Reduced antibody activity against SARS-CoV-2 B.1.617.2 Delta virus in serum of mRNA-vaccinated patients receiving TNF-alpha inhibitors (preprint)

Although vaccines effectively prevent COVID-19 in healthy individuals, they appear less immunogenic in individuals with chronic inflammatory diseases (CID) and/or under chronic immunosuppression, and there is uncertainty of their activity against emerging variants of concern in this population. Here, we assessed a cohort of 74 CID patients treated as monotherapy with chronic immunosuppressive drugs for functional antibody responses in serum against historical and variant SARS-CoV-2 viruses after immunization with Pfizer mRNA BNT162b2 vaccine. Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with TNF- inhibitors, and this pattern appeared worse against the B.1.617.2 Delta virus. Within five months of vaccination, serum neutralizing titers of the majority of CID patients fell below the presumed threshold correlate for antibody-mediated protection. Thus, further vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) likely will be required to prevent SARS-CoV-2 infection in this susceptible population.

Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2 (preprint)

BackgroundIndividuals with chronic inflammatory diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management. MethodsWe conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG+ binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination. ResultsCompared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization. ConclusionsCID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.