Ethics
The study was approved by the ethics committee of the Christian-Albrecht University Kiel (D409/21). All patients signed informed consent. The study is registered at DRKS (DRKS00024214).
To the editor,
Recently, it has been demonstrated that the humoral immune response against SARS-CoV-2 is impaired in patients receiving drugs that inhibit tumor necrosis factor alpha (TNF) (1, 2). These agents, such as adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab, prevent activation of leukocytes, synoviocytes, endothelial cells, and osteoclasts (3) by binding either only TNF or both, TNF and Lymphotoxin-α (4).
Vaccinated anti-TNF patients showed a significantly reduced antibody response against Omicron variants BA.1 and BA.2 circulating in the first half of 2022 (5). Because of the continuous occurrence of SARS-CoV-2 variants that are only partially covered by vaccine-induced antibodies (6), the question arises whether patients on anti-TNF therapy in particular can mount an adequate humoral immune response. Recently, the first data on the effect of mRNA booster vaccination in patients receiving such immunomodulators were presented. These results are based on neutralization experiments with pseudotyped lentiviruses carrying the spike protein of SARS-CoV-2 wild type and Omicron BA.1 as well as BA.5; newer virus variants were not considered. In addition, the authors have not yet been able to investigate the effect of mRNA vaccines adapted to Omicron BA.4/5 (7). The case series presented here with data on serum neutralization of SARS-CoV-2 variants B.1.513, Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (BA.1.17.2, BA.2, BA.5 .2.1, BQ.1 .1.1, and XBB.1.5) in anti-TNF-treated patients who received an Omicron-matched booster vaccination will help fill these knowledge gaps. This report includes three patients with rheumatoid arthritis and one patient with polyarthritis, all receiving anti-TNF therapy and three healthy individuals. All subjects are females and received booster vaccination with a vaccine adapted to Omicron BA.4 and BA.5. Sera were collected and examined on the day of the fourth or fifth vaccination and 7 days later (Table 1). The assays and methods used are described in the Supplement.
Patients had lower SARS-CoV-2 IgG levels (Figure 1a) and generally lower virus neutralization titers (Figure 1b), whereas consistently high IgG avidity was measured (Table 1).
Against the pre-omicron variants B.1.513, Alpha and Delta, patients showed borderline neutralizing titers on the day of the booster dose, which increased 6- to 9-fold thereafter. In contrast to controls, some patient sera failed to neutralize Omicron variants BA.1.17.2, BA.2, BA.5.2.1, and BQ.1.1.1 with sufficient titer levels after booster vaccination (see also Supplementary Figure 1, which illustrates the marked immune escape of the different Omicron variants compared to the pre-Omicron strains). Strikingly, after booster vaccination, the recombinant XBB.1.5 variant could only be neutralized by serum from a healthy individual who had serologic evidence of prior SARS-CoV-2 infection.
According to this small case series, anti-TNF therapy may prevent patients from achieving neutralizing antibody titers against different Omicron variants, even after a booster dose. The results are consistent with the observation of Cheung et al. that at each time point, a significant proportion of anti-TNF patients had neutralizing titers against BA.1 and BA.5 that were at the lower limit of detection (7). The reduced B-cell response shown in previous SARS-CoV-2 and influenza immunization studies (1, 5, 8) is particularly evident in the present study. It is worth noting that all subjects received mRNA vaccines matched to Omicron variants BA.4/5. Although the mechanism by which anti-TNF drugs affect antibody formation remains unclear, experimental data suggest that B cell function is affected by the impairment of follicular dendritic cells and lymphoid germinal centers (9, 10).
Patients showed an up to an 11-fold increase in variant-specific neutralizing titer after booster vaccination, but this cannot be considered sufficient in every case.
From the results of the IgG antibody and IgG avidity assays, only limited conclusions can be drawn regarding current humoral anti-SARS CoV-2 immunity because the antigens used in these assays are related to the original Wuhan virus. In addition, this study does not address cellular immunity to SARS-CoV-2, which initial data suggest is also robust to Omicron in patients with immune-mediated inflammatory diseases (7).
In summary, present data indicate that only low virus-neutralizing titers against current SARS-CoV-2 variants can be induced, particularly in anti-TNF-treated patients, even after adapted booster vaccination. This small case series thus provides a rationale for seeking improved vaccines and vaccination regimens for this patient population. Furthermore, the results suggest that breakthrough infections may contribute to the development of broader immunity.
AUTHOR CONTRIBUTIONS
Ulf Martin Geisen, Jan Henrik Schirmer, Bimba Franziska Hoyer, Melike Sümbül, Florian Tran, Dennis Berner, Ann Carolin Longardt, Paula Hoff, and Sascha Gerdes: Patient recruitment and sampling; Ulf Martin Geisen, Mathias Voß, Ruben Rose, Franziska Neumann, Carina Bäumler, Sina Müller, Elena Hildebrand, Andi Krumbholz, and Bimba Hoyer: Antibody testing; Lea Paltzow, Christina Martínez Christophersen, Merle Münier, Ruben Rose, Mathias Voß, Andi Krumbholz: Recovery and characterization of SARS-CoV-2 isolates; Ulf Martin Geisen, Helmut Fickenscher, Andi Krumbholz, and Bimba Hoyer: Conceptualization of the study and writing of the draft manuscript; Ulf Martin Geisen, Mathias Voß, Ruben Rose, and Franziska Neumann: Analysis and presentation of the results; Thomas Lorentz, Helmut Fickenscher, Stefan Schreiber, and Bimba Hoyer: Provision of technical resources; All authors: review of the final manuscript.