Assessing Immune Response of Different COVID-19 Vaccines in Older Adults

Study Overview
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Brief Summary
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This is a randomised controlled, adaptive, multicentre Phase II protocol evaluating different booster strategies in individuals aged 75 years and older already vaccinated against SARS-CoV-2. Part B of this trial foresees testing of different vaccines as a 4th vaccination dose (second booster) for comparative assessment of their immunogenicity and safety against SARSCoV- 2 wild-type and variants in the elderly, a usually neglected population. Additional vaccines and extended follow-up visits can be added through amendments of this sub-protocol. As stated in the EU-COVAT master protocol, this trial, i.e., the EU-COVAT-1_AGED study, implements a specific safety monitoring strategy (see below). Cohorts and arms can be withdrawn or added as deemed necessary according to the criteria specified in this protocol

Detailed Description
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PLEASE NOTE: This protocol refers to Part B of the clinical trial in which new accruals are randomized to a 4th vaccination (second booster) with either BNT162b2 or mRNA-1273. Part A of the present trial in which individuals received a 3rd vaccination (first booster) is closed to further recruitment as of January 13, 2022. With the massive roll-out of booster campaigns throughout Europe, Part A was abandoned because of a poor recruitment rate. Individuals in Part A are followed-up as specified in protocol version V04_0 and analyzed descriptively, the statistical analysis plan will be adapted accordingly. Randomisation in Part B Subjects who - prior to study entry - got a primary vaccination series and 3rd vaccination dose of either BNT162b2 & BNT162b2 & BNT162b2 or BNT162b2 & BNT162b2 & mRNA-1273 or mRNA-1273 & mRNA-1273 & mRNA-1273 or mRNA-1273 & mRNA-1273 & BNT162b2 or ChAdOx-1-S & ChAdOx-1-S & BNT162b2 or ChAdOx-1-S & ChAdOx-1-S & mRNA-1273 will receive a 4th vaccination dose with an allocation ratio of 1:1 to either BNT162b2 or mRNA-1273. Accordingly, there are 6 cohorts/arms (equalling 12 intervention arms). All individuals who were randomized to BNT162b2 represent Group 1, all individuals who were randomized to mRNA-1273 represent Group 2.

Official Title
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A Multinational, Phase 2, Randomised, Adaptive Protocol to Evaluate Immunogenicity and Reactogenicity of Different COVID-19 Vaccines Administration in Older Adults (≥75) Already Vaccinated Against SARS-COV-2 (EU-COVAT-1_AGED)

Conditions
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Vaccination Reaction, COVID-19, Vaccination; Infection

Intervention / Treatment
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* Biological: Comirnaty(BTN162b2)
* Biological: Spikevax (mRNA-1273)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥75 years old). Prior to study entry the subject was vaccinated with one of the following vaccination regimens (1st + 2nd + 3rd dose): BNT162b2 + BNT162b2 + BNT162b2 BNT162b2 + BNT162b2 + mRNA-1273 mRNA-1273 + mRNA-1273 + mRNA-1273 mRNA-1273 + mRNA-1273 + BNT162b2 ChAdOx-1-S + ChAdOx-1-S + BNT162b2 ChAdOx-1-S + ChAdOx-1-S + mRNA-1273 The last dose of the above listed vaccinations must have been administered at least 1 month prior to study entry. Vaccination status should be documented in the source data and will be captured in the eCRF. - Written informed consent from subject has been obtained. Exclusion Criteria: Prior to study entry the subject got vaccinated with a regimen not included in the list given above. Last anti-SARS-CoV-2 vaccine dose administered less than one month prior to study entry. Vaccination against a disease other than COVID-19 within 2 weeks prior to study entry. Only exception: Influenza vaccination which is allowed at any time. Subjects with any significant or uncontrolled disease posing a risk due to vaccination as judged by the investigator. Current immunosuppressive therapy, for example continuous glucocorticosteroid treatment equivalent to >10 mg/day prednisolone. Subject simultaneously participates in another clinical trials or has participated in the past 30 days. Subjects unable to report solicited adverse events. Subject with any contraindications to the vaccines in the trial. A list of contraindications as listed in the Summary of medicinal Product Characteristics (SmPC, the Fachinformation in Germany), if appropriate.

