Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

Fathi, Anahita; Dahlke, Christine; Addo, Marylyn M.

Efficacy of VSV-EBOV and utilization during outbreaks VSV-EBOV contains the GP of the EBOV Kikwit strain, yet, in an NHP model, it showed cross-protection against the heterologous West African outbreak strain of EBOV Makona. 50 The subsequent phase III trial "Ebola Ça Suffit" is the only completed clinical trial reporting human efficacy data of VSV-EBOV to dateand, as such, is the only trial reporting efficacy data of any EVD vaccine at the time of this review. The study was conducted towards the end of the West African epidemic and has yielded highly encouraging results. The trial utilized a ring-vaccination strategy: a cluster of contacts and contacts-of-contacts around a case of EVD was identified and randomized to receive either immediate or delayed vaccination after 21 days, the duration of one incubation period reported for EBOV, and EVD cases from day 10 p. v. were assessed. 33, 51 As the study reported a vaccine efficacy of 100%, randomization was lifted and all ring contacts were offered the vaccine, now also including children. None of the 3796 immediately vaccinated individuals developed EVD from 10 days post vaccination (p.v.), while EVD occurred in 16/2041 contacts of the delayed vaccination cohort plus in seven never vaccinated contacts. The perfect efficacy rate had initially been questioned and spurred a controversial debate since the trial design was unblinded and, as the number of EVD cases had already decreased, only few EVD cases were reported in the delayed vaccination cohort. The authors', however, rejected the notion that trial results were biased due to the open trial design. 52, 53 On the basis of these efficacy data, VSV-EBOV has received Priority Medicine (PRIME) designation by the European Medical Association (EMA) as well as Breakthrough Therapy designation by the Food and Drug Administration (FDA), which enables a faster licensure process. The submission of a rolling licensure application to the FDA has been initiated by the manufacturer Merck in November 2018. 54 Owing to its PRIME and Breakthrough Therapy designation, VSV-EBOV has been pre-approved for emergency use during outbreaks by SAGE as part of its Expanded Access framework (also called compassionate use program), while pending licensure. 55 Under the framework, WHO provides the vaccine to consenting at-risk individuals, health-care workers as well as ring contacts outside of clinical studies. 55, 56 In a new flare-up of EVD in Guinea in March 2016, after the end of the West African epidemic was declared, the framework was utilized to vaccinate over 1500 individuals including children from the age of 6, and no EVD cases were reported in the vaccinated population. 57 Another 3481 people were vaccinated during the 9th EBOV outbreak in the DRC in May and June 2018. 58 During the current 10th EBOV outbreak in the DRC, which was declared on August 1 st , 2018 and has claimed the lives of 2592 humans as of July 21 st , 2019, VSV-EBOV has been administered a total of 171,052 times since the initiation of vaccination seven days later. 59 In addition to WHO, MSF is also providing the vaccine using the ring vaccination strategy and has assessed vaccine efficacy in a clinical trial including 500 individuals from the age of one. The trial was reportedly completed on November 30, 2018 (clinicaltrials.gov, NCT03161366) and the results are awaited with great anticipation. Meanwhile, WHO recently reported highly encouraging preliminary results of the ring vaccinat