Challenges in the Reproductive tox assessment of a live attenuated vaccine

Challenges in the Reproductive Toxicity Assessment of a Live Attenuated Vaccine: a case study

Srinivasan R. 1*, Mantel N. 2, Desert P. 1

*Presenting author

1 Nonclinical Safety & Predictive Sciences, Global Immunology

2, Virology EU Platform, Global Antigen Design, Sanofi, Marcy L’Etoile, France

Yellow Fever (YF) is an acute viral haemorrhagic disease, caused by a member of Flaviviridae family, transmitted to humans by bites of infected mosquitoes, Aedes and Haemogogus species. The Eliminate Yellow Fever Epidemics (EYE) program has been developed by a coalition of Gavi, UNICEF and WHO to face yellow fever’s increased risk of urban outbreaks and international spread. The principal competency of success is to ensure affordable vaccines and sustained vaccine supply (WHO EYE strategy 2017-2026) to the increased demand for YF immunization activities. Sanofi has developed new cell-based Yellow Fever vaccine (vYF) to replace the traditional egg-based marketed vYF vaccines. The development of live attenuated vYF warrant to be assessed for their potential developmental and reproductive toxicity (DART) liabilities due to (i) YF vaccine-induced viremia and (ii) vYF induced immune response in relevant models as per the applicable WHO guidelines.

Cynomolgus monkey is the WHO recommended animal model for YF vaccines, and a routine species used for DART assessments of biologicals. Considering 3Rs and reducing the default use of NHPs for DART assessment, an alternative strategy to utilize relevant lower-order species was envisaged to evaluate the DART effects of vYF. In the specific context of vYF, potential DART effects of both the humoral response as well as the viremia have to be assessed. No single lower order species can address both aspects; as such, New Zealand White rabbits and A129 transgenic mice of interferon deficient model were used to provide a careful safety assessment of DART liabilities related to antibody and viremia effects, respectively. This presentation details the testing strategies to assess any vYF DART liabilities.

This work was funded by Sanofi. The authors are employees of Sanofi and may hold shares and/or stock options in the company.