Ages Eligible for Study
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Minimum Age: 75 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: This is a randomised controlled, adaptive, multicentre Phase II Part B protocol evaluating different booster strategies in individuals aged 75 years and older already vaccinated against SARS-CoV-2. This trial foresees testing of different vaccines as a fourth vaccine dose ( second booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 and SARS-CoV-2 variants in the elderly.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Comirnaty-Comirnaty-Comirnaty<br>Participants are already fully vaccinated with 3x Comirnaty (BNT162b2) when entering the trial, only the 4th dose will be administered in the study. Treatment will be given as a single shot of either Comirnaty (BTN162b2) or Spikevax (mRNA-1273) using the approved dose and mode of administration of each vaccine included in this trial. | Biological: Comirnaty(BTN162b2)<br>* Single booster shot (4th dose) of already approved BioNTech/ Pfizer vaccine that protect against COVID-19 infection<br>* Other names: BioNTech/ Pfizer;Biological: Spikevax (mRNA-1273)<br>* Single booster shot (4th dose) of already approved Moderna vaccine that protect against COVID-19 infection<br>* Other names: Moderna;|
| Active Comparator: Spikevax-Spikevax-Spikevax<br>Participants are already fully vaccinated with 3x Spikevax (mRNA-1273) when entering the trial, only the 4th dose will be administered in the study. Treatment will be given as a single shot of either Comirnaty (BTN162b2) or Spikevax (mRNA-1273) using the approved dose and mode of administration of each vaccine included in this trial. | Biological: Comirnaty(BTN162b2)<br>* Single booster shot (4th dose) of already approved BioNTech/ Pfizer vaccine that protect against COVID-19 infection<br>* Other names: BioNTech/ Pfizer;Biological: Spikevax (mRNA-1273)<br>* Single booster shot (4th dose) of already approved Moderna vaccine that protect against COVID-19 infection<br>* Other names: Moderna;|
| Active Comparator: Vaxzevria-Vaxzevria-Spikevax<br>Participants are already fully vaccinated with 2x Vaxzevria (ChAdOx-1-S) and 1x Spikevax (mRNA-1273) when entering the trial, only the 4th dose will be administered in the study. Treatment will be given as a single shot of either Comirnaty (BTN162b2) or Spikevax (mRNA-1273) using the approved dose and mode of administration of each vaccine included in this trial. | Biological: Comirnaty(BTN162b2)<br>* Single booster shot (4th dose) of already approved BioNTech/ Pfizer vaccine that protect against COVID-19 infection<br>* Other names: BioNTech/ Pfizer;Biological: Spikevax (mRNA-1273)<br>* Single booster shot (4th dose) of already approved Moderna vaccine that protect against COVID-19 infection<br>* Other names: Moderna;|
| Active Comparator: Vaxzevria-Vaxzevria-Comirnaty<br>Participants are already fully vaccinated with 2x Vaxzevria (ChAdOx-1-S) and 1x Comirnaty (BNT162b2) when entering the trial, only the 4th dose will be administered in the study. Treatment will be given as a single shot of either Comirnaty (BTN162b2) or Spikevax (mRNA-1273) using the approved dose and mode of administration of each vaccine included in this trial. | Biological: Comirnaty(BTN162b2)<br>* Single booster shot (4th dose) of already approved BioNTech/ Pfizer vaccine that protect against COVID-19 infection<br>* Other names: BioNTech/ Pfizer;Biological: Spikevax (mRNA-1273)<br>* Single booster shot (4th dose) of already approved Moderna vaccine that protect against COVID-19 infection<br>* Other names: Moderna;|
| Active Comparator: Spikevax-Spikevax-Comirnaty<br>Participants are already fully vaccinated with 2x Spikevax (mRNA-1273) and 1x Comirnaty (BNT162b2) when entering the trial, only the 4th dose will be administered in the study. Treatment will be given as a single shot of either Comirnaty (BTN162b2) or Spikevax (mRNA-1273) using the approved dose and mode of administration of each vaccine included in this trial. | Biological: Comirnaty(BTN162b2)<br>* Single booster shot (4th dose) of already approved BioNTech/ Pfizer vaccine that protect against COVID-19 infection<br>* Other names: BioNTech/ Pfizer;Biological: Spikevax (mRNA-1273)<br>* Single booster shot (4th dose) of already approved Moderna vaccine that protect against COVID-19 infection<br>* Other names: Moderna;|
| Active Comparator: Comirnaty-Comirnaty-Spikevax<br>Participants are already fully vaccinated with 2x Comirnaty (BNT162b2) and 1x Spikevax (mRNA-1273) entering the trial, only the 4th dose will be administered in the study. Treatment will be given as a single shot of either Comirnaty (BTN162b2) or Spikevax (mRNA-1273) using the approved dose and mode of administration of each vaccine included in this trial. | Biological: Comirnaty(BTN162b2)<br>* Single booster shot (4th dose) of already approved BioNTech/ Pfizer vaccine that protect against COVID-19 infection<br>* Other names: BioNTech/ Pfizer;Biological: Spikevax (mRNA-1273)<br>* Single booster shot (4th dose) of already approved Moderna vaccine that protect against COVID-19 infection<br>* Other names: Moderna;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody titre increase 14 days after 4th vaccination dose. | Rate of 2-fold antibody titre increase 14 days after 4th vaccination dose measured by qualitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wildtype virus. | 14 days after 4th vaccination dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody titre level against wild-type SARS-CoV-2 after a 4th vaccination dose | Antibody titre level at 12 months after a 4th vaccination dose measured by a quantitative enzyme-linked immunosorbent assay (anti-RBD-ELISA assay). | Up to 12 months after 4th vaccination dose | 
| Neutralizing antibody titre (Virus Neutralisation Assay) after a 4th vaccination dose. | Neutralizing antibody titre (Virus Neutralisation Assay) against wild-type 14 days after a 4th vaccination dose, to be determined in a subgroup only. | 14 days after 4th vaccination dose | 
| Neutralizing antibody titre (Virus Neutralisation Assay) after a 4th vaccination dose. | Neutralizing antibody titre (Virus Neutralisation Assay) against variants of Concern (VOC) 14 days after a 4th vaccination dose, to be determined in a subgroup only. | 14 days after 4th vaccination dose | 
| Neutralizing antibody titre (Virus Neutralisation Assay) after a 4th vaccination dose. | Neutralizing atibody titre (Virus Neutralisation Assay) against wild-type SARS-CoV-2 at 12 months after a 4th vaccination dose, to be determined in a subgroup only. | Up to 12 months after 4th vaccination dose | 
| Neutralizing antibody titre (Virus Neutralisation Assay) after a 4th vaccination dose. | Neutralizing atibody titre (Virus Neutralisation Assay) against variants of concern at 12 months after a 4th vaccination dose, to be determined in a subgroup only. | Up to 12 months after 4th vaccination dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Vaccination, Immunisation, Comirnaty, Spikevax, Booster, Elderly, SARS-CoV-2