Robust evaluation of vaccine effects based on estimation of vaccine efficacy curve

TL;DR

This paper introduces a new method to estimate vaccine efficacy over time, addressing biases and limitations of traditional models, and demonstrates its advantages through simulations and real trial data analysis.

Contribution

It proposes a novel approach to estimate vaccine efficacy as a function of time using the Cox model, improving robustness and comparability across trials.

Findings

The method provides unbiased estimates under waning immunity scenarios.

It improves comparability of vaccine efficacy across different trial designs.

The approach helps optimize vaccine delivery timing in seasonal disease regions.

Abstract

Background: The Cox model and its extensions assuming proportional hazards is widely used to estimate vaccine efficacy (VE). In the typical situation that VE wanes over time, the VE estimates are not only sensitive to study duration and timing of vaccine delivery in relation to disease seasonality but also biased in the presence of sample attrition. Furthermore, estimates of vaccine impact such as number of cases averted (NCA) are sensitive to background disease incidence and timing of vaccine delivery. Comparison of the estimates between trials with different features can be misleading. Methods: We propose estimation of VE as a function of time in the Cox model framework, using the area under the VE curve as a summary measure of VE, and extension of the method to estimate vaccine impact. We use simulations and re-analysis of a RTS,S/AS01 malaria vaccine trial dataset to demonstrate their properties and applications. Results: Simulation under scenarios with different trial duration, magnitude of sample attrition and timing of vaccine delivery, all assuming vaccine protection wanes over time, demonstrated the problems of conventional methods assuming proportional hazard, robustness and unbiasedness of the proposed methods, and comparability of the proposed estimates of vaccine efficacy and impact across trials with different features. Furthermore, the proposed NCA estimators are informative in determining the optimal vaccine delivery strategy in regions with highly seasonal disease transmission. Conclusions: The proposed method based on estimation of vaccine efficacy trajectory provides a robust, unbiased, and flexible approach to evaluate vaccine effects.