Abstract
The risk of a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults with Down syndrome is increased, resulting in an up to 10-fold increase in mortality, in particular in those >40 years of age. After primary SARS-CoV-2 vaccination, the higher risks remain. In this prospective observational cohort study, SARS-CoV-2 spike S1–specific antibody responses after routine SARS-CoV-2 vaccination (BNT162b2, messenger RNA [mRNA]–1273, or ChAdOx1) in adults with Down syndrome and healthy controls were compared. Adults with Down syndrome showed lower antibody concentrations after 2 mRNA vaccinations or after 2 ChAdOx1 vaccinations. After 2 mRNA vaccinations, lower antibody concentrations were seen with increasing age.
Clinical Trials Registration
Keywords: Down syndrome, antibody response, COVID-19 vaccination, SARS-CoV-2
In this prospective cohort study that included 222 adults with Down syndrome, a significantly lower antibody response was found after SARS-CoV-2 mRNA or vector vaccination compared to healthy controls. After mRNA vaccination, lower antibodies were found with increasing age.
Down syndrome (DS), also known as trisomy 21, is the most common chromosomal abnormality in the Netherlands. Individuals with DS show, at all ages, an increased incidence of respiratory morbidity and mortality. The risk of a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with DS is substantially increased, resulting in hospitalization rates up to 56% [1–3]. Viral pneumonia, acute respiratory distress syndrome, and bacterial pneumonia are the most prevalent complications seen in individuals with DS during a SARS-CoV-2 infection [1]. The risk of death is 3- to 10-fold higher compared with individuals without DS [1, 2]. Aging is an additional risk factor, as is shown by higher mortality rates in people with DS >40 years of age [1].
Recent evidence shows a 12.7-fold increased risk for individuals with DS in coronavirus disease 2019 (COVID-19)–related mortality and hospital admissions, even after 1 or 2 SARS-CoV-2 vaccinations [4]. T-cell and B-cell responses in people with DS are impaired and previous, non–SARS-CoV-2, vaccine responses are known to be suboptimal [5, 6]. SARS-CoV-2 vaccines have been registered for adults and children ≥12 years of age, but none of them have been studied in people with DS. In this study, we investigated the antibody response after SARS-CoV-2 vaccination in individuals with DS and compared these with the antibody response in healthy controls (HCs).
METHODS
Study Design and Participants
The PRIDE study (Prospective Monitoring of Antibody Response Following COVID-19 Vaccination in Patients With Down Syndrome) is a prospective, observational cohort study. Adults (≥18 years of age) with Down syndrome (DS cohort) were compared with a healthy control cohort without Down syndrome (HC cohort). Participants with DS were recruited through patient networks and specialized DS outpatient clinics throughout the Netherlands. Household contacts of the DS participants and healthcare workers were asked to participate in the HC cohort. Exclusion criteria were receipt of organ transplant, active malignancy or completion of treatment for malignancy in the previous 3 months, or an infection with human immunodeficiency virus. For the HC cohort, additional exclusion criteria were any disease or condition for which regular visits to a healthcare provider were necessary. Participants received 2 doses of the following SARS-CoV-2 vaccines as part of the Dutch national immunization program: BNT162b2 (Pfizer/BioNTech, interval 3–6 weeks), mRNA-1273 (Moderna, interval 4–6 weeks), and ChAdOx1 (AstraZeneca, interval 10–14 weeks). Given the same general vaccine mechanism and efficacy in other populations, BNT162b2 and mRNA-1273 were combined and referred to as messenger RNA (mRNA) vaccine. The study was approved by the University Medical Center Utrecht medical research ethics committee (NL76336.041.21). All participants and/or legal representatives provided written informed consent before inclusion.
Procedures
Blood samples were collected at baseline (<2 months before the first vaccination) (T = 1), 21–28 days after the first vaccination (T = 2), and 28 days (range, 21–42 days) after the second vaccination (T = 3). SARS-CoV-2 immunoglobulin G (IgG) antibodies against the spike protein (S), receptor-binding domain, and nucleocapsid protein (N) were measured by multiplex immunoassay and reported as binding antibody units (BAU)/mL as previously described [7], according to the first serum standard for COVID-19 (20/136), as provided by the National Institute for Biological Standards and Control and recommended by the World Health Organization to define specific serum antibody concentrations in an international perspective.
