Prevention of COVID-19
Conditions
Keywords
SARS-CoV-2, COVID-19, Vaccination, Immunogenicity, BNT162b2, mRNA-1273, Booster, Elderly, head-to-head comparison
Brief summary
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 A of this trial foresees testing of different vaccines as a 3rd vaccination dose (first booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and variants in the elderly, a usually neglected population. 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 identical population.
Detailed description
Part A of the present trial in which individuals received a 3rd vaccination (first booster) of either BNT162b2 or mRNA-1273 was closed to further recruitment as of January 13, 2022. This was due to a change in vaccination policies, recommending a 3rd vaccination with either BNT162b2 or mRNA-1273. Therefore, Part A was supplanted by Part B that investigated a 4th COVID-19 vaccination and started on 21 Jan 2022. The initial study protocol started the trial with Part A in which participants were randomized to a 3rd vaccination (first booster) with either BNT162b2 or mRNA-1273: Subjects who - prior to study entry - received a vaccination series of either BNT162b2 & BNT162b2 or mRNA-1273 & mRNA-1273 or ChAdOx-1-S & ChAdOx-1-S. For the reasons mentioned above, the study protocol was amended to continue the trial with Part B in which participants were randomized to a 4th vaccination (second booster) with either BNT162b2 or mRNA-1273: Subjects who - prior to study entry - received a vaccination series 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.
Interventions
BIOLOGICALComirnaty (BTN162b2)
Single booster shot (3rd dose in Part A and 4th dose in Part B)
BIOLOGICALSpikevax (mRNA-1273)
Single booster shot (3rd dose in Part A and 4th dose in Part B)
Sponsors
VACCELERATE
European Commission
Oliver Cornely, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Masking description
No blinding is foreseen in this trial.
Intervention model description
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. This trial foresees testing of different vaccines as a third (first booster, Part A) or fourth vaccine dose (second booster, Part B) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 and SARS-CoV-2 variants in the elderly.
Eligibility
Sex/Gender
ALL
Age
75 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
(Part A): * Subject is ≥75 years old. * Prior to study entry the subject was vaccinated with BNT162b2, mRNA-1273 or ChAdOx-1-S (same vaccine product for 1st + 2nd dose) BNT162b2 + BNT162b2 mRNA-1273 + mRNA-1273 ChAdOx-1-S + ChAdOx-1-S * 9 ± 3 months since the second vaccine dose at time of enrolment for the planned 3rd vaccine dose in the trial. Vaccination status should be documented in the source data and captured in the eCRF. * No contra-indication against any of the vaccine products in the trial. * Written informed consent from subject has been obtained.
Exclusion criteria
(Part A): * Primary vaccination performed with different vaccine products as sole (e.g., COVID-19 Vaccine Janssen) or, 1st and 2nd vaccination doses (heterologous vaccination scheme). * 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. * Participation in other interventional trials. * Subjects unable to report solicited adverse events. * Subject with any contraindications to the vaccines in the trial at randomisation. A list of contraindications as listed in the Summary of medicinal Product Characteristics (SmPC, the Fachinformation in Germany), if appropriate. * Use of drugs with significant interaction with the investigational product according to the SmPC or similar documents. * Diseases or findings that may have a significant effect on the target variables and which may therefore mask or inhibit the therapeutic effect under investigation. * Any current SARS-CoV-2 infection or proven in the preceding 3 months. * Persons with any kind of dependency on the principal investigator or employed by the sponsor or principal investigator. * Legally incapacitated persons. * Persons held in an institution by legal or official order. Inclusion Criteria (Part B): * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Antibody Titre Increase 14 Days After Study Vaccination Dose. | From Day 0 until Day 14 | Rate of 2-fold antibody titre increase 14 days after 3rd (Part A) or 4th vaccination dose (Part B) measured by qualitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wildtype virus. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After Study Vaccination Dose | From Day 0 until Day 14 | Change in neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern 14 days after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities. |
