Leveraging pathogen sequence and contact tracing data to enhance vaccine trials in emerging epidemics

Introduction: Advance planning of the design and analysis of vaccine trials conducted during infectious disease outbreaks increases our ability to rapidly define the efficacy and potential impact of a vaccine and inform public health response. Vaccine efficacy against infectiousness (VEI) is an important measure for understanding the full impact of a vaccine, yet it is currently not identifiable in many vaccine trial designs because it requires knowledge of the vaccination status of infectors. Recent advances in pathogen genomics have improved our ability to accurately reconstruct transmission networks. We aim to assess if augmenting classical randomized controlled trial designs with pathogen sequence and contact tracing data can permit these trials to estimate VEI. Methods: We develop a transmission model with a vaccine trial in an outbreak setting, incorporate pathogen sequence evolution data and sampling as well as contact tracing data, and assign probabilities to likely infectors. We then propose and evaluate the performance of an estimator of VEI. Results: 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 the 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. Conclusion: Pathogen genomics enhance identifiability of VEI from individually randomized controlled trials, but imperfect transmission network reconstruction biases the estimates towards 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 in reconstructing transmission networks.