Statistical Analysis
Antibody concentrations are presented as geometric mean antibody concentrations (GMCs). An S antibody concentration >10.08 BAU/mL was considered positive. Participants with a concentration below this value at T = 3 were defined as nonresponders. At the moment of analysis, no specific threshold in correlation to neutralization is known for individuals with DS. Participants with a positive anti-S IgG concentration at T = 1 (>10.08 BAU/mL) were considered to be previously infected with SARS-CoV-2 and excluded from primary analysis. In case no T = 1 sample was available, a positive anti-N IgG concentration at T = 2 or T = 3 (>14.3 BAU/mL) was also regarded as a possible previous infection and excluded from primary analysis [8]. Statistical analyses after log-transformation included a Student t test for comparison between the DS cohort and HC cohort and between the administered mRNA vaccines. For correlations, a Pearson test was used. Unfortunately, we were not powered to undertake a multivariable analysis. Statistical analyses were performed in IBM SPSS Statistics 26 software (IBM, Armonk, New York). A P value < .05 was considered statistically significant.
RESULTS
Population
Between February and September 2021, 318 participants were included, of whom 214 DS participants (51.8% male) and 93 HC participants (27.4% male) had results available at T = 3 at the time of preliminary analysis (Figure 1). Further baseline characteristics are presented in Supplementary Table 1.
Figure 1.
Flow diagram of included participants for analysis. *Participants with a positive anti-spike immunoglobulin G concentration at T = 1 or a positive anti-nucleocapsid IgG concentration at T = 2 or T = 3. Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Antibody Concentrations
None of the participants, HC or DS, were nonresponders. However, the DS cohort showed a significantly lower GMC after vaccination with an mRNA vaccine compared with the HC cohort (1055.2 BAU/mL [95% confidence interval {CI}, 889.4–1251.9] vs 2271.4 BAU/mL [95% CI, 1763.6–2925.4], respectively) (P < .001, Figure 2A). The significant difference in GMCs between the DS cohort and HC cohort was found in both subgroups <40 years of age (1429.8 BAU/mL [95% CI, 1199.3–1704.5] vs 2837.4 BAU/mL [95% CI, 2054.7–3918.2], respectively) (P = 0.003) and ≥40 years of age (614.0 BAU/mL [95% CI, 451.3–835.3] vs 1927.9 BAU/mL [95% CI, 1322.0–2811.6], respectively) (P < .001). After vaccination with ChAdOx1, the DS cohort also showed significantly lower GMCs compared with the HC cohort (343.1 BAU/mL [95% CI, 264.7–444.8] vs 592.1 BAU/mL [95% CI, 466.9–750.9], respectively) (P = .002, Figure 2B). In general, antibody concentrations after ChAdOx1 were lower compared with antibody concentrations after mRNA vaccines, showing values <100 BAU/mL in DS participants <30 years of age.
Figure 2.
Overview of anti-spike (S1) immunoglobulin G (IgG) concentrations (COV19S1) after different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Antibody concentration at T = 1, T = 2, and T = 3 for the Down syndrome (DS) cohort. Each data point represents an individual’s response. The black solid line represents the geometric mean concentration (GMC) and its 95% confidence interval (CI). *COVID+ indicates evidence of past SARS-CoV-2 infection based on a positive anti-S IgG concentration at T = 1 or a positive anti-nucleocapsid IgG concentration at T = 2 or T = 3. A, A significantly lower antibody response is seen in the DS cohort after messenger RNA (mRNA) vaccination in comparison with the healthy control cohort (HC). Participants with evidence of past SARS-CoV-2 infection in the DS cohort show a significant higher antibody response with a GMC of 3583.2 binding antibody units (BAU)/mL (95% CI, 2436.2–5270.1) compared with SARS-CoV-2–naive participants (GMC, 1055.2 BAU/mL [95% CI, 899.4–1251.9]). B, After ChAdOx1 vaccination, a significant lower antibody response is found in the DS cohort compared to HCs. The participants of the DS cohort with evidence of SARS-CoV-2 infection receiving the ChAdOx1 vaccine also show a higher antibody response compared with naive participants (GMC, 1245.3 BAU/mL [95% CI, 791.3–1959.6] vs 343.1 BAU/mL [95% CI, 264.7–444.8]). C, Antibodies at T = 3 (±28 days after second vaccination) after mRNA vaccine per decade. In the DS cohort, a negative correlation between age and antibody concentration was found. D, Antibodies at T = 3 (±28 days after second vaccination) after ChAdOx1 per decade. No correlation between age and antibody concentration was found.
