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.