Prospective Monitoring of Antibody Response Following COVID-19 Vaccination in Patients With Down Syndrome.

Study Overview
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Brief Summary
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The risk of severe course of SARS-CoV-2 infection in people with Down Syndrome is substantially increased. The risk of death is 3-10 fold higher than in healthy people. SARS-CoV-2 vaccines have been registered for adults and adolescents but none of them have been studied in people with Down Syndrome. Vaccine responses in people with Down Syndrome are known to be suboptimal. Therefor the objective of this study is to assess the immunogenicity of SARS-CoV-2 vaccination in people with Down syndrome. To do so, the antibody response, cellulair and mucosal immuneresponse in people with Down syndrome after the SARS-CoV-2 vaccination will be evaluated and compared to healthy controls.

Detailed Description
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All participants will receive two vaccinations against COVID-19 according to the manufacturer's instructions as part of the Dutch SARS-CoV-2 vaccination program (GGD/RIVM). To assess the immune response after vaccination, blood samples will be collected at baseline (i.e. <2 months prior to first vaccination (t=1)), 21-28 days after first vaccination and prior to second vaccination (t=2), 28 days (3-6 weeks) (t=3) and 12 (+/- 1) months (t=4) after the second vaccination. To evaluate haematological parameters, additional blood samples will be collected at baseline, 21-28 days after the first vaccination and 28 days after the second vaccination. Per visit/time-point maximum 60 ml blood will be drawn. In children the maximum amount of blood taken per visit/time-point will be 0,8 ml/kg up to 60 ml. In addition Mucosal Lining Fluid (MLF) samples will be collected at 28 days (3-6 weeks) (t=3) and 12 (+/- 1) months (t=4) after the second vaccination to evaluate the mucosal immune response after SARS-CoV-2 vaccination. In the pediatric part of the study Mucosal Lining Fluid (MLF) samples will be collected at all timepoints. Although vaccine administration is not part of this study, vaccine type, batch number and dosing will be registered. This information will be obtained from the COVID-vaccination information and monitoring system (CIMS) of the RIVM. Clinical course including the occurrence of COVID-19 will be monitored during the first year after vaccination. To evaluate vaccination related AEs, patients will be asked to collect solicited local and systemic AEs for 7 days after each vaccination using an online questionnaire, as vaccination related AEs are mainly expected in the first week after vaccination. The link to the online questionnaires will be sent to the emailaddress of the participants and/or their representative/carer. If the participants and/or their representative/carers are not able to fill out the diary online, they will be contacted by phone. Although this study is not powered to detect differences in protection against COVID-19 between patients and controls, information on incidence of SARS-CoV-2 infection, outcome of COVID-19 will be collected up to 12 months after vaccination for descriptive purposes.

Official Title
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Prospective Monitoring of Antibody Response Following COVID-19 Vaccination in Patients With Down Syndrome

Conditions
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Down Syndrome, SARS-CoV-2 Vaccination

Intervention / Treatment
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* Biological: Immune response to Sars-CoV-2 vaccinations; including COVID-19 vaccin Moderna, Comirnaty (Pfizer) and Vaxzevria (AstraZeneca)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to receive routine COVID-19 vaccination with Pfizer, Moderna or AstraZeneca vaccine. Age: ≥12 years or < 12 years once vaccine is recommended for routine use in the respective age group Either Down syndrome (DS) or household contacts without DS of participant with DS. Exclusion Criteria: Down syndrome cohort: History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of the study intervention(s). Organ transplant recipients Active malignancy or completion of treatment for malignancy in previous 3 months Infection with Human Immunodeficiency Virus (HIV) Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. Healthy control cohort: - As in Down Syndrome cohort Plus: Active medical care for inherited or acquired immune deficiency Any severe comorbidity for which regular medical care is needed (e.g. heart failure, COPD, diabetes)

