Following changes were made: Any study conducted in healthy volunteers could be put on hold by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) due to any SAE. Consequently, the SAE “multiple crises of abnormal movements in both arms and legs” led to the temporary halt of the study from 06 September 2019 to 10 September 2019. That SAE was considered as related to the vaccine by the Investigator and unrelated by the Sponsor. As per the recommendations of the ANSM, all subjects who were participating in the study had to be informed about the related SAEs in the informed consent form (ICF) or through an addendum to the ICF. The subjects were also informed about the temporary halt and the increase in sample size. The Investigators were notified and the Investigator’s Brochure was updated with this information. Due to the temporary halt, the Sponsor increased the sample size to replace subjects who were to be excluded from the PPAS due to inability to perform the vaccination within allowed time windows for the first 4 dose and adjusted the attrition rate of the study from 15% to 20% to ensure the adequate power to fulfill the primary and key secondary objectives.

Following changes were made: Due to coronavirus disease 2019 (COVID 19) pandemic, enrollment of subjects was paused on 12 March 2020 due to increased number of cases in France. Ongoing vaccinations were stopped on 16 March 2020 due to the confinement established in the country and consequent impossibility to follow study visits within requested time window. As the study vaccine was administered in healthy individuals in simulated schedule, there was no safety issue in case of incomplete vaccination. Different measures were taken according to the stage of vaccination:• For 3 subjects who had finished their vaccination scheme, follow-up was monitored by phone. The 2 due visits (Visit [V] 06 [Day 42] and V07 [Day 56]) were replaced by phone call to monitor safety (no blood sample was taken). • For 29 subjects who had not finished their vaccination scheme, they were withdrawn from the study due to protocol deviation (ie, inability to attend vaccination visit within allowed time windows), but they continued to be followed for safety. The follow-up of these subjects was monitored by phone. •The 6-month follow-up was done by phone as planned in protocol. These measures were taken by Sponsor to ensure the well-being of subjects (ie, to limit exposure to COVID-19) and were implemented without IRB/IEC approval, as per national and international guidance’s. However, IRB/IEC and health authorities were informed promptly about measures reported in the amendment. The enrollment resumed as soon as subjects’ safety was ensured, and national health authorities and Ethic Committee approved. The Sponsor increased sample size of the study to replace subjects who were to be excluded from PPAS due to inability to attend vaccination visit within allowed time windows for the first 4 dose or inability to take blood samples during the confinement and to ensure adequate statistical power to fulfill the primary and key secondary objectives and allowed further replacement of withdrawn subjects.

Following changes were made: Most of the subjects were expected to have reached RVNA titers >= 0.5 IU/mL after 4 or 5 doses of any rabies vaccine. If this did not occurred (i.e., RVNA titers < 0.5 IU/mL at Day 42) or occurred lately (i.e., RVNA titers < 0.5 IU/mL up to Day 28 and RVNA titers >= 0.5 IU/mL from Day 42), the absence or delayed immune response to the rabies vaccination might suggested an undiagnosed comorbidity that causes immunosuppression. Therefore, any subject in this situation was to be offered additional blood tests to evaluate a potential immunosuppression, the assessment of the RVNA titer in case of non-response to the rabies vaccine before and after a vaccination with a licensed vaccine in the country might be offered, as applicable and according to the pre-exposure prophylaxis recommendations in national guidelines.