PMID- 36197845 OWN - NLM STAT- MEDLINE DCOM- 20221007 LR - 20221013 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 17 IP - 10 DP - 2022 TI - 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. PG - e0274906 LID - 10.1371/journal.pone.0274906 [doi] LID - e0274906 AB - 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 Tai 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. FAU - Bockstal, Viki AU - Bockstal V AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Shukarev, Georgi AU - Shukarev G AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - McLean, Chelsea AU - McLean C AUID- ORCID: 0000-0002-3548-3482 AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Goldstein, Neil AU - Goldstein N AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Bart, Stephan AU - Bart S AD - Optimal Research, LLC, Rockville, Maryland, United States of America. FAU - Gaddah, Auguste AU - Gaddah A AD - Janssen Infectious Diseases and Vaccines, Beerse, Belgium. FAU - Anumenden, Dickson AU - Anumenden D AD - Janssen Infectious Diseases and Vaccines, Beerse, Belgium. FAU - Stoop, Jeroen N AU - Stoop JN AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Marit de Groot, Anne AU - Marit de Groot A AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Pau, Maria G AU - Pau MG AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Hendriks, Jenny AU - Hendriks J AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - De Rosa, Stephen C AU - De Rosa SC AD - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - Cohen, Kristen W AU - Cohen KW AD - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - McElrath, M Juliana AU - McElrath MJ AD - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - Callendret, Benoit AU - Callendret B AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Luhn, Kerstin AU - Luhn K AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Douoguih, Macaya AU - Douoguih M AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. FAU - Robinson, Cynthia AU - Robinson C AD - Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands. LA - eng SI - ClinicalTrials.gov/NCT02860650 GR - HHSN272200800056C/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial DEP - 20221005 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Neutralizing) RN - 0 (Antibodies, Viral) RN - 0 (Ebola Vaccines) RN - 0 (Glycoproteins) RN - 0 (Nucleoproteins) RN - 0 (Vaccines, Combined) SB - IM MH - Adolescent MH - Adult MH - Animals MH - Antibodies, Neutralizing MH - Antibodies, Viral MH - *Ebola Vaccines MH - *Ebolavirus MH - Glycoproteins MH - *Hemorrhagic Fever, Ebola MH - Humans MH - *Marburgvirus MH - Middle Aged MH - Nucleoproteins MH - Vaccines, Combined MH - Vaccinia virus MH - Young Adult PMC - PMC9534391 COIS- Viki Bockstal, Neil Goldstein, and Cynthia Robinson were full-time employees of Janssen Vaccines and Prevention, B.V. at the time of the study and may hold shares of Johnson & Johnson. Georgi Shukarev, Chelsea McLean, Auguste Gaddah, Dickson Anumenden, Jeroen N. Stoop, Anne Marit de Groot, Maria G. Pau, Jenny Hendriks, Benoit Callendret, Kerstin Luhn, and Macaya Douoguih are full-time employees of Janssen Vaccines and Prevention, B.V., and may hold shares of Johnson & Johnson. Stephan Bart, Stephen C. De Rosa, Kristen W. Cohen, and M. Juliana McElrath report grants from Janssen during the conduct of the study paid to their institutions. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Janssen has an agreement with the Yale Open Data Access (YODA) Project to serve as the independent review panel for the evaluation of requests for clinical study reports and participant-level data from investigators and physicians for scientific research that will advance medical knowledge and public health. Data will be made available following publication and approval by YODA of any formal requests with a defined analysis plan. For more information on this process or to make a request, please visit the Yoda Project site at http://yoda.yale.edu. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. EDAT- 2022/10/06 06:00 MHDA- 2022/10/12 06:00 PMCR- 2022/10/05 CRDT- 2022/10/05 13:32 PHST- 2021/12/01 00:00 [received] PHST- 2022/07/22 00:00 [accepted] PHST- 2022/10/05 13:32 [entrez] PHST- 2022/10/06 06:00 [pubmed] PHST- 2022/10/12 06:00 [medline] PHST- 2022/10/05 00:00 [pmc-release] AID - PONE-D-21-35963 [pii] AID - 10.1371/journal.pone.0274906 [doi] PST - epublish SO - PLoS One. 2022 Oct 5;17(10):e0274906. doi: 10.1371/journal.pone.0274906. eCollection 2022.