previously proposed for capturing VE waning, was unreliable in capturing both the degree of waning and its functional form and identified the mathematical factors contributing to this unreliability. We showed that partitioning time and including a time-vaccine interaction term in the Cox model significantly improved estimation of VE waning, even in the case of dramatic, rapid waning. We also proposed how to optimize the partitioning scheme. Using simulated data, we compared different measures of VE for capturing the intra-seasonal waning of vaccine-induced protection. We propose an extension of the Cox model based on including a time-vaccine interaction term with further optimization of partitioning time. These findings may guide future analysis of VE waning in observational data.