In the DS cohort, a negative correlation was found between age and log-transformed antibody concentration after mRNA vaccination, showing lower antibodies with increasing age (Pearson r = −0.522, P < .001; Figure 2D). No such correlation was found in the HC cohort (Pearson r = −0.245, P = .170). No correlation for antibody concentration in relation to age was found in the DS cohort after vaccination with ChAdOx1 (Pearson r = −0.176, P = .247), nor in the HC cohort (Pearson r = −0.092, P = .544).
For the DS cohort, the GMC after BNT162b2 (n = 100; 918.0 BAU/mL [95% CI, 748.2–1126.2]) was significantly lower than after mRNA-1273 (n = 28; 1679.9 BAU/mL [95% CI, 1332.5–2117.9]) (P < .001). The HC cohort also showed a lower GMC after BNT162b2 (n = 28; 2228.9 BAU/mL [95% CI, 1542.3–2669.4]) compared with mRNA-1273 (n = 6; 3774.8 BAU/mL [95% CI, 1975.3–7213.4]). The significant differences in GMCs observed between the DS and HC cohort remained when BNT162b2 and mRNA-1273 were analyzed separately.
The relation with age is also found after BNT162b2 vaccination but could not be determined after mRNA-1273 vaccination (only 4 participants were >40 years of age). The participants with evidence of past SARS-CoV-2 infection showed a significantly higher GMC after vaccination compared with SARS-COV-2–naive participants (Figure 2A and 2B).
DISCUSSION
Our results show that adults with DS have decreased antibody concentrations after SARS-CoV-2 vaccination with mRNA or ChAdOx1 vaccine compared with healthy controls. To our knowledge, this is the first report determining SARS-CoV-2 vaccine antibody responses in a large cohort of adults with DS. Our findings are important since recent evidence shows that individuals with DS have a higher risk for COVID-19–related mortality and hospital admissions even after 1 or 2 vaccinations [4]. It is not fully clear how our results relate to protection. Currently, no validated cutoff values for either the mRNA or ChAdOx1 vaccines are validated; suggestions in literature differ based on testing technique and timing of measurement [9, 10].
Antibody concentrations were measured at peak levels and will decline over time [11]. It is conceivable that vaccine protection decreases more rapidly in adults with DS than in controls. The Dutch Health Council recently recommended an early booster vaccination for adults with DS, based on our preliminary results. Since vaccine efficacy is higher for mRNA vaccines and recent studies showed high antibody concentrations with a potent T-cell response and only limited side effects after heterologous vaccine schedules with a vector vaccine followed by an mRNA vaccine, a third vaccination with an mRNA vaccine is administered to adults with DS in the Netherlands [12].
A strength of our study is the large number of participants in our DS cohort. There was no loss to follow-up. Besides this, the control group is relatively large, which makes it possible to draw solid conclusions from the data.
