SARS-CoV-2 Delta Breakthrough Infections in Vaccinated Patients with Immune-Mediated Inflammatory Diseases Using Immunosuppressants – Data from Two Controlled Prospective Cohort Studies

Background: The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between vaccinated patients with immune-mediated inflammatory diseases (IMIDs) using immunosuppressants, and controls (IMID patients without immunosuppressants and healthy controls). The secondary objective was to explore determinants of breakthrough infections, including humoral immune responses after vaccination.Methods: In this study we pooled data collected in two large ongoing prospective multi-center cohort studies (Target to-B! [T2B!] study and Amsterdam Rheumatology Center [ARC] study). Clinical data were collected from standardized electronic case record forms, digital questionnaires and medical files. Data were collected before the omicron variant of SARS-CoV-2 became dominant in the Netherlands (February-December 2021). A SARS-CoV-2 breakthrough infection with the SARS-CoV-2 delta variant was defined as a PCR or antigen confirmed SARS-CoV-2infection that occurred at least 14 days after vaccination, and was detected between July 1 and December 14, 2021. Post-vaccination serum samples were analyzed for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC study only). Multivariable logistic regression analyses were used to explore potential clinical and humoral determinants associated with the incidence of breakthrough infections.Results: We included 3207 IMID patients with immunosuppressants and simultaneously enrolled 1807 controls (985 IMID patients without immunosuppressants and 822 healthy controls). The incidence of PCR/antigen test confirmed SARS-CoV-2 breakthrough infections was similar in patients with immunosuppressants (148/3207; 4.6%, 95% CI: 3.9 – 5.4) and controls (86/1807; 4.7%, 95% CI: 3.8 – 5.8). In the ARC-COVID cohort, the proportion of asymptomatic COVID-19 cases identified serologically was also similar (55/628; 8.8% vs 56/571; 9.8%). Seroconversion after vaccination and SARS-CoV-2 infection prior to vaccination were associated with a lower incidence of breakthrough infections. Hospitalization was required in 8 (5.4%, 95% CI: 2.4 – 10.3) of 148 IMID patients with immunosuppressants and 5 (5.8%, 95% CI: 1.9 – 13.0) of 86 controls with a SARS-CoV-2 breakthrough infection. Hospitalized COVID-19 breakthrough cases were older, and had more comorbidities compared with non-hospitalized cases. Hospitalization rates were higher in IMID patients treated with anti-CD20 therapy (3 [19%] of 16 patients) compared to IMID patients using other immunosuppressants (5 [4%] of 132 patients; P 0.04).Conclusion: The incidence of SARS-CoV-2 breakthrough infections in IMID patients with immunosuppressants was similar to controls. SARS-CoV-2 infection prior to vaccination and the presence of a humoral response after SARS-CoV-2 vaccination were associated with fewer breakthrough infections. Breakthrough infections were mostly mild and severe disease was primarily seen in people with traditional risk factors and those on anti-CD20 therapy.Funding Information: The T2B study was supported by ZonMw (the Netherlands Organization for Health Research and Development; project number 10430012010009). The ARC-was supported by ZonMw (project number: 10430022010020) and Reade foundation. Declaration of Interests: None to declare. Ethics Approval Statement: The research protocol of this study was approved by the medical ethical committee of the Amsterdam UMC (T2B-COVID study: 2020.194). All participants provided written informed consent.