| Antibody Titre Level at 12 Months After a Study Vaccination Dose | From Day 0 until Month 12 | Antibody titre level at 12 months after a 3rd (Part A) or 4th vaccination dose (Part B) measured by a quantitative enzyme-linked immunosorbent assay (anti-RBD-ELISA assay). |
| Neutralizing Antibody Titre Against Wild-type at 12 Months After Study Vaccination Dose | From Day 0 until Month 12 | Neutralizing antibody titre (Virus Neutralisation Assay) against wild-type SARS-CoV-2 at 12 months after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities. |
| Neutralizing Antibody Titre Against Variants of Concern at 12 Months After Study Vaccination Dose | From Day 0 until Month 12 | Neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern at 12 months after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities. |
| Change in Neutralizing Antibody Titre Against Wild-type 14 Days After Study Vaccination Dose | From Day 0 until Day 14 | Change in neutralizing antibody titre (Virus Neutralisation Assay) against wild-type 14 days after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Unsolicited AEs | From Day 0 until Month 12 | Number of Participants with Unsolicited AEs until the end of trial |
| Number of Participants With Solicited AEs | From Day 0 until Day 7 | Number of Participants with Solicited AEs for 7 days after study vaccination dose. |
| Number of Participants With Rate of SAEs Grade ≥3 | From Day 0 until Month 3 | Number of Participants with Rate of serious adverse events (SAEs) Grade ≥3 according to the National Cancer Institute Common Toxicity Criteria up to three months after study vaccination dose. |
| Change in Cellular Immune Response Measured by qPCR 14 Days After 4th Vaccination Dose | From Day 0 until Day 14 | Change in cellular immune response (CD4+ and CD8+ T cell response) to SARS-CoV-2 measured by fold change of CXCL10 mRNA levels measured by qPCR after 4th vaccination dose, to be determined in a subgroup only. |
| Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After Study Vaccination Dose | From Day 0 until Month 12 | Neutralizing antibody titre (Virus Neutralisation Assay) against newly emerging variants in bio-banked samples after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities. |
Countries
Germany, Lithuania, Norway, Spain
Participant flow
Pre-assignment details
Due to poor recruitment, Part A of the trial (3rd COVID-19 vaccination) was closed to further enrolment on 13 Jan 2022. Part B (4th COVID-19 vaccination) started on 21 Jan 2022. In Part A, one randomised subject did not receive the allocated intervention (mRNA-1273) due to an acute onset of SARS-CoV-2 infection. Both Part A and B belong to one trial and fall under one NCT number.
Participants by arm
| Arm | Count |
|---|---|
| BNT162b2 (Part A) Part A:
Participants were pre-vaccinated with 2 vaccinations when entering the trial, as follows:
BNT162b2 + BNT162b2 mRNA-1273 + mRNA-1273 ChAdOx-1-S + ChAdOx-1-S A 3rd dose was administered in the study, either Comirnaty (BTN162b2) or Spikevax (mRNA-1273). | 25 |
| mRNA-1273 (Part A) Part A:
Participants were pre-vaccinated with 2 vaccinations when entering the trial, as follows:
BNT162b2 + BNT162b2 mRNA-1273 + mRNA-1273 ChAdOx-1-S + ChAdOx-1-S A 3rd dose was administered in the study, either Comirnaty (BTN162b2) or Spikevax (mRNA-1273). | 27 |
| BNT162b2 (Part B) Part B:
Participants were pre-vaccinated with 3 vaccinations when entering the trial, as follows:
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 A 4th dose was administered in the study, either Comirnaty (BTN162b2) or Spikevax (mRNA-1273). | 135 |
