Abstract
BACKGROUND: Immunosuppressed (IS) children show increased vulnerability to infections including SARS-CoV-2. Therefore, it is necessary to better understand correlates of protection in that particularly vulnerable population to avoid critical illness due to COVID-19. OBJECTIVES: The objective was to determine whether the three-doses primary vaccination regimen is sufficient for immunosuppressed children to develop comparable immunity as healthy children after two doses of vaccine. DESIGN/METHODS: To interrogate the impact of vaccination of IS children, we compared a cohort of healthy children (n=52) receiving the standard two-doses regimen to children affected by primary (PID) or secondary humoral immune deficiencies (n=30) who received two or three vaccine doses. In the secondary antibody deficiency (SAD) group (n=14), 11 children were treated with rituximab and three had persistent hypogammaglobulinemia after stem cell transplantation or treatment with CAR T cell therapy. IgG, IgA, and IgM binding the spike protein, its receptor-binding-domain, and nucleocapsid were measured in serum and saliva. Neutralizing antibody titers (nAbs) were determined via live-SARS-CoV-2 micro-neutralizations. Cell-mediated immunity was quantified by assessing interferon-gamma secretion using ELISpot. RESULTS: After the second vaccine dose, IS children showed reduced circulating binding and nAbs compared to their healthy counterparts. While all healthy children had nAbs after two doses, only 27% of IS children did. Importantly, the third dose significantly increased nAb titers in PID children to levels comparable to healthy children (median nAb titers of 101 [32-403] in PID after three doses compared to 101 [32-254] in healthy children after two doses), but this finding did not last over time, since PID children had much lower antibody levels in the long term. In contrast, children with SAD did not develop nAb following vaccination. Interestingly, breakthrough (BT) infection induced a profound increase in nAbs in all children, including in children with SAD. Indeed, 80% of infected SAD children developed nAbs after SARS-CoV-2 infection. Functional T cell immunity seemed sufficient to protect against symptomatic disease and complications in children without nAb. CONCLUSION: Three intramuscular vaccine doses are not sufficient for immunosuppressed children to develop potent and persistent immunity against SARS-CoV-2. As BT infection mimics mucosal challenge, these results support the idea that mucosal vaccination strategies could improve immune responses in IS children.