Challenges in the Reproductive Toxicity Assessment...

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

Authors: Srinivasan R.1*, Mantel N.2, Piolat J3, Desert P.1

*Presenting author: 1 Nonclinical Safety & Predictive Sciences, Global Immunology 2, Virology EU Platform, Global Antigen Design, 3, Preclinical Statistics 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. As of 2023, 34 countries in Africa and 13 countries in Central and South America are either endemic or have regions endemic for yellow fever (WHO Fact Sheet, 31 May 2023), posing a risk to travelers. 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. The Sanofi next generation cell culture based yellow fever vaccine (vYF) is developed in compliance with the WHO EYE strategy to replace the egg-based Stamaril and YF-VAX in travel market and endemic countries. The clinical development and subsequent licensure of the live attenuated vYF vaccine warrant an assessment of potential developmental and reproductive toxicity (DART) liabilities due to vaccine-induced viremia and/or the immune response in relevant models as per the applicable WHO guidelines. Cynomolgus monkey is an established animal model for YF vaccines as per the WHO TRS 978 for general toxicity and neurotropism assessments. Considering 3R principles and to reduce the defaulting approach of NHPs usage in biomedical research for DART assessment, an alternative approach to utilize lower-order species relevant to the risk factors, was followed to evaluate the DART effects, if any, for the human risk assessment. This presentation details the challenges faced and advantages following this approach without compromising the scientific integrity to inform the risk assessment for administration of YF vaccine in women-of-child-bearing-potential and support associated labelling.

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