Safety and immunogenicity of a simian-adenovirus-vectored rabies vaccine: an open-label, non-randomised, dose-escalation, first-in-human, single-centre, phase 1 clinical trial.


Journal

The Lancet. Microbe
ISSN: 2666-5247
Titre abrégé: Lancet Microbe
Pays: England
ID NLM: 101769019

Informations de publication

Date de publication:
09 2022
Historique:
received: 11 03 2022
revised: 13 04 2022
accepted: 09 05 2022
pubmed: 31 7 2022
medline: 9 9 2022
entrez: 30 7 2022
Statut: ppublish

Résumé

Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults. We did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 10 Between Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0-54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7-18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0-486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL. In this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation. UK Medical Research Council and Engineering and Physical Sciences Research Council.

Sections du résumé

BACKGROUND
Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults.
METHODS
We did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 10
FINDINGS
Between Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0-54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7-18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0-486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL.
INTERPRETATION
In this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation.
FUNDING
UK Medical Research Council and Engineering and Physical Sciences Research Council.

Identifiants

pubmed: 35907430
pii: S2666-5247(22)00126-4
doi: 10.1016/S2666-5247(22)00126-4
pmc: PMC7614839
mid: EMS181595
pii:
doi:

Substances chimiques

Antibodies, Neutralizing 0
Antibodies, Viral 0
Rabies Vaccines 0

Banques de données

ClinicalTrials.gov
['NCT04162600']

Types de publication

Clinical Trial Clinical Trial, Phase I Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e663-e671

Subventions

Organisme : Medical Research Council
ID : MC_PC_13073
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 220679/Z/20/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 220679
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P017339/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 201477/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P017339
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests AJR might receive royalties arising from the University of Oxford— AstraZeneca COVID-19 vaccine, which also uses the chimpanzee adenovirus technology platform. SF has received payment from Merck for a presentation at the ISPE Virtual Annual Conference, and is a contributor to intellectual property assigned to Oxford University Innovation relating to the ChAdOx1 nCoV-19 vaccine and might receive a proportion of proceeds from out-licensing of the property. CG has received a personal honorarium from the Duke Human Vaccine Institute ISAB and is director of Vaxxers. HCJE reports funding from the Wellcome Trust; grants from the US Department of Defense, Virion Therapeutics, Corona Discovery Fund, and Commonwealth of Pennsylvania, USA; research funding from Virion Therapeutics; consulting fees from Takeda, Biogen, RegenXBio; support for attending meetings or travel from Society for Immunotherapy of Cancer; support from Virion Therapeutics for travel to the Genetic Vaccine Development for Infectious Diseases Summit, Boston, MA, USA; has patents filed (US Patent 11291716 adenoviral vectors encoding hepatitis B viral antigens fused to herpes virus glycoprotein D and methods of using the same; and US Patent 11207402 constructs for enhancing immune responses); and has stock options in Ring Therapeutics. ADD reports grant funding from the Medical Research Council, Engineering and Physical Sciences Research Council, and the Wellcome Trust; might receive income arising from licensing of intellectual property related to ChAdOx2 RabG or other adenovirus-vectored vaccines; has received consultancy fees from AstraZeneca, relating to another adenovirus-vectored vaccine; and is a named inventor on patent applications relating to chimpanzee adenovirus platform technology. All other authors declare no competing interests.

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Auteurs

Daniel Jenkin (D)

Jenner Institute, University of Oxford, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, UK.

Adam J Ritchie (AJ)

Jenner Institute, University of Oxford, Oxford, UK.

Jeremy Aboagye (J)

Jenner Institute, University of Oxford, Oxford, UK.

Sofiya Fedosyuk (S)

Jenner Institute, University of Oxford, Oxford, UK.

Luke Thorley (L)

Jenner Institute, University of Oxford, Oxford, UK.

Samuel Provstgaad-Morys (S)

Jenner Institute, University of Oxford, Oxford, UK.

Helen Sanders (H)

Jenner Institute, University of Oxford, Oxford, UK.

Duncan Bellamy (D)

Jenner Institute, University of Oxford, Oxford, UK.

Rebecca Makinson (R)

Jenner Institute, University of Oxford, Oxford, UK.

Zhi Quan Xiang (ZQ)

Wistar Institute of Anatomy & Biology, Philadelphia, PA, USA.

Emma Bolam (E)

Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK.

Richard Tarrant (R)

Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK.

Fernando Ramos Lopez (F)

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, UK.

Abigail Platt (A)

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, UK.

Ian Poulton (I)

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, UK.

Catherine Green (C)

Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK.

Hildegund C J Ertl (HCJ)

Wistar Institute of Anatomy & Biology, Philadelphia, PA, USA.

Katie J Ewer (KJ)

Jenner Institute, University of Oxford, Oxford, UK.

Alexander D Douglas (AD)

Jenner Institute, University of Oxford, Oxford, UK. Electronic address: sandy.douglas@ndm.ox.ac.uk.

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