Clinical and humoral responses after SARS-CoV-2 breakthrough infections in patients with immunosuppressants

Despite impaired humoral responses in patients treated with immunosuppressants (ISPs), recent studies found similar severity of SARS-CoV-2 breakthrough infections compared to controls. One potential explanation is the rapid generation humoral responses upon infection, but evidence is lacking. To investigate longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infections in patients with immune-mediated inflammatory diseases (IMID) on ISPs and controls. As prospective sub-study of the national Target-to-B! (T2B!) consortium, we included IMID patients on ISPs and controls who reported SARS-CoV-2 breakthrough infections between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, three antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at four time points after SARS-CoV-2 breakthrough infections. We included 302 IMID patients on ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infections in both groups. However, in IMID patients on anti-CD20 therapy and sphingosine-1 phosphate receptor (S1P) modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild and hospitalization was required in less than 1% of the cases. Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones towards new viral variants. However, in patients treated with anti-CD20 therapy or S1P modulators, the dynamics were greatly impaired, and to a lesser extent in those anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.