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BACKGROUND

The risk of severe course of SARS-CoV-2 infection in people with Down Syndrome (DS) is substantially increased. The risk of death is 3-10 fold higher than in healthy people. COVID vaccines have been registered but none of them have been studied in people with DS. Vaccine responses in people with DS are suboptimal, probably related to the partial immune deficiency in DS characterized by – among other things - a lack of naïve T-cells. In this study (PRIDE), we aim to assess the immunogenicity of SARS-CoV-2 vaccination in patients with DS.

 

OBJECTIVES

Primary objective: to assess the antibody response after mRNA SARS-CoV-2 vaccination in people with Down Syndrome.

 

Secondary Objectives: To assess:

- durability of the antibody response

- the SARS-CoV-2-specific T and B cell response

- adverse events

 

Exploratory Objectives: To assess:

- the association between baseline (immune) parameters and the immune response to SARS-CoV-2 vaccination

- the neutralizing capacity of anti-COVID-19 antibodies produced after vaccination

- the incidence of SARS-CoV-2 infection and outcome of COVID-19 disease 12 months after SARS-CoV-2 vaccination.

- fucosylation of anti-COVID-19 IgG-antibodies in participants with a history of mild or severe SARS-SoV-2 infection

 

CONSORTIUM

This study will be performed by a consortium of experts in the field of DS in adults, DS in children, immune responses in DS, COVID vaccine development and the Down Syndrome Society of the Netherlands.

 

STUDY DESIGN

We will perform a prospective, observational parallel cohort study. People with DS will be compared to age-matched healthy controls (HC). Two studies will be distinguished: study A (adults, initially) and study P (paediatrics). If adult responses are normal, then it is likely that vaccine responses in children will also be normal. Therefore, a condition to start Study P and the intervention study to administer a 3rd vaccination (2nd booster) is a =20% decrease in levels of antibodies against S following the second vaccination (primary endpoint).

 

STUDY POPULATION

We will include adults and children with DS and (HC) from the homes of the people with DS. For pragmatic reasons study A will be started first. Inclusion and exclusion criteria for Study A and Study P are:

Inclusion

All patients who have opted to receive routine COVID-19 vaccination with age >=17 years (study A) or <=16 years (study P) with DS (DS cohort) or age-matched HC living in the same homes (families or facilities).

Exclusion

DS cohort: History of severe adverse reaction associated with a vaccine and/or severe allergic reaction; organ transplant recipients, active malignancy or completion of treatment for malignancy in previous 3 months; infection with Human Immunodeficiency Virus (HIV).

HC cohort: as in DS cohort plus active care for inherited or acquired immune deficiency, any moderate to severe comorbidity for which regular medical care is needed (p.e. heart disease, COPD, diabetes).

 

Sample size: we will recruit 50 participants with DS and 10 HC per age stratum (18-29; 30-39;40-49;=50 years) for study A. If the conditions to start study P are met, we will recruit 300 children and 100 HC for study P.

 

MEASUREMENTS

Venous blood will be drawn before and after routine SARS-CoV-2 vaccination at 4 time points: baseline (t=1, < 2 months prior to first vaccination); t=2: <1 week prior to second vaccination; t=3: 28 days after second vaccination; t=4: 6 months after second vaccination. Peripheral blood mononuclear cells (PBMCs) will be isolated and stored. In serum, we will measure IgG levels against the spike (S) protein of SARS-CoV-2. Antibodies will also be measured at all time points in saliva. General phenotyping of PBMCs will be performed on a relevant subset of =10 participants per age stratum from both groups. We include determination of the concentration of naïve T-cells. Extensive specific (memory) T-cell and B-cell responses to S-peptide pools will be determined using existent assays developed by the National Institute of Health (NIH).

 

MAIN STUDY PARAMETERS/ENDPOINTS

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