Abstract
In the development of new vaccines, understanding the level of vaccine-induced antibody that is sufficient to protect against disease can simplify and expedite the development and licensing process. If there is an accepted threshold antibody level that is indicative of protection, then smaller trials measuring antibody concentration alone can be conducted to test new vaccines, instead of large efficacy studies powered on clinical outcomes. Commonly, threshold levels of protective antibody are determined from clinical efficacy trials in which clinical endpoints are measured on everyone and a small subset of participants have antibody concentrations measured. The proportion of participants with antibody below a threshold in each group in the immunogenicity subset can be compared to the proportions with disease in each group in the larger trial to find an appropriate threshold. Mathematically, this method seeks to compute an absolute threshold whereby antibody above the threshold provides complete, sterilizing immunity. However, in practice it is often understood that such thresholds may only be indicative of a relative degree of protection rather than an absolute one. Although this approach is common, the accuracy of such methods when the underlying mathematical assumptions do not hold true, has never been tested. We simulated data from clinical trial scenarios under varying assumptions of vaccine efficacy and calculated antibody thresholds of protection. We estimated the bias in the calculated thresholds derived from each scenario and showed that in many situations this method produces inflated estimates of thresholds, particularly if a vaccine induces high levels of antibody or when the underlying assumption of sterilizing immunity is violated.
Highlights
The process of developing, testing, and licensing a new vaccine necessitates an assessment of the vaccine’s ability to prevent disease in the population of interest
In this paper we examine this alternative model commonly used to define a threshold cutpoint of the correlate of protection
The horizontal dotted line represents the true threshold of protection and the vertical dotted line indicates the true underlying VE
Summary
We use the term ‘correlate of protection’ in this article to describe a measureable immunological parameter induced by vaccination that is related to protection against a specific clinical endpoint. The term ‘threshold of protection’ is used to describe a cutpoint on the correlate of protection that is used to test and compare vaccines, and above which a certain degree of protection is thought to exist. This can be absolute protection (100%) or relative (< 100%) and is affected by the rate at which the level of the immunological parameter wanes post-vaccination. The threshold (t) is the calculated from a smaller immunogenicity substudy within the main trial, assuming: VE:ims 1⁄4 1 À
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