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. 2021 Dec 10;2(12):1327-1341.e4.
doi: 10.1016/j.medj.2021.11.004. Epub 2021 Nov 18.

Reduced antibody activity against SARS-CoV-2 B.1.617.2 delta virus in serum of mRNA-vaccinated individuals receiving tumor necrosis factor-α inhibitors

Rita E Chen  1   2 , Matthew J Gorman  3 , Daniel Y Zhu  4 , Juan Manuel Carreño  5 , Dansu Yuan  3 , Laura A VanBlargan  1 , Samantha Burdess  1 , Douglas A Lauffenburger  4 , Wooseob Kim  2 , Jackson S Turner  2 , Lindsay Droit  2 , Scott A Handley  2 , Salim Chahin  6 , Parakkal Deepak  1 , Jane A O'Halloran  1 , Michael A Paley  1 , Rachel M Presti  1   7   8 , Gregory F Wu  6 , Florian Krammer  5 , Galit Alter  3 , Ali H Ellebedy  2   7   8 , Alfred H J Kim  1   7 , Michael S Diamond  1   2   7   8   9
Affiliations

Reduced antibody activity against SARS-CoV-2 B.1.617.2 delta virus in serum of mRNA-vaccinated individuals receiving tumor necrosis factor-α inhibitors

Rita E Chen et al. Med. .

Abstract

Background: Although vaccines effectively prevent coronavirus disease 2019 (COVID-19) in healthy individuals, they appear to be less immunogenic in individuals with chronic inflammatory disease (CID) or receiving chronic immunosuppression therapy.

Methods: Here we assessed a cohort of 77 individuals with CID treated as monotherapy with chronic immunosuppressive drugs for antibody responses in serum against historical and variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses after immunization with the BNT162b2 mRNA vaccine.

Findings: Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with tumor necrosis factor alpha (TNF-α) inhibitors (TNFi), and this pattern appeared to be worse against the B.1.617.2 delta virus. Within 5 months of vaccination, serum neutralizing titers of all TNFi-treated individuals tested fell below the presumed threshold correlate for antibody-mediated protection. However, TNFi-treated individuals receiving a third mRNA vaccine dose boosted their serum neutralizing antibody titers by more than 16-fold.

Conclusions: Vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) will likely be required to prevent SARS-CoV-2 infection in this susceptible population.

Funding: This study was supported by grants and contracts from the NIH (R01 AI157155, R01AI151178, and HHSN75N93019C00074; NIAID Centers of Excellence for Influenza Research and Response (CEIRR) contracts HHSN272201400008C and 75N93021C00014; and Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051).

Keywords: Fc effector functions; SARS-CoV-2; TNF inhibitors; antibody; immunosuppression; mRNA vaccine; neutralization; variants of concern.

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Conflict of interest statement

M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, and Emergent BioSolutions. F.K. is a coinventor on a patent application for serological assays and SARS-CoV-2 vaccines (international application numbers PCT/US2021/31110 and 62/994,252). A.H.J.K. participated in consulting, advisory board, or speaker’s bureau for Alexion Pharmaceuticals; Aurinia Pharmaceuticals; Exagen Diagnostics, Inc.; and GlaxoSmithKline and received unrelated funding support under a sponsored research agreement from GlaxoSmithKline. The Ellebedy laboratory received funding under sponsored research agreements that are unrelated to current study from Emergent BioSolutions and AbbVie. A.H.E. is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting LLC. A.H.E., M.S.D., and J.S.T. are recipients of a licensing agreement with Abbvie Inc. for commercial development of a SARS-CoV-2 mAb not described in this study. J.S.T. is a consultant for Gerson Lehrman Group. S.C. received research funding from Biogen and received speaking and/or consulting fees from Biogen, Novartis, Sanofi Genzyme, Genentech, and Bristol Myers Squibb. P.D. has participated in consulting, advisory board, or speaker’s bureau for Janssen, Pfizer, Prometheus Biosciences, Boehringer Ingelheim, AbbVie, and Arena Pharmaceuticals and received funding under an unrelated sponsored research agreement from Takeda Pharmaceutical, Arena Pharmaceuticals, Bristol Myers Squibb-Celgene, and Boehringer Ingelheim. G.F.W. has received honoraria for consulting from Novartis and Genentech, Inc. and research funding from Biogen, EMD Serono, and Roche. F.K. has consulted for Merck, Curevac, and Pfizer in the past and is currently consulting for Pfizer, Seqirus, and Avimex. The Krammer laboratory is collaborating with Pfizer on animal models of SARS-CoV-2. G.A. is the founder of SeromYx Systems Inc. and an equity holder of Leyden Labs.

