High levels of antibodies 6 months after COVID‐19 vaccination in children with severe chronic diseases: A prospective longitudinal case series

Although SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is generally mild in children and adolescents, the disease has been associated with serious illness and increased mortality in individuals with severe comorbidities. Data regarding the immunogenicity of the BNT162b2 mRNA COVID-19 (coronavirus disease of 2019) vaccine in adolescents with severe comorbidities are limited. A recent study found a normal humoral vaccine response in patients with chronic diseases and poor response in patients with impaired immunity such as post-transplantation recipients and adolescents with cancer.1 In Denmark, the BNT162b2 mRNA COVID-19 vaccine was offered to individuals aged 16–17 years with chronic diseases from 27 December 2020, 5 months before the national vaccine recommendation for healthy adolescents. Due to low vaccine availability at that time of the pandemic, only adolescents with the most severe chronic diseases were offered vaccination. We aimed to investigate the immunogenicity of SARS-CoV-2 mRNA vaccination in these adolescents to identify individuals with poor vaccine response. This prospective observational cohort study included adolescents with severe chronic diseases receiving treatment at the tertiary referral centre, Copenhagen University Hospital, Rigshospitalet. Patients were invited to participate if offered a COVID vaccine from ultimo December 2020. Infection with SARS-CoV-2 prior to vaccination was not an exclusion criterion. Antibody response was measured using the Shenzhen Yhlo Biotech (Shenzhen, China) assays iFlash-SARS-CoV-2 IgG (nucleoprotein IgG) and IgG iFlash-SARS-CoV-2 IgG-S (S1 spike protein IgG). Three consecutive blood samples were planned to be collected from day 0 to day 180 following vaccination. Time points for collection of blood samples differed for each patient as they were collected at the time of scheduled outpatient clinical consultations due to the complete lockdown during the first part of the study period. The threshold for positivity was defined as values ≥8.0 AU/mL for both assays. The study was approved by the Ethics Committee of the Capital Region of Denmark (H-20028631) and the Danish Data Protection Agency (P-2019-29). Informed consent was obtained before participation. A total of 23 patients aged 15–18 years participated, including 12 (52%) with severe chronic lung diseases, 6 (26%) with chronic neurological disorders, 2 (9%) with heart diseases, and 3 (13%) following transplantation (details are provided in Table S1). Two patients received T-cell suppressive therapy after heart transplantation (case 1; tacrolimus, mycophenolate, and azathioprine) and 6 months post-haematopoietic stem cell transplantation (case 2; tacrolimus), respectively, and one patient with cystic fibrosis received abatacept (case 3), a biological immune inhibitor of T-cell co-stimulation (Figure 1, Table S1). The remainder did not receive immunosuppressive therapy. SARS-CoV-2 serology was investigated a median of 2 times (range 1–5) in each patient. All patients received two doses of the BNT162b2 mRNA COVID-19 vaccine with a median interval of 22 days (range 21–47). After the first vaccine, and before the second dose, the median anti-spike IgG for patients not receiving immunosuppressive therapy was 115 AU/mL (range 0.4–547; positivity ≥8.0 AU/mL). Following the second vaccine, the median anti-spike IgG was 2765 AU/mL (range 387–4732) day 7–75, 1070 AU/mL (range 452–2385) day 76–150 and 416 AU/mL (38–1785) day 151–236. The median values for different disease categories are given in Figure 1. The two patients who received T-cell suppressive therapy had anti-spike IgG <8 AU/mL on days 41, 109, and 207 (case 1) and 19 AU/mL, 9 AU/mL, and <8 AU/mL on days 37, 80 and 164 (case 2), after the second vaccine. Case 3 who received abatacept had a spike IgG of 2451 AU/mL and 145 IE/mL on days 44 and 156 after the second vaccine, similar to the levels of the patients not receiving immunosuppressive therapy. One patient had SARS-CoV-2 infection during the study period proven by PCR and seroconversion of nucleocapsid IgG, in addition to increasing S1 spike protein IgG day 258 (case 4; Figure 1). The remaining patients had no signs of SARS-CoV-2 infection before or during the study, based on clinical suspicion, PCR results and negative nucleocapsid IgG antibodies (Table S1). In this prospective case series, we found high levels of anti-spike IgG antibodies following the mRNA COVID-19 vaccine, compared with the levels before vaccination, in adolescents with severe chronic diseases who did not receive immunosuppressive therapy. Although the antibodies decreased with time, the patients still had high levels of antibodies at follow-up after 5–9 months. Our findings are in line with high vaccine immunogenicity 3 months after the second vaccine, determined by a surrogate virus neutralisation test, in a larger study including adolescents with chronic diseases.1 We found very low levels of anti-spike IgG antibodies in the two adolescents receiving T-cell suppressive therapy, which has also been observed previously in adolescents and adults receiving immunosuppressive treatment.1, 2 Thus, close monitoring of such patients is warranted to guide their risk of infection. High levels of anti-spike IgG antibodies were observed in one adolescent who received abatacept. This contrasts with the reduced immunogenicity found in adults receiving abatacept, reflecting the inhibition of B- to T cell co-stimulation.3 One fully vaccinated patient with protective levels of spike antibodies had confirmed SARS-CoV-2 infection which significantly boosted the immune response. Such a hybrid immunity has also been observed in adults.4 The limitations of this study include few participants, lack of a control group with healthy adolescents as well as lack of conventional virus-based neutralisation tests and measurements of cellular responses. In conclusion, adolescents with severe chronic disease not receiving immunosuppressive treatment all had high levels of antibodies, also at follow-up after 6 months. The study was funded by a COVID-19 grant from the National Ministry of Higher Education and Science (grant no. 0237-00004B) and Innovation Fund Denmark (0176-00020B). The authors have no conflicts of interests. Table S1. 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