Phase 1 Trial of ChAd68 and Ad5 Adenovirus COVID-19 Vaccines Delivered by Aerosol

Phase 1, Open Label Study to Evaluate the Safety and Immunogenicity of ChAd68 and AdHu5 Vector-based Trivalent COVID-19 Vaccines Delivered Via Inhaled Aerosol

This is a phase 1 study in healthy volunteers who have received at least three doses of an mRNA COVID-19 vaccine, to evaluate the safety and immune responses that develop in the blood and lungs following the administration by aerosol of either Ad5-triCoV/Mac or ChAd-triCoV/Mac, new experimental adenovirus-based vaccines expressing SARS-CoV-2 spike, nucleocapsid and RNA polymerase proteins.

Study Overview

• Status: Active, not recruiting
• Conditions: COVID-19; SARS-CoV2 Infection
• Intervention / Treatment: Biological: Ad5-triCoV/Mac; Biological: ChAd-triCoV/Mac

Detailed Description

This is a phase 1, dose-escalating study to evaluate the safety and immunogenicity of a single dose of either Ad5-triCoV/Mac, a replication deficient human adenovirus vector, or ChAd-triCoV/Mac, a replication deficient chimpanzee adenovirus 68 vector, delivered to the respiratory tract by aerosol, in healthy volunteers who have received at least three doses of an mRNA COVID-19 vaccine. Both vectors have been engineered to express the spike, nucleocapsid and RNA polymerase proteins.

Up to 36 healthy volunteers will be enrolled in this dose escalation study. The first cohort (n=6) will receive Ad5-triCoV/Mac (n=3) or ChAd-triCoV/Mac (n=3) at the lowest dose of 10e5 TCID50, administered using the AeroNeb Solo Vibrating Mesh Nebulizer. Assuming no safety concerns, participants will then be administered Ad5-triCoV/Mac (n=3) or ChAd-triCoV/Mac (n=3) at a dose of 10e6. Assuming no safety signals we will move to vaccinate at the next dose level of 1x10e7 TCID50. Decisions about dose escalation will be made independently for each vaccine based on safety and immunogenicity profile. If the immunogenicity endpoints are not reached, in the absence of a safety signal, at the 10e7 dose level, we will move to the next dose level of 3x10e7 TCID50 and enrol three participants/vaccine group. Similarly, if all of the immunogenicity endpoints in the BAL are not met at 3x10e7, and in the absence of any safety signal, we will further escalate to 1x10e8 TCID50 and enrol three participants/vaccine group, if required. For both vaccines the maximum dose level will be 1x10e8 TCID50.

Antibody and specific T cell responses will be measured in lung from bronchoalveolar lavage fluid collected at bronchoscopy at baseline and at 4 weeks following vaccination and in blood at several time points up to week 48 following vaccination.

Safety endpoints will include the nature of any adverse events, their severity and the probability of a relationship to study procedures and administration of vaccine.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Fiona M Smaill, MD; Phone Number: 74190 905-521-2100; Email: smaill@mcmaster.ca
• Study Contact Backup: Name: Zhou Xing, PhD; Phone Number: 22354 905-525-9140; Email: xingz@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy human subjects who are between 18 and 65 years of age.
2. Have completed a COVID vaccine series with at least three doses of a licensed mRNA vaccine at least 3 months prior.
3. HIV antibody negative.
4. Able to understand and comply with protocol requirements and instructions; able to attend scheduled study visits and complete required investigations.
5. For women, negative pregnancy test and for those women of child-bearing potential practising two acceptable forms of contraception for the duration of the study.
6. For men, using barrier contraception for the duration of the study.
7. No history of COVID infection OR history of documented COVID infection at least 6 months prior, dated from either a self-reported positive rapid antigen test or positive PCR test (self-reported or documented). For participants with a history of COVID infection, anti-nucleocapsid antibodies will be measured prior to enrolment to confirm infection.

Exclusion Criteria:

1. Subjects who have received any recombinant adenoviral-vectored COVID-19 vaccine, e.g. AstraZeneca COVISHIELD COVID-19 vaccine.
2. Pregnant or lactating women.
3. Subjects who have any acute or chronic illnesses, any relevant findings on physical examination or are receiving any immunosuppressive therapy in the opinion of the investigator likely to affect the immune system including current use of inhaled or nasal steroids.
4. Subjects with a history of any bleeding disorder or receiving any drug treatment that in the opinion of the investigator may increase the risk of bleeding.
5. Subjects with a history of respiratory diseases requiring regular treatment, e.g. asthma, COPD, interstitial lung diseases, bronchiectasis.
6. Current cigarette smokers, current e-cigarette smokers and ex-smokers who have quit less than a year ago, as reported by the subject.
7. Subjects with clinically significant abnormal baseline spirometry tests: FEV1<80% predicted, FVC<80% predicted, FEV1/FVC<70%; DLCO<70% predicted.
8. Any health-related condition for which study bronchoscopy is contraindicated.
9. Subjects whose baseline laboratory values are outside of the normal range, unless the abnormality is considered not clinically relevant by the investigator. A single repeat test is allowed during the screening period.
10. Subjects whose use of alcohol or drugs would, in the opinion of the investigator, interfere with adherence to the study protocol.
11. Subjects who are using, or have a history of using, inhaled cocaine, metamphetamine or other inhaled or smoked recreational drugs. Subjects who give a history of smoking marijuana more than a year ago may be enrolled as long as they agree not to smoke marijuana for the duration of the study.
12. Failure to provide written consent.
13. Known allergy to vaccine components.
14. Any abnormality on chest x-ray suggestive of clinically significant respiratory disease.
15. Previous receipt of any experimental adenovirus-vector vaccine by the aerosol route.
16. History of severe reaction to a previous COVID vaccination (including hives, difficulty breathing, angioedema, high fever, seizure).
17. History of venous or arterial thrombosis with thrombocytopenia following any vaccination.
18. History of cerebral venous thrombosis with thrombocytopenia.
19. History of heparin induced thrombocytopenia.
20. History of myocarditis or pericarditis.
21. History of Bell's Palsy.
22. History of hospitalization with an admitting diagnosis of primary COVID infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aerosol Ad5-triCoV/Mac dose level 10e5; Single dose by inhalation of 10e5 Ad5-tri-CoV/Mac	Biological: Ad5-triCoV/Mac; Ad5-triCoV/Mac is a recombinant type 5 human adenovirus vector which has been engineered to express our trivalent SARS-CoV-2 transgene cassette under the control of an MCMV promoter, and is followed by an SV40 polyA signal. The adenovirus construct is E1 and E3 deleted.This trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol ChAd-tri-CoV/Mac dose level 10e5; Single dose by inhalation of 10e5 ChAd-triCoV/Mac	Biological: ChAd-triCoV/Mac; ChAd-triCoV/Mac is an E1 and E3 deleted chimpanzee adenovirus serotype 68 where the trivalent SARS-CoV-2 transgene cassette is under the control of an HCMV promoter and is followed by an SV40 polyA signal. The trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol Ad5-triCoV/Mac dose level 10e6; Single dose by inhalation of 10e6 Ad5-triCoV/Mac	Biological: Ad5-triCoV/Mac; Ad5-triCoV/Mac is a recombinant type 5 human adenovirus vector which has been engineered to express our trivalent SARS-CoV-2 transgene cassette under the control of an MCMV promoter, and is followed by an SV40 polyA signal. The adenovirus construct is E1 and E3 deleted.This trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol ChAd-triCoV/Mac dose level 10e6; Single dose by inhalation of 10e6 ChAd-triCoV/Mac	Biological: ChAd-triCoV/Mac; ChAd-triCoV/Mac is an E1 and E3 deleted chimpanzee adenovirus serotype 68 where the trivalent SARS-CoV-2 transgene cassette is under the control of an HCMV promoter and is followed by an SV40 polyA signal. The trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol Ad5-triCoV/Mac dose level 10e7; Single dose by inhalation of 10e7 Ad5-triCoV/Mac	Biological: Ad5-triCoV/Mac; Ad5-triCoV/Mac is a recombinant type 5 human adenovirus vector which has been engineered to express our trivalent SARS-CoV-2 transgene cassette under the control of an MCMV promoter, and is followed by an SV40 polyA signal. The adenovirus construct is E1 and E3 deleted.This trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol ChAd-triCoV/Mac dose level 10e7; Single dose by inhalation of 10e7 ChAd-triCoV/Mac	Biological: ChAd-triCoV/Mac; ChAd-triCoV/Mac is an E1 and E3 deleted chimpanzee adenovirus serotype 68 where the trivalent SARS-CoV-2 transgene cassette is under the control of an HCMV promoter and is followed by an SV40 polyA signal. The trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol Ad5-triCoV/Mac dose