| mRNA-1273 (Part B) Part B:
Participants were pre-vaccinated with 3 vaccinations when entering the trial, as follows:
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 A 4th dose was administered in the study, either Comirnaty (BTN162b2) or Spikevax (mRNA-1273). | 135 |
| Total | 322 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | COVID-19 infection | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 2 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 |
| Overall Study | No show | 0 | 0 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 |
| Overall Study | travel time | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 5 | 4 | 2 |
Baseline characteristics
| Characteristic | BNT162b2 (Part A) | mRNA-1273 (Part A) | BNT162b2 (Part B) | mRNA-1273 (Part B) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 77 years | 78 years | 79 years | 79 years | 79 years |
| BMI | 25.6 kg/m2 | 24.1 kg/m2 | 25.4 kg/m2 | 25.4 kg/m2 | 25.4 kg/m2 |
| Duration between 1st and 2nd vaccination in days | 42 days | 42 days | 22 days | 22 days | 22 days |
| Duration between 2nd and 3rd vaccination in days | 192 days | 190 days | 207 days | 205 days | 206.5 days |
| Height | 171 cm | 174 cm | 169 cm | 169 cm | 169 cm |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 67 Participants | 68 Participants | 155 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 68 Participants | 67 Participants | 167 Participants |
| Weight | 75 kg | 73 kg | 72 kg | 75 kg | 74 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 27 | 2 / 135 | 5 / 135 |
| other Total, other adverse events | 20 / 25 | 25 / 27 | 103 / 135 | 110 / 135 |
| serious Total, serious adverse events | 0 / 25 | 0 / 27 | 21 / 135 | 22 / 135 |
Outcome results
Primary
Antibody Titre Increase 14 Days After Study Vaccination Dose.
Rate of 2-fold antibody titre increase 14 days after 3rd (Part A) or 4th vaccination dose (Part B) measured by qualitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wildtype virus.
Time frame: From Day 0 until Day 14
Population: All primary analyses were performed on the mITT population set. The primary endpoint was the rate π of 2-fold IgG antibody titre increase following a 3rd (Part A) or 4th dose vaccination (Part B) measured by quantitative enzyme-linked electrochemiluminescent immunoassay (Anti-RBD-ELISA) against wild-type virus at 14 days after study vaccination (versus immediately before vaccination).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BNT162b2 (Part A) | Antibody Titre Increase 14 Days After Study Vaccination Dose. | 100 percentage of participants |
| mRNA-1273 (Part A) | Antibody Titre Increase 14 Days After Study Vaccination Dose. | 100 percentage of participants |
| BNT162b2 (Part B) | Antibody Titre Increase 14 Days After Study Vaccination Dose. | 78.46 percentage of participants |
| mRNA-1273 (Part B) | Antibody Titre Increase 14 Days After Study Vaccination Dose. | 87.22 percentage of participants |
Secondary
Antibody Titre Level at 12 Months After a Study Vaccination Dose
Antibody titre level at 12 months after a 3rd (Part A) or 4th vaccination dose (Part B) measured by a quantitative enzyme-linked immunosorbent assay (anti-RBD-ELISA assay).
Time frame: From Day 0 until Month 12
Population: Subjects in whom a blood sampling was performed at Month 12.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Antibody Titre Level at 12 Months After a Study Vaccination Dose | 9319.7 IU/ml | Standard Deviation 25896.27 |
| mRNA-1273 (Part A) | Antibody Titre Level at 12 Months After a Study Vaccination Dose | 14163.81 IU/ml | Standard Deviation 46209.35 |
| BNT162b2 (Part B) | Antibody Titre Level at 12 Months After a Study Vaccination Dose | 9961.92 IU/ml | Standard Deviation 26292.23 |
| mRNA-1273 (Part B) | Antibody Titre Level at 12 Months After a Study Vaccination Dose | 12024.3 IU/ml | Standard Deviation 29129.18 |
Secondary
Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After Study Vaccination Dose
Change in neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern 14 days after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities.