Our study has limitations. First, the design is observational. Vaccines were given as part of the national immunization program and changed during the observation period. However, we recruited enough participants to draw conclusions for each vaccine type, and this enabled us to compare the antibody response in 2 vaccine types. Second, the HC cohort consists of a higher percentage of women and this could have affected the antibody response. Third, we only analyzed and compared binding antibodies and were not able to determine a threshold for adequate response, for which analysis of neutralizing antibodies is needed. By comparing antibody concentrations between DS and HC and with increasing age we were able to determine relative antibody responses between groups and with increasing age. Fourth, additional information on cellular responses after vaccination is not yet present, which is also important in the evaluation of vaccine immunogenicity, especially in people with DS, as previous studies have shown that individuals with DS have lower amounts of circulating B and T cells [13, 14]. Decreased thymic output results in low amounts of naive T cells [15]. Loss of memory against SARS-CoV-2 may further contribute to risk of severe COVID-19 disease over time in adults with DS. Fifth, long-term response in our cohort is not yet known, so we do not have information about waning immunity in this particular population.
In conclusion, antibody responses after SARS-CoV-2 vaccination in adults with DS are significantly decreased compared with those of healthy adults. In older adults with DS, the decreased antibody responses were even more pronounced, which, combined with the highest mortality rates, makes this group particularly vulnerable. A third or early booster vaccination should be considered in all adults with DS, given their risk for severe disease after SARS-CoV-2 infection.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Supplementary Material
Contributor Information
Bianca M M Streng, Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Marin Bont, Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Eveline M Delemarre, Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Center of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Rob S Binnendijk, Laboratory for Vaccine-Preventable Diseases, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Gaby Smit, Laboratory for Vaccine-Preventable Diseases, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Gerco den Hartog, Laboratory for Vaccine-Preventable Diseases, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Antonia M W Coppus, Department for Primary and Community Care, Radboud University Medical Center, Nijmegen, The Netherlands.
Esther de Vries, Tranzo, Tilburg School of Social and Behavioral Sciences, Tilburg University, Tilburg, The Netherlands; Jeroen Bosch Academy Research, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands.
Michel E Weijerman, Department of Pediatrics, Alrijne Hospital, Leiderdorp, The Netherlands.
Regina Lamberts, Department of Pediatrics, Alrijne Hospital, Leiderdorp, The Netherlands.
Gert de Graaf, Foundation Stichting Down Syndroom, Meppel, The Netherlands.
Fiona R van der Klis, Laboratory for Vaccine-Preventable Diseases, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Gestur Vidarsson, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
Neele Rave, Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Louis J Bont, Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Joanne G Wildenbeest, Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Notes
Author contributions. B. M. M. S., M. B., A. M. W. C., M. E. W., R. L., L. J. B., and J. G. W. contributed to conceptualization and design of the study. B. M. M. S., R. S. B., G. S., G. d. H., L. J. B., and J. G. W. were involved in laboratory experiments and/or analysis and interpretation of collected data. All authors contributed to writing, review, and editing of the manuscript. The corresponding author had full access to all data and takes final responsibility to submit for publication.
Disclaimer. The funder had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; nor in the decision to submit the manuscript for publication.
Financial support. This work was supported by ZonMw, The Netherlands Organization for Health Research and Development (10430072010004). Funding to pay the Open Access publication charges for this article was provided by the Dutch Universities and Academic Hospitals (VSNU).
Potential conflicts of interest. L. J. B. has regular interaction with pharmaceutical and other industrial partners but has not received personal fees or other personal benefits. The University Medical Center Utrecht (UMCU) has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, the Bill & Melinda Gates Foundation, Nutricia (Danone), and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public-private partnership Innovative Medicines Initiative (IMI)-funded Respiratory Syncytial virus Consortium in Europe (RESCEU) project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by GlaxoSmithKline and Julius Clinical for participating in the International Network for Optimal Resistance Monitoring (INFORM) study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015 to 2017 (total annual estimate <€20 000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, mAbxience, Novavax, Pfizer, and Janssen (total annual estimate <€20 000). L. J. B. is the founding chairman of the Respiratory Syncytial Virus Network (ReSViNET) Foundation. R. L. is director of the Dutch Down Syndrome Foundation, a nonprofit organization. G. d. G. had a daughter with Down syndrome, who passed away in 2005 at the age of 15. He works as science and education officer at the Dutch Down Syndrome Foundation, a nonprofit organization. All other authors report no conflicts of interest.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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