Transcriptomic signatures induced by the Ebola virus vaccine rVSVΔG-ZEBOV-GP in adult cohorts in Europe, Africa, and North America: a molecular biomarker study.

BACKGROUND: A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine. METHODS: 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 105 to 1 × 108 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity. FINDINGS: Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 106 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis). INTERPRETATION: Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking.

Effect of Recombinant Vesicular Stomatitis Virus-Zaire Ebola Virus Vaccination on Ebola Virus Disease Illness and Death, Democratic Republic of the Congo.

We conducted a retrospective cohort study to assess the effect vaccination with the live-attenuated recombinant vesicular stomatitis virus-Zaire Ebola virus vaccine had on deaths among patients who had laboratory-confirmed Ebola virus disease (EVD). We included EVD-positive patients coming to an Ebola Treatment Center in eastern Democratic Republic of the Congo during 2018-2020. Overall, 25% of patients vaccinated before symptom onset died compared with 63% of unvaccinated patients. Vaccinated patients reported fewer EVD-associated symptoms, had reduced time to clearance of viral load, and had reduced length of stay at the Ebola Treatment Center. After controlling for confounders, vaccination was strongly associated with decreased deaths. Reduction in deaths was not affected by timing of vaccination before or after EVD exposure. These findings support use of preexposure and postexposure recombinant vesicular stomatitis virus-Zaire Ebola virus vaccine as an intervention associated with improved death rates, illness, and recovery time among patients with EVD.

Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells.

Use of the progesterone (Pg) birth control depot medroxyprogesterone acetate (DMPA) increases a woman's risk for sexually transmitted infection with HIV or HSV-2 via unknown mechanisms. Plasmacytoid dendritic cells (pDCs) are circulating and tissue-resident sentinels capable of making large quantities of IFN-alpha upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN-alpha production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN-alpha production by pDCs in mice, providing a potential explanation for how DMPA impairs innate antiviral immunity in women. Pg failed to inhibit the Mda-5 pathway of IFN-alpha induction in dendritic cells, suggesting that Pg regulates select antiviral DC programs. This may occur through selective blockade of IFN regulatory factor-7 activation, a novel steroid action. Thus, through inhibition of TLR-mediated IFN-alpha production by pDCs, Pg may regulate antiviral immunity.