Time frame: From Day 0 until Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After Study Vaccination Dose | 49.86 percentage of inhibition | Standard Deviation 17.62 |
| mRNA-1273 (Part A) | Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After Study Vaccination Dose | 57.39 percentage of inhibition | Standard Deviation 19.77 |
| BNT162b2 (Part B) | Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After Study Vaccination Dose | 38.17 percentage of inhibition | Standard Deviation 21.74 |
| mRNA-1273 (Part B) | Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After Study Vaccination Dose | 44.04 percentage of inhibition | Standard Deviation 23.94 |
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0498995% CI: [0.005, 18.656]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0174495% CI: [2.61, 25.814]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0203995% CI: [2.305, 26.173]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0440595% CI: [0.338, 23.998]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0225995% CI: [1.514, 19.111]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0158395% CI: [2.279, 20.924]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.0085695% CI: [3.166, 20.56]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0025895% CI: [2.41, 11.249]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0074895% CI: [1.63, 10.466]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0092295% CI: [1.821, 12.782]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0713695% CI: [-0.419, 10.001]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0721895% CI: [-0.36, 8.29]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0294995% CI: [0.484, 9.155]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.0840395% CI: [-0.531, 8.382]ANCOVA
Secondary
Change in Neutralizing Antibody Titre Against Wild-type 14 Days After Study Vaccination Dose
Change in neutralizing antibody titre (Virus Neutralisation Assay) against wild-type 14 days after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities.
Time frame: From Day 0 until Day 14
Population: Number of subjects for whom the difference of neutralizing activity (Day 14 minus Day 0) could be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Change in Neutralizing Antibody Titre Against Wild-type 14 Days After Study Vaccination Dose | 58.49 percentage of inhibition | Standard Deviation 16.25 |
| mRNA-1273 (Part A) | Change in Neutralizing Antibody Titre Against Wild-type 14 Days After Study Vaccination Dose | 65.98 percentage of inhibition | Standard Deviation 18.32 |
| BNT162b2 (Part B) | Change in Neutralizing Antibody Titre Against Wild-type 14 Days After Study Vaccination Dose | 37.33 percentage of inhibition | Standard Deviation 22.93 |
| mRNA-1273 (Part B) | Change in Neutralizing Antibody Titre Against Wild-type 14 Days After Study Vaccination Dose | 41.45 percentage of inhibition | Standard Deviation 24.09 |
Comparison: The statistical analysis reflects Part A of the study.p-value: 0.0314395% CI: [1.168, 23.946]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.010195% CI: [1.04, 7.621]ANCOVA
Secondary
Neutralizing Antibody Titre Against Variants of Concern at 12 Months After Study Vaccination Dose
Neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern at 12 months after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities.
Time frame: From Day 0 until Month 12
Population: Titres of neutralizing antibodies were reported as change in neutralization capacity. Provided values refer to the variant B.1.1.7 (alpha). Besides for B.1.1.7 (alpha), all tests described above were also conducted for the following variants of concern: B.1.351 (beta), P.1 (gamma), BA.1 (omicron), BA.4 (omicron), BA.4.6 (omicron), and BA.5 (omicron).~For values of these variants of concern, please see the open-access publication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Neutralizing Antibody Titre Against Variants of Concern at 12 Months After Study Vaccination Dose | 40.59 percentage of inhibition | Standard Deviation 35.37 |
| mRNA-1273 (Part A) | Neutralizing Antibody Titre Against Variants of Concern at 12 Months After Study Vaccination Dose | 49 percentage of inhibition | Standard Deviation 36.37 |
| BNT162b2 (Part B) | Neutralizing Antibody Titre Against Variants of Concern at 12 Months After Study Vaccination Dose | 15.76 percentage of inhibition | Standard Deviation 38.4 |
| mRNA-1273 (Part B) | Neutralizing Antibody Titre Against Variants of Concern at 12 Months After Study Vaccination Dose | 20.24 percentage of inhibition | Standard Deviation 37.24 |
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4279795% CI: [-13.475, 31.145]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.7396195% CI: [-17.85, 24.929]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.453795% CI: [-13.524, 29.695]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.8732395% CI: [-18.969, 22.241]ANCOVA
Comparison: This statistical analysis relfects Part A of the study.p-value: 0.9348995% CI: [-19.109, 20.728]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.7478495% CI: [-18.425, 25.448]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.8420295% CI: [-18.966, 23.143]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1547795% CI: [-2.207, 13.821]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.3777395% CI: [-4.327, 11.368]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2921295% CI: [-3.821, 12.647]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.141495% CI: [-1.998, 13.919]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.570995% CI: [-5.434, 9.832]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1101295% CI: [-1.491, 14.548]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2975595% CI: [-3.759, 12.237]ANCOVA
Secondary
Neutralizing Antibody Titre Against Wild-type at 12 Months After Study Vaccination Dose
Neutralizing antibody titre (Virus Neutralisation Assay) against wild-type SARS-CoV-2 at 12 months after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities.
