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.

Fig. 1. Up-regulated plasma markers after rVSV-ZEBOV immunization.

Individual values are expressed in picograms per milliliter for each subject in each dose group and at each time point assessed, before and after rVSV-ZEBOV immunization or placebo injection in Geneva (A) or Lambaréné (B). The number of samples assessed at each time point is given in Table 1 and table S12. Samples with undetectable concentrations were arbitrarily given 50% of the specific minimal detection dose, as described in Materials and Methods.

Fig. 2. Plasma chemokines/cytokines and signatures in rVSV-ZEBOV vaccinees from Geneva and Lambaréné.

(A) Day 1 GMCs are expressed in picograms per milliliter (IL-6, TNF-α, and IL-10),1 × 10⁻² (MIP-1β/CCL4), 1 × 10⁻³ (MCP-1/CCL2), or 1 × 10⁻⁴ (IL-1Ra) and illustrated for Geneva (left) and Lambaréné (right) vaccinees. (B) Vaccine responses, expressed by the day 1/day 0 ratios, are illustrated for each chemokine and cytokine for which up-regulation was observed after immunization in Geneva (left) or Lambaréné (right). (C) The plasma signatures are illustrated for Geneva (left) and Lambaréné (right) vaccinees with and without AEs. (D) The plasma signatures are expressed for Geneva (left) and Lambaréné (right) vaccinees reporting grade 0 to 3 AEs.

Fig. 3. Correlation between the Lambaréné signature and the Geneva signature applied to Lambaréné vaccinees.

Representation of the signature (in arbitrary units) calculated directly in vaccine recipients from Lambaréné (vertical axis) and when applying the Geneva signature to the Lambaréné data (horizontal axis).