Ages Eligible for Study
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Minimum Age: 12 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Down syndrome, adults<br>Adults and adolescents with Down syndrome >16 years old. | Biological: Immune response to Sars-CoV-2 vaccinations; including COVID-19 vaccin Moderna, Comirnaty (Pfizer) and Vaxzevria (AstraZeneca)<br>* The vaccination is not part of the study, but part of the national immunization programme of the Netherlands. Blood will be drawn at 4 time points: baseline (t=1, <2 months prior to first vaccination); t=2: 21-28 days after first vaccination and prior to second vaccination; t=3: 28 (21-42) days after second vaccination; t=4: 12 months (+/- 1 month) after second vaccination. Mucosal Lining Fluid (MLF) samples will be collected at 28 days (3-6 weeks) (t=3) and 12 (+/- 1) months (t=4) after the second vaccination.<br>|
| Healthy control, adults<br>Healthy adults and adolescents without Down syndrome > 16 years old. Without any significant comorbidities. | Biological: Immune response to Sars-CoV-2 vaccinations; including COVID-19 vaccin Moderna, Comirnaty (Pfizer) and Vaxzevria (AstraZeneca)<br>* The vaccination is not part of the study, but part of the national immunization programme of the Netherlands. Blood will be drawn at 4 time points: baseline (t=1, <2 months prior to first vaccination); t=2: 21-28 days after first vaccination and prior to second vaccination; t=3: 28 (21-42) days after second vaccination; t=4: 12 months (+/- 1 month) after second vaccination. Mucosal Lining Fluid (MLF) samples will be collected at 28 days (3-6 weeks) (t=3) and 12 (+/- 1) months (t=4) after the second vaccination.<br>|
| Down syndrome, children<br>Children with Down syndrome < 16 years old. | Biological: Immune response to Sars-CoV-2 vaccinations; including COVID-19 vaccin Moderna, Comirnaty (Pfizer) and Vaxzevria (AstraZeneca)<br>* The vaccination is not part of the study, but part of the national immunization programme of the Netherlands. Blood will be drawn at 4 time points: baseline (t=1, <2 months prior to first vaccination); t=2: 21-28 days after first vaccination and prior to second vaccination; t=3: 28 (21-42) days after second vaccination; t=4: 12 months (+/- 1 month) after second vaccination. Mucosal Lining Fluid (MLF) samples will be collected at 28 days (3-6 weeks) (t=3) and 12 (+/- 1) months (t=4) after the second vaccination.<br>|
| Healthy control, children<br>Healthy children without Down syndrome < 16 years old. Without any significant comorbidities. | Biological: Immune response to Sars-CoV-2 vaccinations; including COVID-19 vaccin Moderna, Comirnaty (Pfizer) and Vaxzevria (AstraZeneca)<br>* The vaccination is not part of the study, but part of the national immunization programme of the Netherlands. Blood will be drawn at 4 time points: baseline (t=1, <2 months prior to first vaccination); t=2: 21-28 days after first vaccination and prior to second vaccination; t=3: 28 (21-42) days after second vaccination; t=4: 12 months (+/- 1 month) after second vaccination. Mucosal Lining Fluid (MLF) samples will be collected at 28 days (3-6 weeks) (t=3) and 12 (+/- 1) months (t=4) after the second vaccination.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody based immune response to vaccination against COVID-19 28 days (t=3) after the second vaccination as compared to controls. | Participants will be classified as responders or non-responders. The definition of response will be based on the latest available data from the pivotal studies and will be defined prior to data analyses and the first database lock. The percentage of responders in the DS cohort will be compared with the percentage responders in the HS cohort. | 28 days after the second vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longevity of SARS-CoV-2 specific antibodies | Longevity of SARS-CoV-2 specific antibodies after the second vaccination will be compared between cohorts. | 1 year after the second vaccination | 
| SARS-CoV2 specific T cell response | The number of IFN-ɣ producing SARS-CoV2 specific T cells/million PBMC (mean of 3 measures) | Number of T cells will be measured at baseline, at 21-28 days after the first vaccination and at 28 days after the second vaccination | 
| Mucosal SARS-CoV-2 specific antibodies | Antibody titers will be compared between cohorts and with antibody titers in blood | Mucosal antibodies will be measured 28 days and 12 months after the second vaccination. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Down Syndrome, SARS-CoV-2 vaccination, Immuneresponse