Background: The SARS-CoV-2 virus mutates continuously, posing challenges for patients with immune-mediated inflammatory diseases (IMIDs) on tumour necrosis factor inhibitors (TNFi). These patients often have diminished vaccine responses and are at a higher risk for severe infections. The efficacy of the recommended mono- and bivalent vaccine boosters in this patient population remains unclear.

Objectives: To assess the neutralizing capacity and serologic responses to SARS-CoV-2 in TNFi-treated IMID patients, after receiving a monovalent 4 ^th vaccine dose and a bivalent 5 ^th vaccine dose, including those with hybrid immunity.

Methods: These analyses from the ongoing observational Nor-vaC study included TNFi-treated IMID patients who received either a 5 ^th vaccine dose or experienced SARS-CoV-2 infection following a 4 ^th vaccine dose (hybrid immunity). Blood samples were collected 2-4 weeks after the 4 ^th monovalent vaccine dose and after either subsequent COVID-19 or a 5 ^th bivalent dose (BA.1 or BA.4/5). Neutralizing antibody titres against three viral variants (Wuhan (WT), Omicron BA.1, and Omicron BA.4), and IgG anti-spike antibody levels, were analysed. Group comparisons were performed with Mann Whitney U test, and Spearman correlation.

Results: From Dec 17, 2021, to Jun 20, 2023, 371 IMID patients (86 rheumatoid arthritis, 72 psoriatic arthritis, 95 spondyloarthritis, 75 Crohn’s disease, 43 ulcerative colitis) on TNFi either received a 4 ^th and a 5 ^th vaccine dose or had a SARS-CoV-2 infection after the 4 ^th vaccine dose. (Table 1) In infection-naïve patients, a 5 ^th BA.4/5 vaccine increased neutralizing antibody titres against all viral variants tested (WT, BA.1 and BA.4), compared to post-4 ^th dose levels (WT: median 640, IQR (80-1280) vs median 160, IQR (80-320) p=0.0096, BA.1: 160, IQR (40-640) vs 40, IQR (20-80) p=0.0014, BA.4: 640, IQR (80-2560) vs 80, IQR (30-160) p<0.0001)). (Figure 1A). Hybrid immunity increased neutralizing antibody titres against all tested variants compared to a 4 ^th vaccine dose (WT: median 640, IQR (320-2560), p<0.0001), BA1: median 640, IQR (320-800), p<0.0001, BA4: median 1280, IQR (640-2560) p<0.0001) and 5 ^th vaccine dose with BA.1 (WT: median 160, IQR (80-640) p<0.0001, BA1: median 80, IQR (40-640) p<0.0001, BA4: median 120, IQR (35-640) p<0.0001). In infection naïve patients, a 5 ^th BA.4/5 vaccine gave higher neutralizing antibody responses against BA.4 than a 5 ^th BA.1 vaccine (p=0.006) and comparable to that after hybrid immunity (p=0.21). There was no difference in neutralizing antibody titres between patients receiving TNFi in mono- or combination therapy (WT: p=0.64, BA.1: p=0.77, BA.4/5: p=0.83). Neutralizing antibody titres against WT variant were strongly correlated to anti-spike antibody levels following all immunisations (4 ^th monovalent (r=0.86, p<0.0001), the 5 ^th BA.1 (r=0.72, p<0.0001), the 5 ^th BA.4/5 (r=0.49, p<0.0001)), as well as the hybrid group (r=0.44, p<0.0001). Patients with hybrid immunity had a higher median anti-spike antibody level (23159 IU/ml, IQR (14587-44529), than did infection naïve patients receiving the 5 ^th dose BA.1 vaccine (10095 IU/ml (IQR 5261-30.095), p=0.0009), but comparable to levels after a BA.4/5 vaccine dose (17450 IU/ml (IQR 6705-57767), p=0.16). (Figure 1B)

Conclusion: Our findings highlight the effectiveness of updated, targeted vaccines as booster doses for IMID patients on TNFi, in terms of neutralizing and anti-spike antibody responses. Infection-naïve patients benefit most from updated vaccines, providing a humoral response comparable to that following SARS-CoV-2 infection.

Table 1. Patient characteristics.

Figure 1.

Serology results showing neutralizing antibody titers (A) and anti-spike antibody levels (B) in infection-naïve patients following a 4th monovalent and a 5th bivalent vaccine dose (BA.1 vs BA4/5), as well as in patients with hybrid immunity post-infection following a 4th vaccine dose (4th hybrid). Statistical significance is denoted by * (p<0.05), **, (p<0.01), *** (p<0.001), and **** (p<0.0001).

REFERENCES: NIL.

Acknowledgements: We thank the patients who have participated in the Nor-vaC study. We are grateful for the time and effort they have invested in the project. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. Many people have contributed to the study design and implementation of the study at The Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet hospital, and Oslo University Hospital. We thank all study personnel, laboratory personnel, and other staff at the clinical departments involved.

Disclosure of Interests: Hilde S. Ørbo: None declared, Taissa M. Kasahara: None declared, Asia-Sophia Wolf: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Joe Sexton: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Guri Solum: None declared, Ingrid Fadum Kjønstad: None declared, Andreas Lind: None declared, Veselka P. Dimova-Svetoslavova: None declared, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Jørgen Jahnsen AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, AbbVie/Abbott, Pfizer, Espen A. Haavardsholm Pfizer, UCB, Novartis, Abbvie, Pfizer, Eli Lilly, Ludvig A. Munthe Incyte, Janssen, Sella Aarrestad Provan: None declared, John Torgils Vaage: None declared, Siri Mjaaland: None declared, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Gunnveig Grødeland Bayer, Sanofi, ThermoFisher, Pfizer, Vitusapotek, GSK, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.