key: cord-0733793-tjuaurid authors: Sali, Michela; Carfì, Angelo; Di Paola, Antonella; Boza, Maria Pereyra; Zampino, Giuseppe; Sanguinetti, Maurizio; Landi, Francesco; Onder, Graziano title: SARS-CoV-2 vaccine humoral response in adults with down syndrome date: 2022-04-21 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2022.04.008 sha: 22149b3140b6d818e7d0a71f3f7a54f3b79f6e7b doc_id: 733793 cord_uid: tjuaurid OBJECTIVE: People with Down syndrome (DS) are particularly vulnerable to Covid-19 and show altered immune response to vaccination. We aimed to evaluate the immune response of a group of adults with DS treated with standard regimens of SARS-CoV-2 vaccine as compared with an aged- and sex-matched group of persons without DS. METHODS: We compared antibody responses between 42 subjects with DS (41.6 ±10.8 years, 57% male), and an age- and sex-matched comparison group of healthy health care workers (HCW) (41.4±8.8 years, 54.8% male) after SARS-CoV2 vaccination with the standard regimen of BNT162b2 mRNA COVID-19. Receptor binding domain (RBD) IgG antibodies were assessed at 4 time points (baseline, 21 days after the first dose, 21 days after the second dose and 6 months after the first dose) with Siemens SARS-CoV-2 IgG (COV2G) antibody test. RESULTS: We observed significantly different antibody responses at all time points after vaccination (HCW vs. DS: 7.9±3.9 vs. 1.4±3.6 IU/ml at 21 days after first dose; 358.5±3.8 vs. 38.1±3.0 IU/ml at 21 days after second dose; 34.6±2.4 vs. 7.9±3.1 IU/ml at 6 months after vaccination) and a significantly different time course of decline in antibody titers between the two groups. CONCLUSIONS: Subjects with DS have a valid antibody response to SARS-CoV2 vaccination. However, this response is lower than that of subjects in the HCW group. This finding could indicate a more rapid decline in the protective effects of the vaccination in subjects with DS and could suggest that people with DS may benefit from a booster dose of vaccine. People with Down syndrome (DS) have shown a particular vulnerability when affected by and therefore in many countries they have been prioritized to receive anti-SARS-CoV2 vaccination (1) . It is thought that the causes of this increased risk of adverse events in DS can be ascribed to the contribution of several factors including the impaired inflammatory profile in DS(2), the not fully elucidated interactions between the SARS-CoV-2 genome and the genetic alterations of DS (3, 4) , and the inherent complexity of clinical management of these individuals (5, 6) . Moreover, due to altered immune responses, introduction of additional booster doses is known to be required for other standard vaccines in people with DS (7). Although available data so far indicate good efficacy, safety, and tolerability of SARS-CoV-2 vaccines in the general population, there is no data available on the effects in persons with DS. We aimed to evaluate the immune response of a group of adults with DS treated with standard regimens of SARS-CoV-2 vaccine as compared with an aged-and sex-matched group of persons without DS. This prospective study took place in the Day Hospital of Health Care Continuity of Fondazione Policlinico Universitario A. Gemelli IRCCS since March 2021. We randomly selected adults with DS in clinical follow up at the Day Hospital who received SARS-CoV-2 vaccination. No particular inclusion criteria were applied except not having contracted Covid-19, being eligible for vaccination, and being willing to participate. Data were compared with those obtained from healthy health care workers(HCW) of our institution since January 2021 and meeting the same inclusion criteria. The two groups were matched for age and sex by the cardinality method provided by the MatchIt package in R with the optimization performed by GLPK (8) . All participants received two doses of BNT162b2 mRNA COVID-19 vaccine (Comirnaty) 21 days apart and were assessed for the detection of receptor binding domain (RBD) IgG antibodies using Siemens SARS-CoV-2 IgG (COV2G) antibody tests(9), at 4 time points: 1. T0 -Baseline assessment at day 0 in the same morning before the first vaccine dose. 2. T1 -1st FU visit at day 21, i.e. 21 days after the first dose, in the same morning before the second vaccine dose. 3. T2 -2nd FU visit at day 42, i.e. 21 days after completing the vaccination schedule. 4. T3 -3rd FU visit at day 180, i.e. six months after the first dose. Immune response was normalized according to World Health Organization standards(10) and expressed in international units (IU/mL). Besides the peripheral blood draw for antibody detection, a comprehensive medical assessment and a detailed history on possible SARS-CoV-2 exposure, contagion and clinical course were obtained at each visit. Comparisons were performed with  2 test for categorical variables. Because of their extreme scatter and skewness, antibody titers were analyzed after logarithmic transformation. Results were presented as geometric mean and standard deviation factor. For each timepoint, comparisons of treatment effect were performed by t-test of the ratio of the logarithm of the antibody titer. A linear mixed-effects model for repeated measurements was used to study the time course of antibody responses in the two groups under study. Data were analyzed with R version 4.03. The study received approval from the national ethical committee (331/2021) and informed consent was collected for each study subject. Table, 42 subjects with DS (mean age 41.610.8 years, 57% male) were enrolled. RBD-IgG