Olga Pleguezuelos, PhD; Joep Dille; Sofie de Groen; Fredrik Oftung, PhD; Hubert G.M. Niesters, PhD; Md Atiqul Islam, MSc, PhD; Lisbeth Meyer Næss, PhD; Olav Hungnes, PhD; Nuhoda Aldarij, BSc; Demi L. Idema, BSc; Ana Fernandez Perez, BSc; Emma James, PhD; Henderik W. Frijlink, PhD; Gregory Stoloff; Paul Groeneveld, MD, PhD; Eelko Hak, PhD
Acknowledgment: The authors thank the volunteers, the medical and administrative team at Isala Hospital, Bryan Murray (Medical Monitor, Boyds Consultants, United Kingdom), and Denise Mailly (Service Desk Clinical Research Office, University Medical Centre Groningen) for their assistance with the study. They also thank Dr. Steve Norley (Robert Koch Institute, Germany), who performed the cellular analyses; sadly, he died during the drafting of this manuscript.
Financial Support: By SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project (FP7-Health no. 602012).
Disclosures: Drs. Pleguezuelos, Oftung, Næss, and Hak; Ms. Aldarij; Ms. Idema; and Ms. Fernandez Perez report a grant from the European Commission during the conduct of the study. Dr. James reports that she is an employee of SEEK, the company that developed the vaccine. Mr. Stoloff reports a grant from the European Union FP 7 Programme during the conduct of the study, a patent issued for peptide sequences and compositions (influenza), and ownership of shares in the sponsor company. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0735.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The authors have indicated that they will not be sharing data.
Corresponding Author: Olga Pleguezuelos, PhD, SEEK, Central Point, 45 Beech Street, London EC2Y 8AD, United Kingdom; e-mail, email@example.com.
Current Author Addresses: Drs. Pleguezuelos and James, Ms. Fernandez Perez, and Mr. Stoloff: SEEK, Central Point, 45 Beech Street, London EC2Y 8AD, United Kingdom.
Mr. Dille, Ms. de Groen, and Dr. Groeneveld: Isala Hospital, Dr. van Heesweg 2, 8025AB Zwolle, the Netherlands.
Drs. Oftung, Næss, and Hungnes: Department of Infectious Disease Immunology, Norwegian Institute of Public Health, PO Box 222, Skøyen, 0213 Oslo, Norway.
Dr. Niesters: University Medical Centre Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
Dr. Islam: Department of Statistics, Shahjalal University of Science and Technology, Kumargaon, Akhalia, Sylhet-3114, Bangladesh.
Ms. Aldarij, Ms. Idema, and Drs. Frijlink and Hak: Groningen Research Institute of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Author Contributions: Conception and design: O. Pleguezuelos, F. Oftung, H.W. Frijlink, G. Stoloff, E. Hak.
Analysis and interpretation of the data: O. Pleguezuelos, F. Oftung, M.A. Islam, L.M. Næss, O. Hungnes, N. Aldarij, D.L. Idema, P. Groeneveld, E. Hak.
Drafting of the article: O. Pleguezuelos, F. Oftung, L.M. Næss, O. Hungnes, E. James, P. Groeneveld, E. Hak.
Critical revision of the article for important intellectual content: O. Pleguezuelos, F. Oftung, L.M. Næss, O. Hungnes, H.W. Frijlink, E. Hak.
Final approval of the article: O. Pleguezuelos, J. Dille, S. de Groen, F. Oftung, H.G.M. Niesters, M.A. Islam, L.M. Næss, O. Hungnes, N. Aldarij, D.L. Idema, A. Fernandez Perez, E. James, H.W. Frijlink, G. Stoloff, P. Groeneveld, E. Hak.
Provision of study materials or patients: O. Pleguezuelos, J. Dille, P. Groeneveld, E. Hak.
Statistical expertise: M.A. Islam, N. Aldarij, E. Hak.
Obtaining of funding: G. Stoloff, E. Hak.
Administrative, technical, or logistic support: O. Pleguezuelos, S. de Groen, F. Oftung, H.G.M. Niesters, A. Fernandez Perez, E. James, G. Stoloff, P. Groeneveld, E. Hak.
Collection and assembly of data: J. Dille, S. de Groen, F. Oftung, H.G.M. Niesters, L.M. Næss, O. Hungnes, P. Groeneveld, E. Hak.
FLU-v is a broad-spectrum influenza vaccine that induces antibodies and cell-mediated immunity.
To compare the safety, immunogenicity, and exploratory efficacy of different formulations and dosing regimens of FLU-v versus placebo.
Randomized, double-blind, placebo-controlled, single-center phase 2b clinical trial. (ClinicalTrials.gov: NCT02962908; EudraCT: 2015-001932-38)
175 healthy adults aged 18 to 60 years.
0.5-mL subcutaneous injection of 500 µg of adjuvanted (1 dose) or nonadjuvanted (2 doses) FLU-v (A-FLU-v or NA-FLU-v) or adjuvanted or nonadjuvanted placebo (A-placebo or NA-placebo) (2:2:1:1 ratio).
Vaccine-specific cellular responses at days 0, 42, and 180 were assessed via flow cytometry and enzyme-linked immunosorbent assay. Solicited information on adverse events (AEs) was collected for 21 days after vaccination. Unsolicited information on AEs was collected throughout the study.
The AEs with the highest incidence were mild to moderate injection site reactions. The difference between A-FLU-v and A-placebo in the median fold increase in secreted interferon-γ (IFN-γ) was 38.2-fold (95% CI, 4.7- to 69.7-fold; P = 0.001) at day 42 and 25.0-fold (CI, 5.7- to 50.9-fold; P < 0.001) at day 180. The differences between A-FLU-v and A-placebo in median fold increase at day 42 were 4.5-fold (CI, 2.3- to 9.8-fold; P < 0.001) for IFN-γ–producing CD4+ T cells, 4.9-fold (CI, 1.3- to 40.0-fold; P < 0.001) for tumor necrosis factor-α (TNF-α), 7.0-fold (CI, 3.5- to 18.0-fold; P < 0.001) for interleukin-2 (IL-2), and 1.7-fold (CI, 0.1- to 4.0-fold; P = 0.004) for CD107a. At day 180, differences were 2.1-fold (CI, 0.0- to 6.0-fold; P = 0.030) for IFN-γ and 5.7-fold (CI, 2.0- to 15.0-fold; P < 0.001) for IL-2, with no difference for TNF-α or CD107a. No differences were seen between NA-FLU-v and NA-placebo.
The study was not powered to evaluate vaccine efficacy against influenza infection.
Adjuvanted FLU-v is immunogenic and merits phase 3 development to explore efficacy.
SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project.
Pleguezuelos O, Dille J, de Groen S, et al. Immunogenicity, Safety, and Efficacy of a Standalone Universal Influenza Vaccine, FLU-v, in Healthy Adults: A Randomized Clinical Trial. Ann Intern Med. 2020;:. [Epub ahead of print 10 March 2020]. doi: https://doi.org/10.7326/M19-0735
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Published: Ann Intern Med. 2020.
Infectious Disease, Influenza, Prevention/Screening, Vaccines/Immunization.
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