Improvement of Humoral Immunity by Repeated Dose-Intensified COVID-19 Vaccinations in Primary Non- to Low-Responders and B Cell Deficient Rheumatic Disease Patients

Objective: To determine whether repeated, dose-intensified mRNA vaccinations against COVID-19 increases humoral immunity in previously low-responding patients with autoimmune rheumatic diseases (AIRD), including rituximab-treated and B cell depleted patients.Methods: Of 308 AIRD patients receiving basic immunization, 98 had a low serological response against SARS-CoV-2 with a neutralizing capacity of < 70% using surrogate neutralization assay. 38 patients received a third vaccination with 30 µg BNT162b2 16 weeks after second vaccination. If neutralizing serum capacity was below 70% four weeks after the last vaccination, then the fourth vaccination (n=19) and the fifth (n=4) vaccination with 100 µg mRNA-1273 took place eight weeks after the last vaccination.Results: Each of the three booster vaccinations resulted in a significant increase of median serum neutralizing capacity (3rd: Δ=42%, p<0.001; 4th: Δ=19%, p=0.049) and 5th: Δ=51%, p=0.043) and produced a significant proportion of high-responders (3rd: 34%; 4th: 32% and 5th 75%). Low B cell counts (p=0.047), lower previous antibody response (p<0.001) and rituximab therapy (p=0.021) were negatively associated with successful response to the third but not to the fourth vaccination. Remarkably, substantial increases in neutralization capacity of up to 99% were observed after repeated vaccinations in B cell depleted patients.Conclusion: AIRD patients with low humoral response benefited from up to three repeated dose-intensified mRNA booster vaccinations – despite low B cell count and previous rituximab therapy. Each additional vaccination substantially reduced the number of low-responding, vulnerable patients.Funding Information: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Declaration of Interests: No competing interests to be declared.Ethics Approval Statement: This study was ethically approved by the Regional Office for Health and Social Affairs Berlin, Germany (21/0098-IV E 13), EudraCT number 2021-002245-15 amendment number 1.3. All patients provided written informed consent.