Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial

Meera Madhavan; Adam J Ritchie; Jeremy Aboagye; Daniel Jenkin; Samuel Provstgaad-Morys; Iona Tarbet; Danielle Woods; Sophie Davies; Megan Baker; Abigail Platt; Amy Flaxman; Holly Smith; Sandra Belij-Rammerstorfer; Deidre Wilkins; Elizabeth J Kelly; Tonya Villafana; Justin A Green; Ian Poulton; Teresa Lambe; Adrian V S Hill; Katie J Ewer; Alexander D Douglas

doi:10.1016/j.ebiom.2022.104298

Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial

EBioMedicine. 2022 Nov:85:104298. doi: 10.1016/j.ebiom.2022.104298. Epub 2022 Oct 10.

Authors

Meera Madhavan¹, Adam J Ritchie², Jeremy Aboagye², Daniel Jenkin¹, Samuel Provstgaad-Morys², Iona Tarbet², Danielle Woods², Sophie Davies², Megan Baker³, Abigail Platt³, Amy Flaxman², Holly Smith², Sandra Belij-Rammerstorfer², Deidre Wilkins⁴, Elizabeth J Kelly⁴, Tonya Villafana⁵, Justin A Green⁶, Ian Poulton³, Teresa Lambe⁷, Adrian V S Hill², Katie J Ewer², Alexander D Douglas⁸

Affiliations

¹ Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7BN, UK; Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
² Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7BN, UK.
³ Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
⁴ Translational Medicine, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, 1 Medimmune Way, Gaithersburg, MD 20878, USA.
⁵ Clinical Development, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
⁶ Clinical Development, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
⁷ Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7BN, UK; Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK; China Academy of Medical Sciences Oxford Institute, University of Oxford, NDM Research Building, Old Road Campus, Headington, Oxford OX3 7FZ, UK.
⁸ Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7BN, UK. Electronic address: sandy.douglas@ndm.ox.ac.uk.

Abstract

Background: Intranasal vaccination may induce protective local and systemic immune responses against respiratory pathogens. A number of intranasal SARS-CoV-2 vaccine candidates have achieved protection in pre-clinical challenge models, including ChAdOx1 nCoV-19 (AZD1222, University of Oxford / AstraZeneca).

Methods: We performed a single-centre open-label Phase I clinical trial of intranasal vaccination with ChAdOx1 nCoV-19 in healthy adults, using the existing formulation produced for intramuscular administration. Thirty SARS-CoV-2 vaccine-naïve participants were allocated to receive 5 × 10⁹ viral particles (VP, n=6), 2 × 10¹⁰ VP (n=12), or 5 × 10¹⁰ VP (n=12). Fourteen received second intranasal doses 28 days later. A further 12 received non-study intramuscular mRNA SARS-CoV-2 vaccination between study days 22 and 46. To investigate intranasal ChAdOx1 nCoV-19 as a booster, six participants who had previously received two intramuscular doses of ChAdOx1 nCoV-19 and six who had received two intramuscular doses of BNT162b2 (Pfizer / BioNTech) were given a single intranasal dose of 5 × 10¹⁰ VP of ChAdOx1 nCoV-19. Objectives were to assess safety (primary) and mucosal antibody responses (secondary).

Findings: Reactogenicity was mild or moderate. Antigen-specific mucosal antibody responses to intranasal vaccination were detectable in a minority of participants, rarely exceeding levels seen after SARS-CoV-2 infection. Systemic responses to intranasal vaccination were typically weaker than after intramuscular vaccination with ChAdOx1 nCoV-19. Antigen-specific mucosal antibody was detectable in participants who received an intramuscular mRNA vaccine after intranasal vaccination. Seven participants developed symptomatic SARS-CoV-2 infection.

Interpretation: This formulation of intranasal ChAdOx1 nCoV-19 showed an acceptable tolerability profile but induced neither a consistent mucosal antibody response nor a strong systemic response.

Funding: AstraZeneca.

Keywords: Adenovirus vector; Intranasal vaccination; Mucosal antibody; SARS-CoV-2.

Publication types

Clinical Trial, Phase I
Randomized Controlled Trial

MeSH terms

Adenoviridae / genetics
Adult
Antibodies, Viral
BNT162 Vaccine
COVID-19 Vaccines / adverse effects
COVID-19* / prevention & control
ChAdOx1 nCoV-19
Humans
SARS-CoV-2
Vaccination / adverse effects
Viral Vaccines*
mRNA Vaccines

Substances

Antibodies, Viral
BNT162 Vaccine
ChAdOx1 nCoV-19
COVID-19 Vaccines
Viral Vaccines