Cellular and humoral responses after second and third SARS-CoV-2 vaccinations in patients with autoimmune diseases treated with rituximab: specific T cell immunity remains longer and plays a protective role against SARS-CoV-2 reinfections

Abstract

BackgroundHumoral and cellular immune responses are known to be crucial for patients to recover from COVID-19 and to protect them against SARS-CoV-2 reinfection once infected or vaccinated.ObjectivesThis study aimed to investigate humoral and T cell responses to SARS-CoV-2 vaccination in patients with autoimmune diseases after the second and third vaccine doses while on rituximab and their potential protective role against reinfection.MethodsTen COVID-19-naïve patients were included. Three time points were used for monitoring cellular and humoral responses: pre-vaccine to exclude virus exposure (time point 1) and post-second and post-third vaccine (time points 2 and 3). Specific IgG antibodies were monitored by Luminex and T cells against SARS-CoV-2 spike-protein by ELISpot and CoVITEST. All episodes of symptomatic COVID-19 were recorded.ResultsNine patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and one with an undifferentiated autoimmune disease were included. Nine patients received mRNA vaccines. The last rituximab infusion was administered for a mean (SD) of 15 (10) weeks before the first vaccine and six patients were CD19-B cell-depleted. After a mean (SD) of 19 (10) and 16 (2) days from the second and third vaccine dose, IgG anti-SARS-CoV-2 antibodies were detected in six (60%) and eight (80%) patients, respectively. All patients developed specific T cell responses by ELISpot and CoVITEST in time points 2 and 3. Previous B cell depletion correlated with anti-SARS-CoV-2 IgG levels. Nine (90%) patients developed mild COVID-19 after a median of 7 months of the third dose.ConclusionRituximab in patients with autoimmune diseases reduces humoral responses but does not avoid the development of T cell responses to SARS-CoV-2 vaccination, which remain present after a booster dose. A steady cellular immunity appears to be protective against subsequent reinfections.

COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases

“…In this context, the data on the cellular response to the COVID-19 vaccine in patients with IMIDs treated with rituximab are especially relevant, given the foreseeable negative effect on the humoral response due to its mechanism of action. As expected, a negative association between seroconversion rates to the COVID-19 vaccine and rituximab has been confirmed, identifying the interval between the last RTX infusion and the first vaccination, the number of peripheral B-cells and the immunoglobulin quantity among the related factors [50,51], while the cellular response seems to be preserved [52]. Intervals of 6 to 9 months between the last rituximab administration and COVID-19 vaccination appear to improve the humoral response, although pharmacokinetic studies suggest that the presence of B cells and/or rituximab in the blood predict seroconversion better than time since last infusion [50,51,53].…”

When Cell-Mediated Immunity after Vaccination Is Important

“…Another group of immunocompromised patients are those affected by autoimmune diseases requiring immunosuppressive therapies. Even in these cases, steady T cell responses to SARS-CoV-2 vaccination have been found at levels similar to controls [22], and were found to be present after a booster dose, therefore appearing to be protective against subsequent reinfections.…”

BA.1/BA.5 Immunogenicity, Reactogenicity, and Disease Activity after COVID-19 Vaccination in Patients with ANCA-Associated Vasculitis: A Prospective Observational Cohort Study

“…Other studies reported comparable results of impaired humoral immune response, including not only AAV patients, but large and diverse groups of individuals with autoimmune inflammatory rheumatic diseases [ 29 , 30 ]. Following mRNA booster vaccination, we and others have shown that neutralizing antibody activity is significantly increased in most AAV patients [ 31 , 32 , 33 ]. However, patients treated with the CD20 monoclonal antibody rituximab had severely limited humoral immune responses even after booster vaccinations and high breakthrough infection rates have been reported for this cohort [ 7 , 34 , 35 , 36 ].…”

“…A limitation of our study is the lack of data on cellular immunity data after SARS-CoV-2 vaccination. Especially in some patients under rituximab therapy, it could be shown that in the absence of humoral immune response at least antigen-specific activation of cellular immunity was detected [ 18 , 32 , 54 ]. Nevertheless, it has been clearly demonstrated that neutralizing antibodies are considered highly predictive of protection against symptomatic SARS-CoV-2 infection [ 4 ].…”