level 3x10e7; Single dose by inhalation of 3x10e7 Ad5-triCoV/Mac	Biological: Ad5-triCoV/Mac; Ad5-triCoV/Mac is a recombinant type 5 human adenovirus vector which has been engineered to express our trivalent SARS-CoV-2 transgene cassette under the control of an MCMV promoter, and is followed by an SV40 polyA signal. The adenovirus construct is E1 and E3 deleted.This trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol ChAd-triCoV/Mac dose level 1x10e8; Single dose by inhalation of 1x10e8 ChAd-triCoV/Mac	Biological: Ad5-triCoV/Mac; Ad5-triCoV/Mac is a recombinant type 5 human adenovirus vector which has been engineered to express our trivalent SARS-CoV-2 transgene cassette under the control of an MCMV promoter, and is followed by an SV40 polyA signal. The adenovirus construct is E1 and E3 deleted.This trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).; Biological: ChAd-triCoV/Mac; ChAd-triCoV/Mac is an E1 and E3 deleted chimpanzee adenovirus serotype 68 where the trivalent SARS-CoV-2 transgene cassette is under the control of an HCMV promoter and is followed by an SV40 polyA signal. The trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).
Experimental: Aerosol ChAd-triCoV/Mac dose level 6x10e7; Single dose by inhalation of 6x10e7 ChAd-triCoV/Mac	Biological: ChAd-triCoV/Mac; ChAd-triCoV/Mac is an E1 and E3 deleted chimpanzee adenovirus serotype 68 where the trivalent SARS-CoV-2 transgene cassette is under the control of an HCMV promoter and is followed by an SV40 polyA signal. The trivalent transgene cassette consists of the S1 region of SARS-CoV-2 spike protein (aa 47-716), full-length SARS-CoV-2 nucleoprotein (N) fused to a highly conserved portion of the SARS-CoV-2 polymerase (RdRp or POL).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants reporting adverse events and severity of adverse events following Ad5-triCoV/Mac vaccination	Adverse events will be assessed according to the CTCAE Expanded Common Toxicity Criteria at 48-72 hours after vaccination, and at weeks 2, 4, 8, 12,16, 24, 32, 40 and 48	Over 48 weeks post vaccination
Number of participants reporting adverse events and severity of adverse events following ChAd-triCoV/Mac vaccination	Adverse events will be assessed according to the CTCAE Expanded Common Toxicity Criteria at 48-72 hours after vaccination, and at weeks 2, 4, 8, 12,16, 24, 32, 40 and 48	Over 48 weeks post vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunogenicity of Ad5-triCoV/Mac administered by aerosol	Change from baseline in: 1) spike-specific and anti-RBD antibodies including neutralizing antibodies both in the blood and airways; 2) spike/N/POL-specific CD4 and CD8 T cells in the airways (BAL fluid) four weeks post vaccination and 3) spike/N/POL-specific CD4 and CD8 T cells in the blood up to the last timepoint of examination.	Over 48 weeks post vaccination
Immunogenicity of ChAd-triCoV/Mac administered by aerosol	Change from baseline in: 1) spike-specific and anti-RBD antibodies including neutralizing antibodies both in the blood and airways; 2) spike/N/POL-specific CD4 and CD8 T cells in the airways (BAL fluid) four weeks post vaccination and 3) spike/N/POL-specific CD4 and CD8 T cells in the blood up to the last timepoint of examination.	four weeks after vaccination
Immune response to Ad5-triCoV/Mac and ChAd-triCoV/Mac correlated with pre-existing adenovirus antibodies	Change from baseline in: 1) spike-specific and anti-RBD antibodies including neutralizing antibodies both in the blood and airways; 2) spike/N/POL-specific CD4 and CD8 T cells in the airways (BAL fluid) four weeks post vaccination and 3) spike/N/POL-specific CD4 and CD8 T cells in the blood up to the last timepoint of examination, correlated with baseline Ad5 antibodies	Over 48 weeks
Correlation of antibodies measured in saliva with antibodies measured in BAL fluid and blood	Change from baseline in spike-specific and anti-RBD antibodies including neutralizing antibodies both in the blood and airways the airway (BAL fluid), correlated with antibodies measured in saliva	Over 12 weeks

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Fiona M Smaill, MD, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2022
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: October 25, 2021
• First Submitted That Met QC Criteria: October 25, 2021
• First Posted (Actual): October 26, 2021

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Vaccine; COVID-19; Immunogenicity; Vaccination; Inhalation; Aerosol; Adenovirus; Chimpanzee
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: M010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: On request, individual patient data that underlie the results in a publication will be made to other researchers
• IPD Sharing Time Frame: 3 months after publication
• IPD Sharing Access Criteria: Requests will be reviewed by the principal investigator and be judged on the scientific validity of the request and academic qualifications of those requesting access.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No