Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

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

As studies published to date differ widely across variables such as size, study population characteristics, dosage, etc., a comprehensive concluding safety assessment has not been made. Nonetheless, VSV-EBOV has been described as safe and overall well tolerated, while also being reactogenic in the clinical studies published to date. The adverse events documented were generally mild to moderate and transient. Importantly, there were no vaccine-related serious adverse events (SAE), other than one case of fever and two allergic reactions (one of them when the vaccine was co-administered with amoxicillin)all which were resolved without sequelaein now over 18,000 individuals who have received the vaccine in clinical trials. 16, 33 Besides local reactogenicity, which was reported in up to 90-100% of the volunteers, 28,29 the most frequently reported adverse events were systemic solicited reactions such as headaches, which were reported in 21-71%, fever in 10-50%, and fatigue in 12-50% of vaccinees in all published phase II/III studies. [33] [34] [35] [36] [37] An initially unexpected adverse event constituted the emergence of arthritis cases that tested PCR-positive for rVSV in the phase I trial in Geneva, Switzerland. The study was halted when 11/51 volunteers developed oligoarthritis after having received 1 × 10 7 PFU or 5 × 10 7 PFU of VSV-EBOV and was ultimately resumed with a reduced dose of 3 × 10 5 PFU. Arthritis occurred on median 11 days after vaccination and lasted for 8 days. The development of arthritis did, however, not correlate with the dosage, as 13/51 individuals who had received the reduced dose likewise developed arthritis. In the reduced dose cohort, the risk of arthritis furthermore correlated with increasing age. 39 It was also observed that its development correlated with higher vaccine efficacy. 40 Three affected participants also developed rVSV-PCR positive skin lesions, with infectious rVSV recovered from one participant. After the study halt, simultaneously running phase I studies of VSV-EBOV included arthralgia/arthritis as a solicited adverse event, but while transient arthralgia was likewise reported, the high frequency of arthritis cases was not observed to the same extent. [28] [29] [30] [31] 41 Finally, arthritis frequency was assessed in a large placebocontrolled phase III trial. Here, the incidence of arthritis or joint swelling was 4.9% in a study population of 1050 individuals. Its onset and duration was comparable to the observations in the Geneva trial, and again, age was associated with a higher All trials except for "rVSV-EBOV-01" are utilizing the vaccine candidate VSV-EBOV.