Time frame: From Day 0 until Month 12
Population: Titres of neutralizing antibodies were reported as change in neutralization capacity.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Neutralizing Antibody Titre Against Wild-type at 12 Months After Study Vaccination Dose | 54.5 percentage of inhibition | Standard Deviation 33.64 |
| mRNA-1273 (Part A) | Neutralizing Antibody Titre Against Wild-type at 12 Months After Study Vaccination Dose | 62.65 percentage of inhibition | Standard Deviation 33.26 |
| BNT162b2 (Part B) | Neutralizing Antibody Titre Against Wild-type at 12 Months After Study Vaccination Dose | 12.93 percentage of inhibition | Standard Deviation 39.29 |
| mRNA-1273 (Part B) | Neutralizing Antibody Titre Against Wild-type at 12 Months After Study Vaccination Dose | 18.15 percentage of inhibition | Standard Deviation 33.24 |
Other Pre-specified
Change in Cellular Immune Response Measured by qPCR 14 Days After 4th Vaccination Dose
Change in cellular immune response (CD4+ and CD8+ T cell response) to SARS-CoV-2 measured by fold change of CXCL10 mRNA levels measured by qPCR after 4th vaccination dose, to be determined in a subgroup only.
Time frame: From Day 0 until Day 14
Population: Inclusion required completed visits at Day 0 and Day 14 with a sufficient number of aliquots as per CTP.~Provided results are absolute values of the cellular immune response on Day 14 of tubes stimulated with peptides from spike (tube A). Samples were also stimulated with peptides from a virus membrane nucleoprotein (tube B) and with peptides from the Omicron variant (tube C). All trial results will be provided upon request.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Change in Cellular Immune Response Measured by qPCR 14 Days After 4th Vaccination Dose | 26.63 Fold change of CXCL10 mRNA levels | Standard Deviation 1.58 |
| mRNA-1273 (Part A) | Change in Cellular Immune Response Measured by qPCR 14 Days After 4th Vaccination Dose | 26.63 Fold change of CXCL10 mRNA levels | Standard Deviation 1.59 |
Other Pre-specified
Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After Study Vaccination Dose
Neutralizing antibody titre (Virus Neutralisation Assay) against newly emerging variants in bio-banked samples after a 3rd (Part A) or 4th vaccination dose (Part B), to be determined in a subgroup only. Microneutralization assay results were proposed to be reported as change in neutralizing antibody titre (Virus Neutralisation Assay) in the trial protocol. However, as the pandemic progressed, the need arose to assess neutralization against different variants. In our stud(ies), we evaluated not only the Wuhan strain but also 25 distinct variants of concern (VoCs) and/or variants of interest (VoIs). For VoCs and VoIs, expressing results as change in neutralization capacity expressed as a percentage (%) is more effective as it illustrates the impact of mutations on neutralization, thereby allowing cross-variant comparisons. This adjustment did not alter the suggested endpoint, as both reporting methods reflect the ability of patients' antibodies neutralizing capacities.