Figures

None
Graphical abstract
Figure 1
Figure 1
Serum IgG titers against SARS-CoV-2 variant spike proteins 3 months after the second vaccination (A–G) Analyses of spike-specific endpoint IgG serum titers measured by ELISA from humans 3 months after the second vaccination with the BNT162b2 mRNA vaccine. Individuals were grouped as (A) immunocompetent volunteers (n = 25) and (B) individuals with CID (n = 45) or subdivided by immunosuppressive drug class: (C) TNFi (n = 8), (D) antimetabolites (n = 7), (E) antimalarials (n = 5), (F) anti-integrin inhibitors (n = 5), or (G) non-steroidal anti-inflammatory drugs (NSAIDs) (n = 4). Geometric mean titer (GMT) values are shown on the graph. The dotted line represents the limit of detection of the assay. One-way ANOVA with Dunnett’s post-test; ∗p < 0.05, ∗∗∗∗p < 0.0001. (H) Heatmap of GMT values relative to healthy volunteer GMT values for each SARS-CoV-2 spike protein. Blue, reduction; red, increase.
Figure 2
Figure 2
Serum NT50 against SARS-CoV-2 variant viruses 3 months after the second vaccination (A–H) Paired analyses of neutralization titers (NT50) in serum measured by focus reduction neutralization test (FRNT) against fully infectious SARS-CoV-2 strains 3 months after the second vaccination with the BNT162b2 mRNA vaccine. Individuals were grouped as (A) immunocompetent volunteers (n = 25) and (B) individuals with CID (n = 75) or subdivided by immunosuppressive drug class: (C) antimetabolites (n = 12), (D) TNFi (n = 12), (E) antimalarials (n = 8), (F) anti-integrin inhibitors (n = 9), (G) NSAIDs (n = 9), or (H) anti-IL-23 inhibitors (n = 9). GMT values are shown on the graph. The dotted line represents the limit of detection of the assay. One-way ANOVA with Dunn’s post-test; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. (I) Heatmap of GMT values relative to healthy volunteer GMT values for each SARS-CoV-2 spike protein. Blue, reduction; red, increase.
Figure 3
Figure 3
Effector functions against SARS-CoV-2 variant viruses 3 months after the second vaccination (A–D) Serum from humans 3 months after the second vaccination with the BNT162b2 mRNA vaccine were assayed for (A and B) total IgG, IgG subclasses (IgG1, IgG2, IgG3, IgG4, and IgM), and C1q binding or (C and D) antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent complement deposition (ADCD), or FcγR (FcγR2A, FcγR2B, or FcγR3A) binding as measured by Luminex. Reponses were measured against (A and C) Wuhan-1 D614G or (B and D) B.1.617.2. Individuals were grouped as immunocompetent volunteers (n = 25) or subdivided by immunosuppressive drug class: TNFi (n = 8), antimetabolites (n = 7), antimalarials (n = 6), or anti-integrin inhibitors (n = 5). One-way ANOVA with Dunnett’s post-test; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. (E) Composite polar plots depicting shifted Z score only median of antibody titer, FcγR binding, and antibody function against Wuhan-1 D614G, B.1.351, and B.1.617.2 for each group.
Figure 4
Figure 4
Serum NT50 of individuals with CID against SARS-CoV-2 variant viruses 5 months after the second vaccination (A–H) Paired analyses of NT50 in serum measured by FRNT against fully infectious SARS-CoV-2 strains from humans 5 months (individuals with CID) or 6 months (immunocompetent volunteers) after the second vaccination with the BNT162b2 mRNA vaccine; different time points were used based on variability of the separate study designs and availability of samples. Individuals were grouped as (A) immunocompetent volunteers (n = 24) or (B) individuals with CID (n = 43) or subdivided by immunosuppressive drug class: (C) antimetabolites (n = 5), (D) TNFi (n = 7), (E) antimalarials (n = 7), (F) anti-integrin inhibitors (n = 3), (G) NSAIDs (n = 5), (H) anti-IL-23 inhibitors (n = 3), or (I) B cell depletion therapy (BCDT) (n = 3). GMT values are shown on the graph. The dotted line represents the limit of detection of the assay. One-way ANOVA with Dunn’s post-test; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. (J) Heatmap of GMT values relative to healthy volunteer GMT values for each SARS-CoV-2 spike protein. Blue, reduction; red, increase.
Figure 5
Figure 5
Serum NT50 of individuals with CID receiving TNFi 1 month after receiving a third dose of the BNT162b2 mRNA vaccine (A–C) Paired analyses of NT50 in serum measured by FRNT against fully infectious SARS-CoV-2 strains (A) WA1/2020, (B) Wash-B.1.351, and (C) B.1.617.2 from humans 5 months after the second dose or 1 month after the third dose of the BNT162b2 mRNA vaccine. None of the individuals held TNFi medication at the time of third dose administration. GMT values are shown on the graph. The dotted line represents the limit of detection of the assay. Paired t test; ∗p < 0.05, ∗∗p < 0.01.
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