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

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.

Figure 1

CONSORT flow diagram of study design and volunteer recruitment. CONSORT flow diagram showing recruitment, allocation, and disposition of participants within this trial. Safety follow-up of all enrolled participants was completed, to day 112. After documented SARS-CoV-2 infection, individuals were excluded from categorisation as responders or non-responders to vaccination as indicated, but samples collected after infection are included (denoted by distinct symbols) in graphical representations of immunological data.

Figure 2

Solicited adverse events following vaccination with intranasal ChAdOx1 nCoV-19. For each of the individual solicited local (panel a) and systemic (panel b) reactions, the maximum severity reported by each volunteer over the seven days after vaccination is shown, broken down by study group and, for groups 1-3, vaccination number (dose 1 = first IN dose, dose 2 = second IN dose). In addition, to provide a global view of reactogenicity, the highest-graded of all local and all systemic reactions is shown for each volunteer. Yellow shading represents grade 1 (mild) events, orange shading represents grade 2 (moderate) events. Denominators were as shown in Figure 1.

Figure 3

Mucosal antibody responses. Summary of anti-S IgA (panels a-c) and IgG (panels d-f) responses in nasal mucosal samples, measured by electrochemiluminescence assay. Panels a and d show absolute responses (with horizontal dotted lines labelled LOD indicating assay limits of detection), panels b and e show responses normalized for total IgA (TIN), panels c and f show fold change in TIN values (FCTIN, with horizontal dotted lines indicating the arbitrary cut-off of FCTIN>3 used to define responses to vaccination in Supplementary Table 7). Each point represents a sample from a single individual at a given timepoint, and is the mean of results from technical duplicate assays. Colour represents the dose of IN vaccine administered: black represent no IN vaccination; red represents low dose (group 1); blue represents medium dose (group 3); and green represents high dose (groups 2, 4 and 5). Open symbols represent samples from individuals with evidence of preceding SARS-CoV-2 infection. To facilitate visualisation, selected timepoints are shown, and data is combined from the previously vaccine-naïve groups (groups 1-3) and from the previously vaccinated groups (groups 4-5), as indicated in X-axis label. ‘Conval’ represents samples from 10 convalescent individuals with documented SARS-CoV-2 infection (for further details, see Methods). Dotted vertical lines separate data from convalescent samples, groups 1-3, and groups 4-5. The study day on which each sample was collected is indicated in italics in X-axis labels, and corresponds to the main immunological analysis timepoint for each vaccine regime (see Figure 1). For groups 1-3, data is presented for naïve subjects (at enrolment, day 0), after a single IN vaccination (‘INx1’, day 28), and for individuals receiving two IN vaccinations (‘INx2’, day 56) or a non-study IM vaccine after IN vaccination (‘INx1 – IMx1’, day 56). For groups 4-5, data is presented at enrolment (‘IMx2’, day 0), and after IN vaccination (‘IMx2 – INx1’, day 28). Unavailable data is indicated by ‘n/a’. AU/mL indicates arbitrary units per mL. For full antibody kinetics including all timepoints, and with separate presentation of each individual group, see Supplementary Figures 5-6.

Figure 4

Systemic antibody and cellular responses. Panels a-b show summaries of anti-S IgG (panel a) and IgA (panel b) responses in serum samples, measured by electrochemiluminescence assay. Results from 39 recipients of two IM doses of 5 × 10¹⁰ VP of ChAdOx1 nCoV-19 are shown as a comparator data set (these individuals had received two doses with a 28 day interval, and samples were collected after a further 28 days). Each point represents a sample from a single individual at a given timepoint, and is the mean of results from technical duplicate assays. Colour represents the dose of IN vaccine administered: black represent no IN vaccination; red represents low dose (group 1); blue represents medium dose (group 3); and green represents high dose (groups 2, 4 and 5). Open symbols represent samples from individuals with evidence of preceding SARS-CoV-2 infection. To facilitate visualisation, selected timepoints are shown, and data is combined from the previously vaccine-naïve groups (groups 1-3) and from the previously vaccinated groups (groups 4-5), as indicated in X-axis label. The study day on which each sample was collected is indicated in italics in X-axis labels, and corresponds to the main immunological analysis timepoint for each vaccine regime (see Figure 1). For groups 1-3, data is presented for naïve subjects (at enrolment, day 0), after a single IN vaccination (‘INx1’, day 28), and for individuals receiving two IN vaccinations (‘INx2’, day 56) or a non-study IM vaccine after IN vaccination (‘INx1 – IMx1’, day 56). For groups 4-5, data is presented at enrolment (‘IMx2’, day 0), and after IN vaccination (‘IMx2 – INx1’, day 28). Unavailable data is indicated by ‘n/a’. AU/mL indicates arbitrary units per mL. Panel c shows peripheral blood mononuclear cell IFN-γ ELISpot results for each group at days 0 and 14 similarly, with results from 23 recipients of two IM doses. For full systemic response kinetics, including all timepoints and with separate presentation of each individual group, see Supplementary Figures 8-9.