Time frame: From Day 0 until Month 12
Population: Titres of neutralizing antibodies were reported as change in neutralization capacity. Provided values refer to the VoI XBB.1 (omicron).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNT162b2 (Part A) | Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After Study Vaccination Dose | 19.28 percentage of inhibition | Standard Deviation 30.94 |
| mRNA-1273 (Part A) | Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After Study Vaccination Dose | 27.18 percentage of inhibition | Standard Deviation 28.14 |
| BNT162b2 (Part B) | Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After Study Vaccination Dose | 16.75 percentage of inhibition | Standard Deviation 34.24 |
| mRNA-1273 (Part B) | Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After Study Vaccination Dose | 19.03 percentage of inhibition | Standard Deviation 33.01 |
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.3942695% CI: [-12.995, 32.275]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4205595% CI: [-13.011, 30.539]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4439195% CI: [-13.683, 30.627]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4377595% CI: [-13.402, 30.368]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.5351195% CI: [-13.819, 26.2]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.6757695% CI: [-17.295, 26.399]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4544395% CI: [-14.15, 31.027]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.3890495% CI: [-11.768, 29.569]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4746695% CI: [-13.147, 27.751]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.771195% CI: [-16.993, 22.749]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.8664695% CI: [-19.195, 22.701]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.5797295% CI: [-14.21, 25.049]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.9016695% CI: [-17.859, 20.199]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.9227995% CI: [-20.099, 22.136]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.7119195% CI: [-15.675, 22.74]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.7341595% CI: [-14.714, 20.703]ANCOVA
Comparison: This statistical analysis reflects Part A of the study.p-value: 0.4579895% CI: [-12.155, 26.469]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2358295% CI: [-3.169, 12.808]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1935495% CI: [-2.713, 13.337]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1703395% CI: [-2.471, 13.899]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1389595% CI: [-1.94, 13.808]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2692495% CI: [-3.288, 11.732]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.170895% CI: [-2.382, 13.362]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1850295% CI: [-2.683, 13.818]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.3834495% CI: [-4.318, 11.195]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.41195% CI: [-4.565, 11.124]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.506695% CI: [-5.237, 10.577]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2860495% CI: [-3.82, 12.891]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1171595% CI: [-1.582, 14.1]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.3356795% CI: [-3.978, 11.613]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.1523295% CI: [-2.147, 13.697]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2123495% CI: [-2.766, 12.383]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.2268795% CI: [-2.866, 12.026]ANCOVA
Comparison: This statistical analysis reflects Part B of the study.p-value: 0.3883295% CI: [-4.475, 11.47]ANCOVA
Other Pre-specified
Number of Participants With Rate of SAEs Grade ≥3
Number of Participants with Rate of serious adverse events (SAEs) Grade ≥3 according to the National Cancer Institute Common Toxicity Criteria up to three months after study vaccination dose.
Time frame: From Day 0 until Month 3
Population: Provided values refer to SAEs related to the IMP. All other trial data is available upon request.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BNT162b2 (Part A) | Number of Participants With Rate of SAEs Grade ≥3 | 0 Participants |
| mRNA-1273 (Part A) | Number of Participants With Rate of SAEs Grade ≥3 | 0 Participants |
| BNT162b2 (Part B) | Number of Participants With Rate of SAEs Grade ≥3 | 1 Participants |
| mRNA-1273 (Part B) | Number of Participants With Rate of SAEs Grade ≥3 | 0 Participants |
Other Pre-specified
Number of Participants With Solicited AEs
Number of Participants with Solicited AEs for 7 days after study vaccination dose.
Time frame: From Day 0 until Day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BNT162b2 (Part A) | Number of Participants With Solicited AEs | 20 Participants |
| mRNA-1273 (Part A) | Number of Participants With Solicited AEs | 25 Participants |
| BNT162b2 (Part B) | Number of Participants With Solicited AEs | 76 Participants |
| mRNA-1273 (Part B) | Number of Participants With Solicited AEs | 80 Participants |
Other Pre-specified
Number of Participants With Unsolicited AEs
Number of Participants with Unsolicited AEs until the end of trial
Time frame: From Day 0 until Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BNT162b2 (Part A) | Number of Participants With Unsolicited AEs | 22 Participants |
| mRNA-1273 (Part A) | Number of Participants With Unsolicited AEs | 26 Participants |
| BNT162b2 (Part B) | Number of Participants With Unsolicited AEs | 110 Participants |
| mRNA-1273 (Part B) | Number of Participants With Unsolicited AEs | 112 Participants |