Uses of pathogen detection data to estimate vaccine direct effects in case-control studies

Abstract

The diagnosis of infectious disease syndromes such as fever, diarrhea, and pneumonia is complicated by the potential for shedding or carriage of putatively etiologic pathogens among individuals experiencing symptoms due to other causes. Symptomatic individuals among whom a pathogen is detected, but whose symptoms are caused by other factors, may be misclassified by diagnostic criteria based on pathogen detection. Case-control studies are commonly undertaken to estimate vaccine effectiveness, and present an opportunity to compare pathogen detection among individuals with and without clinically-relevant symptoms. Considering this study context, we derive simple estimators for the direct effects of vaccination on various aspects of host susceptibility. These include protection against acquisition of the pathogen of interest, and protection against progression of this pathogen to disease following acquisition. We assess the impact of test sensitivity on these estimators, and extend our framework to identify a 'vaccine probe' estimator for pathogen-specific etiologic fractions. We also derive biases affecting vaccine effectiveness estimates under the test-negative design, an alternative approach using similar data. Our results provide strategies for estimation of pathogen-specific vaccine effectiveness in the absence a diagnostic gold standard. These approaches can inform the design and analysis of studies addressing numerous pathogens and vaccines.

Theoretical framework for retrospective studies of the effectiveness of SARS-CoV-2 vaccines

“…Studies addressing VE against common or less-severe clinical endpoints may benefit from using extended analytic methods that have been proposed previously for estimation of VE against diseases with non-specific diagnostic criteria. 11,38,39 As these analysis methods must generally account for the strength of association between SARS-CoV-2 infection and clinical symptoms, enrollment and testing of control groups without symptoms related to SARS-CoV-2 infection may be of value for researchers studying VE against such endpoints.…”

“…Cases are typically individuals who meet clinical criteria such as the presence of predefined symptoms together with laboratory-confirmed detection of a vaccine-targeted infectious agent. 11 Under the TCC, controls are selected from a pool of individuals who are not known to be experiencing the clinical endpoint of interest at the time of enrollment, but are members of the same population from which cases are identified. Such individuals may be community controls, selected from among asymptomatic individuals in the community; registry controls, selected from population-based registries; or healthcare controls, selected among patients experiencing an alternate disease unrelated to the pathogen and vaccine of interest.…”