A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa

Abstract

The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.

Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study

“…28 Studies are in progress to elucidate immune mechanisms of protection, including the roles of antibody-dependent cellular cytotoxicity, innate immunity, and T cells. 29,30 Data from this study support several important conclusions. First, we confirm the previously described pattern of early onset, mild to moderate, well tolerated, transient, and dose-dependent local and systemic adverse events induced by rVSVΔG-ZEBOV-GP.…”

Rapid dose-dependent Natural Killer (NK) cell modulation and cytokine responses following human rVSV-ZEBOV Ebolavirus vaccination

“…Many cytokines and chemokines detected at elevated levels immediately after rVSV-ZEBOV immunization (IL-1ra, IL-6, IL-10, TNF-α, MCP-1/CCL2, and MIP-1β/CCL4) 8,9 can also influence the maturation/trafficking of NK cells and may be secreted by them 5,[10][11][12] . Early rVSV-ZEBOV responses (including IL-15 and type I interferon) were hypothesized to activate NK cells 4 , and additionally, certain post-vaccination NK cell phenotypes have been shown to correlate with long-term vaccine-specific Ab responses 8 .…”

Post-exposure treatments for Ebola and Marburg virus infections

“…Vaccines that were assessed in phase I and/or II studies during the 2013-2016 EBOV epidemic include rVSV-EBOV [268][269][270][271][272] , Ad5-EBOV [273][274][275] , rVSV-EBOV combined with rAd5-EBOV 276 , ChAd3-EBOV with or without MVA-EBOV [277][278][279][280] , Ad26-EBOV combined with MVA-EBOV 281 , and DNA encoding multiple filovirus GPs 282,283 . These EBOV vaccines generally elicited good immunogenicity against EBOV GP, and no serious adverse events were described.…”