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

Deepak, Parakkal; Kim, Wooseob; Paley, Michael A.; Yang, Monica; Carvidi, Alexander B.; El-Qunni, Alia A.; Haile, Alem; Huang, Katherine; Kinnett, Baylee; Liebeskind, Mariel J.; Liu, Zhuoming; McMorrow, Lily E.; Paez, Diana; Perantie, Dana C.; Schriefer, Rebecca E.; Sides, Shannon E.; Thapa, Mahima; Gergely, Maté; Abushamma, Suha; Klebert, Michael; Mitchell, Lynne; Nix, Darren; Graf, Jonathan; Taylor, Kimberly E.; Chahin, Salim; Ciorba, Matthew A.; Katz, Patricia; Matloubian, Mehrdad; O’Halloran, Jane A.; Presti, Rachel M.; Wu, Gregory F.; Whelan, Sean P.J.; Buchser, William J.; Gensler, Lianne S.; Nakamura, Mary C.; Ellebedy, Ali H.; Kim, Alfred H.J.

BACKGROUND: Individuals 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. METHODS: We 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. RESULTS: Compared 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. CONCLUSIONS: CID 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.