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1.
Gastroenterology ; 162(7):S-278, 2022.
Article in English | EMBASE | ID: covidwho-1967264

ABSTRACT

Introduction: More adverse clinical outcomes following SARS-CoV-2 infection are reported in patients treated with infliximab/thiopurines (IFX/THIO), compared with biological monotherapy with anti-TNF or vedolizumab (VDZ). VDZ has been associated with a heightened and more durable serological response after infection and vaccination, compared to IFX. However, whether IBD patients on VDZ have a fully intact systemic response to SARS- CoV2 remains unknown. We explored the serological and functional neutralizing response after SARS-CoV-2 infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to true healthy controls to guide treatment decisions and vaccination strategies. Methods: Serum from 640 IBD patients attending routine infusions in Oxford and London (May to December 2020) was screened by the Abbott assay for SARS-CoV-2 nucleocapsid (N) antibodies. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type (WT) strain receptor-binding domain (RBD), full-length spike, and N was assayed by IgG/IgA ELISA over time as well as by IgG MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralizing antibodies to the WT, and an ELISA-based inhibition assay to compare differential inhibition of the WT vs. delta variant (DV) SARS-CoV-2 RBD-ACE2 interaction. Results: All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls to all SARS-CoV-2 antigens, using MSD V-PLEX (Figure 1A-C). The greatest reduction in IgG response by ELISA was observed in patients treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ group. The rate of decline in these monotherapy groups was not significantly different to healthy controls. Compared to healthy controls, functional SARS-CoV-2 neutralization was reduced in each treatment group (Figure 1D), with the greatest effect in patients receiving IFX/THIO (p=0.00000091). Neutralizing capacity to the DV was significantly reduced in 68.1% of IBD patients (30/44, p=0.0005). Conclusion: Both IFX and VDZ are associated with significantly reduced IgG responses to multiple SARS-CoV-2 antigens, and with impaired functional SARS-CoV-2 neutralizing antibody capacity, compared to healthy individuals. However, whilst IgG and neutralization responses are reduced in IBD patients on biological monotherapy, these findings were most pronounced in the combination treatment group. As neutralizing antibody responses are associated with protection, these observations may impact on decision-making regarding treatment and vaccination strategies.(Table Presented)(Figure Presented)

2.
Journal of Crohn's and Colitis ; 16:i069-i070, 2022.
Article in English | EMBASE | ID: covidwho-1722298

ABSTRACT

Background: Recent data have highlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/ THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies. Methods: Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction. Results: All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A;p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B;p=0.0005). Conclusion: IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.

3.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326575

ABSTRACT

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNgamma based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

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