Infectious Disease
Use of the test-negative design to estimate the protective effect of a scalar immune measure: identification and estimation Christopher Boyer* Christopher Boyer Marc Lipsitch Ziyuan Zhang
The relationship between antibody levels (more generally, a scalar measure of immune protection) at the time of exposure to infection (so-called exposure-proximal correlates of protection) and the risk of infection given exposure is of central interest in evaluating the evolution of immune protection conferred by prior infection and/or vaccination. Recently, a modified version of the test-negative study design (TND) has been proposed to assess this relationship. Under this design, those enrolled and tested in a TND also have an antibody titer taken and the odds ratio comparing titer levels among test-positive cases and test-negative controls is taken as an exposure-proximal measure of protection. However, the conditions under which such a study identifies the relationship between immune measurements and protection have not been rigorously defined. Here we propose formal identifiability criteria under which the TND recovers the population level conditional probability of protection given marker value as well as the causal effect of a hypothetical intervention to change marker level. We suggest possible estimation strategies and interrogate their performance using an agent-based simulation. Finally, we discuss other potential uses of collecting antibody titers in TND to better understand vaccine waning.