Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia

I V Dolzhikova, O V Zubkova, A I Tukhvatulin, A S Dzharullaeva, N M Tukhvatulina, D V Shcheblyakov, M M Shmarov, E A Tokarskaya, Y V Simakova, D A Egorova, D N Scherbinin, I L Tutykhina, A A Lysenko, A V Kostarnoy, P G Gancheva, T A Ozharovskaya, B V Belugin, L V Kolobukhina, V B Pantyukhov, S I Syromyatnikova, I V Shatokhina, T V Sizikova, I G Rumyantseva, A F Andrus, N V Boyarskaya, A N Voytyuk, V F Babira, S V Volchikhina, D A Kutaev, A N Bel'skih, K V Zhdanov, S M Zakharenko, S V Borisevich, D Y Logunov, B S Naroditsky, A L Gintsburg, I V Dolzhikova, O V Zubkova, A I Tukhvatulin, A S Dzharullaeva, N M Tukhvatulina, D V Shcheblyakov, M M Shmarov, E A Tokarskaya, Y V Simakova, D A Egorova, D N Scherbinin, I L Tutykhina, A A Lysenko, A V Kostarnoy, P G Gancheva, T A Ozharovskaya, B V Belugin, L V Kolobukhina, V B Pantyukhov, S I Syromyatnikova, I V Shatokhina, T V Sizikova, I G Rumyantseva, A F Andrus, N V Boyarskaya, A N Voytyuk, V F Babira, S V Volchikhina, D A Kutaev, A N Bel'skih, K V Zhdanov, S M Zakharenko, S V Borisevich, D Y Logunov, B S Naroditsky, A L Gintsburg

Abstract

Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).

Keywords: Ad5; Ebola; Ebola virus disease; VSV; ZEBOV; heterologous vaccination; prime-boost; vaccine.

Figures

Figure 1.
Figure 1.
Trial design.
Figure 2.
Figure 2.
Summary of surveilled local and systemic adverse events after vaccine administration. For groups receiving VSV-glycoprotein and Ad5-glycoprotein in one or 2 doses, reactions occurring within 7 days of vaccination are reported. For groups receiving half and full dose of both vectors, reactions occurring within 42 days of vaccination are reported. In groups receiving half and full dose of both vectors reactions occurring within 7 days of vaccination of VSV-glycoprotein are reported as I injection, reactions occurring within 7 days of vaccination of Ad5-glycoprotein are reported as II injection.
Figure 3.
Figure 3.
Humoral immune response. A) Glycoprotein-specific antibodies at days 21, 28, and 42, as measured by ELISA, in volunteers immunized at half or full dose of VSV-glycoprotein and Ad5-glycoprotein, and at 42 days in volunteers immunized with VSV-glycoprotein only. B) Results plotted as reciprocal end-point titres, with curves showing the distribution of individual antibody titres in each group at days 28 and 42. C) Neutralization antibodies at days 0 and 28 in volunteers immunized at full dose. *, p < 0.001.
Figure 4.
Figure 4.
Cell-mediated immune response to Ebola virus glycoprotein at days 0, 28, and 42 in volunteers immunized at half and full dose of VSV-glycoprotein and Ad5-glycoprotein. A) Fold increase in interferon-γ production by peripheral blood mononuclear cells exposed to glycoprotein. B) Glycoprotein-specific proliferation of CD4+ T-cells. C) Fold increase in interferon-γ production by peripheral blood mononuclear cells exposed to glycoprotein. Curves show the distribution of individual interferon-γ production in each treatment group at days 0, 28, and 42. D) Glycoprotein-specific proliferation of CD8+ T-cells. *, p < 0.0001.

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