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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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COVID-19, SARS-CoV2 Infection

Intervention / Treatment
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* Biological: Ad5-triCoV/Mac
* Biological: ChAd-triCoV/Mac


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy human subjects who are between 18 and 65 years of age. Have completed a COVID vaccine series with at least three doses of a licensed mRNA vaccine at least 3 months prior. HIV antibody negative. Able to understand and comply with protocol requirements and instructions; able to attend scheduled study visits and complete required investigations. 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. For men, using barrier contraception for the duration of the study. 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: Subjects who have received any recombinant adenoviral-vectored COVID-19 vaccine, e.g. AstraZeneca COVISHIELD COVID-19 vaccine. Pregnant or lactating women. 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. 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. Subjects with a history of respiratory diseases requiring regular treatment, e.g. asthma, COPD, interstitial lung diseases, bronchiectasis. Current cigarette smokers, current e-cigarette smokers and ex-smokers who have quit less than a year ago, as reported by the subject. Subjects with clinically significant abnormal baseline spirometry tests: FEV1<80% predicted, FVC<80% predicted, FEV1/FVC<70%; DLCO<70% predicted. Any health-related condition for which study bronchoscopy is contraindicated. 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. Subjects whose use of alcohol or drugs would, in the opinion of the investigator, interfere with adherence to the study protocol. 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. Failure to provide written consent. Known allergy to vaccine components. Any abnormality on chest x-ray suggestive of clinically significant respiratory disease. Previous receipt of any experimental adenovirus-vector vaccine by the aerosol route. History of severe reaction to a previous COVID vaccination (including hives, difficulty breathing, angioedema, high fever, seizure). History of venous or arterial thrombosis with thrombocytopenia following any vaccination. History of cerebral venous thrombosis with thrombocytopenia. History of heparin induced thrombocytopenia. History of myocarditis or pericarditis. History of Bell's Palsy. History of hospitalization with an admitting diagnosis of primary COVID infection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Dose escalation: 3 participants will receive the Ad5-triCoV/Mac at the dose of 10e5 TCID50/dose, then assuming no safety concerns, ChAd-triCoV/Mac at 10e5/dose. Assuming no safety concerns, the next 3 participants will get Ad5-triCoV/Mac at 10e6 TCID50/dose then 3 participants will get ChAd-triCoV/Mac at 10e6/dose. Assuming no safety signals, we will move to the 1x10e7 TCID50 dose. If immunogenicity endpoints are not reached and there is no safety signal, we will move to the dose level of 3x10e7 TCID50 and enrol three participants/vaccine group. Based on the poor immune responses generated to Ad5-triCoV/Mac at doses up to and including 3x10e7 the dose of Ad5-triCoV/Mac will not be further escalated. Since the immunogenicity endpoints were not met at 3x10e7 for ChAd-triCoV/Mac and there was no safety signal, we will escalate to 6x10e7. If the mmunogenecity endpoints are not met at 6x10e7 and in the absence of a safety signal, we will escalate the ChAd-triCoV/Mac dose to 1x10e8.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerosol Ad5-triCoV/Mac dose level 10e5<br>Single dose by inhalation of 10e5 Ad5-tri-CoV/Mac | Biological: Ad5-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol ChAd-tri-CoV/Mac dose level 10e5<br>Single dose by inhalation of 10e5 ChAd-triCoV/Mac | Biological: ChAd-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol Ad5-triCoV/Mac dose level 10e6<br>Single dose by inhalation of 10e6 Ad5-triCoV/Mac | Biological: Ad5-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol ChAd-triCoV/Mac dose level 10e6<br>Single dose by inhalation of 10e6 ChAd-triCoV/Mac | Biological: ChAd-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol Ad5-triCoV/Mac dose level 10e7<br>Single dose by inhalation of 10e7 Ad5-triCoV/Mac | Biological: Ad5-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol ChAd-triCoV/Mac dose level 10e7<br>Single dose by inhalation of 10e7 ChAd-triCoV/Mac | Biological: ChAd-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol Ad5-triCoV/Mac dose level 3x10e7<br>Single dose by inhalation of 3x10e7 Ad5-triCoV/Mac | Biological: Ad5-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol ChAd-triCoV/Mac dose level 6x10e7<br>Single dose by inhalation of 6x10e7 ChAd-triCoV/Mac | Biological: ChAd-triCoV/Mac<br>* 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).<br>|
| Experimental: Aerosol ChAd-triCoV/Mac dose level 1x10e8<br>Single dose by inhalation of 1x10e8 ChAd-triCoV/Mac | Biological: Ad5-triCoV/Mac<br>* 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).<br>Biological: ChAd-triCoV/Mac<br>* 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).<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, Aerosol, Adenovirus, Chimpanzee, Immunogenicity, Inhalation, Vaccine, Vaccination