antibodies, determined at different times from the administration of the first two doses of vaccine, were compared with those of 42 HCWs (mean age 41.48.8 years, 54.8% male) with significantly different antibody responses at all the time points after vaccination (Table and Figure -upper panel) . The model compared rate of change of the logarithm of the antibody titer of the two groups at different timepoints using HCW group values at time T0 as a reference point. Statistically significant interactions between group and timepoint emerged: at all timepoints, the DS group presented a significantly lower trend indicating a lower treatment effect (Figurebottom panel, details in the supplemental materials) . However, it is worth noting that between timepoints T2 and T3, the decrease in antibody titer in the DS group was smaller. This study reports a first evidence of antibody response to SARS-CoV-2 vaccination in a sample of people with DS. A significant difference is seen both at time T2 and at time T3. Importantly, the DS group has appreciable responses even if evidently lower compared to the ones in the comparison group. However, the fact that antibody levels decline to a lower level could reflect the risk of no longer being protected by the effects of vaccination at an earlier time than the general population. These findings appear to be in line with previous research highlighting an altered immune response against various microbial species and after vaccine administration (11) . A similar pattern of response resembles that observed also in other conditions of immunosuppression (12) . The study has several limitations as it assesses only the effect of a single type of vaccine, it compares two groups of subjects consisting of convenience samples, it only measured IgG titers and no other immunoglobulins and most of all it lacks analyses of the cell-mediated immune response. Nonetheless, these preliminary results raise the question on how to properly manage large-scale vaccination in this vulnerable population. While further research in the field is certainly recommended, we believe that in view of our findings, of the increased risk of adverse events from Covid-19 in these individuals, and of the worryingly different accessibility to care these people received during the pandemic(13), it would be important to encourage their prioritization to receive a third booster dose. The authors declare no conflict of interest No external funding was received Michela Sali -conceptualization, methodology, validation, resources, data curation, writing review/editing, supervision Angelo Carfì -conceptualization, methodology, software, formal analysis, data curation, writing original draft, visualization, supervision Antonella Di Paola -investigation, data curation, project administration Maria Pereyra Boza -investigation, data curation Giuseppe Zampino -conceptualization, methodology, supervision Maurizio Sanguinetti -conceptualization, methodology, resources, supervision Francesco Landi -conceptualization, methodology, resources, supervision Graziano Onder -conceptualization, methodology, validation, resources, data curation, writing review/editing J o u r n a l P r e -p r o o f Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey. EClinicalMedicine Down Syndrome and COVID-19: A Perfect Storm? Specific Susceptibility to COVID-19 in Adults with Down Syndrome Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19 Adults with Down syndrome: a comprehensive approach to manage complexity The burden of chronic disease, multimorbidity, and polypharmacy in adults with Down syndrome Generation of switched memory B cells in response to vaccination in Down syndrome children and their siblings MatchIt : Nonparametric Preprocessing for Parametric Causal Inference Performance Evaluation of the Siemens SARS-CoV-2 Total Antibody and IgG Antibody Test WHO International Standard for anti-SARS-CoV-2 immunoglobulin Inborn Errors of Adaptive Immunity in Down Syndrome Immunogenicity of BNT162b2 mRNA SARS-CoV-2 vaccine in patients with psoriatic arthritis on TNF inhibitors Understanding inequalities in COVID-19 outcomes following hospital admission for people with intellectual disability compared to the general population: a matched cohort study in the UK We thank the editor-in-chief for the important notes. We have edited the manuscript following the suggestions and it seems to us further improved The changes made are listed below point by point:Objectives are now clearly stated b. Results now include numerical data c. Conclusions are now based on the results 2. METHODS a. Random selection of subjects with DS is now explicitly stated b. The matching procedure is now detailed 3. RESULTS a. We added supplementary materials which include the DS group clinical characteristics b. We agree with the Editor that the analysis on the trend of antibody titers could be unnecessary. In fact, the differences between the two groups are so evident that, in principle, any hypothesis test could be omitted. Nevertheless, we felt it was useful to perform the analysis of the trend in antibody titers to give a mathematical representation of the lower panel of the figure and to provide an analysis of the entire data set. However, if the editor feels that the analysis is superfluous, counterproductive, or may be confusing to the reader, we will readily provide a new version without it. c. Model details are now included in the supplemental file 4. DISCUSSION a. Limitations now include that both groups are convenience samples 5.