Leveraging Pathogen Sequence and Contact Tracing Data to Enhance Vaccine Trials in Emerging Epidemics.

Abstract

Advance planning of vaccine trials conducted during outbreaks increases our ability to rapidly define the efficacy and potential impact of a vaccine. Vaccine efficacy against infectiousness (VEI) is an important measure for understanding a vaccine's full impact, yet it is currently not identifiable in many trial designs because it requires knowledge of infectors' vaccination status. Recent advances in genomics have improved our ability to reconstruct transmission networks. We aim to assess if augmenting trials with pathogen sequence and contact tracing data can permit them to estimate VEI. We develop a transmission model with a vaccine trial in an outbreak setting, incorporate pathogen sequence data and contact tracing data, and assign probabilities to likely infectors. We then propose and evaluate the performance of an estimator of VEI. We find that under perfect knowledge of infector-infectee pairs, we are able to accurately estimate VEI. Use of sequence data results in imperfect reconstruction of transmission networks, biasing estimates of VEI towards the null, with approaches using deep sequence data performing better than approaches using consensus sequence data. Inclusion of contact tracing data reduces the bias. Pathogen genomics enhance identifiability of VEI, but imperfect transmission network reconstruction biases estimate toward the null and limits our ability to detect VEI. Given the consistent direction of the bias, estimates obtained from trials using these methods will provide lower bounds on the true VEI. A combination of sequence and epidemiologic data results in the most accurate estimates, underscoring the importance of contact tracing.