First-in-human study to evaluate safety, tolerability, and immunogenicity of heterologous regimens using the multivalent filovirus vaccines Ad26.Filo and MVA-BN-Filo administered in different sequences and schedules: A randomized, controlled study

PLoS ONE, vol. 17, pp. e0274906

Abstract

BACKGROUND: Though clinically similar, Ebola virus disease and Marburg virus disease are caused by different viruses. Of the 30 documented outbreaks of these diseases in sub-Saharan Africa, eight were major outbreaks (≥200 cases; five caused by Zaire ebolavirus [EBOV], two by Sudan ebolavirus [SUDV], and one by Marburg virus [MARV]). Our purpose is to develop a multivalent vaccine regimen protecting against each of these filoviruses. This first-in-human study assessed the safety and immunogenicity of several multivalent two-dose vaccine regimens that contain Ad26.Filo and MVA-BN-Filo. METHODS: Ad26.Filo combines three vaccines encoding the glycoprotein (GP) of EBOV, SUDV, and MARV. MVA-BN-Filo is a multivalent vector encoding EBOV, SUDV, and MARV GPs, and Taï Forest nucleoprotein. This Phase 1, randomized, double-blind, placebo-controlled study enrolled healthy adults (18-50 years) into four groups, randomized 5:1 (active:placebo), to assess different Ad26.Filo and MVA-BN-Filo vaccine directionality and administration intervals. The primary endpoint was safety; immune responses against EBOV, SUDV, and MARV GPs were also assessed. RESULTS: Seventy-two participants were randomized, and 60 (83.3%) completed the study. All regimens were well tolerated with no deaths or vaccine-related serious adverse events (AEs). The most frequently reported solicited local AE was injection site pain/tenderness. Solicited systemic AEs most frequently reported were headache, fatigue, chills, and myalgia; most solicited AEs were Grade 1-2. Solicited/unsolicited AE profiles were similar between regimens. Twenty-one days post-dose 2, 100% of participants on active regimen responded to vaccination and exhibited binding antibodies against EBOV, SUDV, and MARV GPs; neutralizing antibody responses were robust against EBOV (85.7-100%), but lower against SUDV (35.7-100%) and MARV (0-57.1%) GPs. An Ad26.Filo booster induced a rapid further increase in humoral responses. CONCLUSION: This study demonstrates that heterologous two-dose vaccine regimens with Ad26.Filo and MVA-BN-Filo are well tolerated and immunogenic in healthy adults. CLINICALTRIALS.GOV: NCT02860650.

Authors 18

1. Viki Bockstal Aachen Janssen Infectious Diseases and Vaccines

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

2. Georgi Shukarev Aachen Janssen Infectious Diseases and Vaccines

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

3. Chelsea M. McLean corresponding Aachen Janssen Infectious Diseases and Vaccines

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

4. Neil H. Goldstein Aachen Janssen Infectious Diseases and Vaccines

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

5. Stephan Bart
   Affiliation as printed

   Optimal Research, LLC, Rockville, Maryland, United States of America

6. Auguste Gaddah

   Janssen (Belgium)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Beerse, Belgium

7. Dickson Anumenden

   Janssen (Belgium)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Beerse, Belgium

8. Jeroen N. Stoop Aachen Janssen Infectious Diseases and Vaccines

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

9. Anne Marit de Groot Aachen Janssen Infectious Diseases and Vaccines

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

10. Maria Grazia Pau Aachen Janssen Infectious Diseases and Vaccines

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

11. Jenny Hendriks Aachen Janssen Infectious Diseases and Vaccines

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

12. Stephen C. De Rosa

    Fred Hutch Cancer Center

    Affiliation as printed

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

13. Kristen W. Cohen

    Fred Hutch Cancer Center

    Affiliation as printed

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

14. M. Juliana McElrath

    Fred Hutch Cancer Center

    Affiliation as printed

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

15. Benoît Callendret Aachen Janssen Infectious Diseases and Vaccines

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

16. Kerstin Lühn Aachen Janssen Infectious Diseases and Vaccines

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

17. Macaya Douoguih Aachen Janssen Infectious Diseases and Vaccines

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands

18. Cynthia Robinson Aachen Janssen Infectious Diseases and Vaccines

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands