Background: Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. Methods: This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks following vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor binding domain (anti-RBD) antibodies. Findings: Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 21 healthy controls were included. In both IBD and arthritis patients, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p=0·008) after three SARS-CoV-2 vaccine doses. IBD patients had a comparable quantity (median CD4 0·11% vs. 0·11%, p=0·26, CD8 0·031% vs. 0·047%, p=0·33) and quality (polyfunctionality score: 0·403 vs. 0·371, p=0·39; 0·105 vs. 0·101, p=0·87) of spike-specific T cells to healthy controls. Arthritis patients had lower frequency, but comparable quality, of responding T cells to controls and IBD patients. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation: IBD patients on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality and breadth of T cell responses. Our results indicate that IBD patients on TNFi treatment may follow the same COVID-19 vaccine recommendations as the healthy population in future. Funding: South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.Declaration of Interest: KHB reports funding from Akershus University Hospital and speaker bureaus for Janssen-Cilag. TKK reports grants from AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, speakers’ bureaus from Grünenthal, Janssen, Sandoz, consultant fees from AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, and participation on advisory board for AbbVie. JJ reports grants from Boehringer-Ingelheim, speakers bureaus from AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, consultant fees from AbbVie/Abbott, Pfizer, and participation in advisory board for AbbVie/Abbott, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda. LAM reports funding from KG Jebsen foundation, support for infrastructure and biobanking from the university of Oslo and Oslo University Hospital, grants from the Coalition of Epidemic Preparedness Innovations (CEPI), speakers bureaus from Incyte, Janssen, and expert testimony for Norwegian Medicines Agency. EAH reports speakers’ bureaus from Pfizer, UCB, Novartis, and consulting fees from Abbvie, Pfizer, Eli Lilly. GG reports speaker bureaus from AbbVie/Abbott, Galapagos, Pfizer, UCB, participation in advisory board from AstraZeneca, Janssen, Moderna, Seqirus. and consulting fees from The Norwegian System of Patient Injury Compensation. JTV reports grant from CEPI. FLJ reports funding from South-East Health Authorities in Norway, CEPI and Oslo University Hospital. GLG reports speakers’ bureaus from AbbVie/Abbott, Galapagos, Pfizer, UCB, and participation in advisory board from AbbVie/Abbott, Galapagos, Pfizer, UCB, Novartis. KKJ reports speakers’ bureaus from Bristol-Myers Squibb and Janssen, and participation in advisory board for AstraZeneca and IPSEN. SWS reports participation in advisory board for AstraZeneca. ASW, HSØ, SB, GS, IFK, IJ, UCN, ABK, IEC, SEJ, KPL, AC, ATT, JS, SAP, HK, and SM report nothing to disclose.Ethical Approval: The study was approved by the Norwegian Regional Committees for Medical and Health Research Ethics (reference numbers 235424 and 135924). Written informed consent was obtained from all the patients.
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 4th vaccine dose and a bivalent 5th 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 5th vaccine dose or experienced SARS-CoV-2 infection following a 4th vaccine dose (hybrid immunity). Blood samples were collected 2-4 weeks after the 4th monovalent vaccine dose and after either subsequent COVID-19 or a 5th 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 4th and a 5th vaccine dose or had a SARS-CoV-2 infection after the 4th vaccine dose. (Table 1) In infection-naïve patients, a 5th BA.4/5 vaccine increased neutralizing antibody titres against all viral variants tested (WT, BA.1 and BA.4), compared to post-4th 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 4th 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 5th 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 5th BA.4/5 vaccine gave higher neutralizing antibody responses against BA.4 than a 5th 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 (4th monovalent (r=0.86, p<0.0001), the 5th BA.1 (r=0.72, p<0.0001), the 5th 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 5th 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.
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.
Patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapies are known to be at greater risk of severe COVID-19 disease, hospitalisation and death. Protective levels of anti-Spike antibodies following vaccination are yet to be determined.
Objectives
To examine whether post-vaccination anti-Spike antibody levels were predictive of breakthrough infection and the clinical outcome of COVID-19.
Methods
The Nor-vaC study is a prospective cohort study that includes IMID patients on immunosuppressive therapies[1]. In the present analyses we included patients who provided post-vaccination samples and responded to follow-up questionnaires after three vaccine doses. Hospital records and the Norwegian Death Cause Registry provided information on hospital admissions and cause of death. Anti-Spike antibody levels were measured 2 – 4 weeks after vaccination. Analyses were performed using a cox-regression with time running from two weeks post 3rd vaccine dose until COVID-19 or a 4th vaccine dose, adjusting for age, sex, diagnosis, medication and comorbidity, with calendar month as a time varying covariate.
Results
A total of 1051 IMID patients (375 rheumatoid arthritis (RA), 148 psoriatic arthritis (PsA), 155 spondyloarthritis (SpA), 215 Crohn's disease (CD), 158 ulcerative colitis (UC)) on immunosuppressive therapies were included in these analyses, median age 56 (IQR 43 – 65), and 586 (56%) female, with an observation period spanning from July 7th 2021 to December 14th 2022. Patients had received either BNT162b2 (61%) or mRNA-1273 (39%) as a 3rd dose. Immunosuppressive medication included TNF inhibitors (TNFi) monoa- (41%) or combination therapyb (23%), methotrexate (16%), interleukin (IL) inhibitorsc (5%), janus kinase (JAK) inhibitorsd (3%), vedolizumab (5%) and other medicatione(2%). During the observation period 265 patients (25%) were registered with COVID-19 after the 3rd vaccine dose. In total, 24 patients had COVID-19 before the Omicron variant became predominant in Norway (1st January 2022). Symptoms of COVID-19 for more than two weeks were reported by 53 patients (20 %). One patient was hospitalised, and no patients died due to COVID-19 during the observation period. A post-vaccination antibody level above 12.000 BAU/ml gave a reduced risk of clinical COVID-19 infection (hazard ratio (HR) 0.56, p=0.007, 95% CI (0.36, 0.85) (Figure 1). Antibody levels above this cut-off were found in 10 % of patients. The presence of comorbidities (HR 1.85, p = 0.001, 95% CI (1.27,2.70)) or UC (HR 1.6, p= 0.001, 95 %CI (1.11, 2.35) increased the risk of breakthrough infections. Post-vaccination anti-Spike antibody levels were not associated with duration of COVID-19 over two weeks.
Conclusion
Patients with the highest post-vaccination anti-Spike levels had a lower risk of COVID-19 infection, supporting the role of repeated vaccination in IMID patients on immunosuppressive therapies. These results also underline the good prognosis of Omicron infections in vaccinated IMID patients. Though patients knowing they had low anti-Spike levels may have shielded during periods of high transmission, the absence of severe infections and deaths in this large cohort indicates that low antibody levels did not greatly increase risk of severe COVID-19. aTNF inhibitors: infliximab, etanercept, adalimumab, golimumab, certolizumab pegol. bCombination therapy: methotrexate, sulfasalazine, leflunomide, azathioprine. cIL-inhibitors: tocilizumab, secukinumab. dJAK-inhibitors: filgotinib, baricitinib, upadacitinib, tofacitinib. eOther: abatacept, sulfasalazine, leflunomide, azathioprine.
Reference
[1]Syversen S.W et al Arthritis Rheumatol. 2022
Acknowledgements
We thank the patients and health-care workers who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff involved at the clinical departments involved, particularly Synnøve Aure, Margareth Sveinsson, May Britt Solem, Elisabeth Røssum-Haaland, and Kjetil Bergsmark.
Disclosure of Interests
Hilde Ørbo: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Janssen-Cilag, Joseph Sexton: None declared, Anne Therese Tveter: None declared, Ingrid Jyssum: None declared, Ingrid E. Christensen: None declared, Grete B. Kro: None declared, Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi, ThermoFisher, Consultant of: AstraZeneca, Siri Mjaaland: None declared, John Torgils Vaage: None declared, Kristin Kaasen Jørgensen Speakers bureau: Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott, Galapagos, Pfizer, UCB, Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.
Patients on immunosuppressive therapies have diminished humoral vaccine responses to SARS-CoV-2 vaccines. Cellular immunity is crucial for long-term protection against severe COVID-19. Interferon gamma release assay (IGRA) SARS-CoV-2 tests are now commercially available for evaluation of cellular responses in clinical practice. Knowledge on the durability of T cell responses is important to plan further booster doses.
Objectives:
To evaluate durability of cellular and humoral responses following a 5th vaccine dose.
Methods:
The observational, prospective Nor-VaC study examines vaccine responses in patients with inflammatory joint diseases on immunosuppressive therapies. The present analyses include a subgroup of patients eligible for a 5th vaccine dose with samples available for analyses. CD4, plus combined CD4 and CD8 T-cell responses (CD4;CD8), were determined by interferon gamma release assay (IGRA) Elecsys QuantiFERON SARS-CoV-2, along with spike IgG antibodies measured by Elecsys Anti-SARS-CoV 2 S immunoassay (Roche), prior to and 2-4 weeks and 6 months following the 5th dose. T-cell responses were defined as negative (<0.030 IU/mL), uncertain (0.030-0.050 IU/mL) or positive (>0.050 IU/mL). Serologic poor responders were defined by response <2000 IU/mL. SARS-CoV-2 infections were defined as a positive PCR or antigen test, self-reported by patients.
Results:
Between Nov 10, 2022, and Apr 19, 2023, a total of 63 patients (37 rheumatoid arthritis, 15 psoriatic arthritis, 11 spondyloarthritis) using TNFia (n=28), methotrexate (n=20) or other DMARDb (n=15), median age 63 (IQR 55-69), 65 % female, were included. Patients received a 5th bivalent BA.1 (13%) or BA.4/5 (79%) vaccine dose. Five patients were lost to follow-up after the pre-vaccination sample. 2-4 weeks after the 5th dose, there was an increase in both CD4 (p=0.001) and CD4;CD8 T cell activity (p=0.002) compared to prior 5th dose (Table 1, Figure 1), with subsequent waning in activity after 6 months for both CD4 (p=0.006) and CD4;CD8 (p=0.044). (Table 1, Figure 1) Prior to the 5th vaccine dose vs 2-4 weeks post-vaccination, 18% (10/57) vs 9% (5/57) had negative CD4-responses, and 9 % (5/57) vs 4% (2/56) had negative CD4;CD8 T cell responses. In comparison, 6 months post-vaccination 4% (2/52) had negative CD4 and 2% (1/52) had negative CD4;CD8 T cell responses. This reduction of patients with negative CD4 and CD4;CD8 T cell responses after six months may be attributed to undergoing SARS-CoV-2 infection prior to the 6-month sample. Overall, 6 patients (10%) reported a SARS-CoV-2 infection between the 5th vaccine dose and the 6-month sample. In addition, subclinical infections may have occurred. Anti-spike antibody levels increased 2-4 weeks post- vs pre-vaccination, p=0.002, with a decrease at 6 months compared to 2-4 weeks post-vaccination (p=0.003). (Table 1) Among the serologic poor responders (n=7), two had negative CD4 responses following a 5th vaccine dose, but all showed positive or intermediate CD4;CD8 responses.
Conclusion:
Despite a decline in both cellular and humoral immunity over the observation period, most patients had detectable T cell activity and high antibody levels six months after receiving a 5th vaccine dose of the updated SARS-CoV-2 vaccine. Individualised testing of cellular immunity in patients with poor serologic responses to vaccines could be valuable to determine timing of future vaccine boosters. Table 1. Cellular and humoral immune responses pre-, 2-4 weeks- and 6 months post-vaccination. a Tumour necrosis factor inhibitors in mono- or combination therapy b Rituximab, interleukin inhibitors, janus kinase inhibitors, abatacept
REFERENCES:
NIL.
Acknowledgements:
We thank the patients who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff at the clinical departments involved, particularly Margareth Sveinsson, May Britt Solem, and Kjetil Bergsmark.
Disclosure of Interests:
Hilde S. Ørbo: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Andreas Lind: None declared, Veselka P. Dimova-Svetoslavova: None declared, Ingrid E. Christensen: None declared, Joe Sexton: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Espen A. Haavardsholm Pfizer, UCB, Novartis, Abbvie, Pfizer, Eli Lilly, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.
Patients with inflammatory joint diseases on immunosuppressive therapies are vulnerable to severe COVID-19 and are recommended to receive targeted vaccine boosters. Since these patients were excluded from phase 3 vaccine trials, it is important to evaluate safety of the updated XBB.1.5 vaccine as a 3rd booster dose in this patient group. Knowledge on the frequency of vaccine side effects is also helpful to inform patients and alleviate vaccine hesitancy.
Objectives:
To compare the safety of a booster dose with the updated monovalent XBB.1.5 vaccine to that of the previous bivalent vaccine type (BA.1/BA.4/5).
Methods:
The present analyses included patients with inflammatory joint diseases participating in the observational prospective Nor-vaC study [1,2], who received six vaccine doses while using immunosuppressive therapies. Patients received vaccines according to the national Norwegian vaccination program. After primary vaccination with three doses and a first booster dose, the further 2nd booster was bivalent (BA.1/BA.4/5) and the 3rd booster was monovalent (XBB.1.5). Data on adverse events within two weeks from vaccination were self-reported through questionnaires. The safety data following the 2nd bivalent and the 3rd monovalent booster were compared with Fisher's exact test.
Results:
Between September 14th 2022 and December 21th 2023 a total of 371 arthritis patients (192 rheumatoid arthritis, 100 psoriatic arthritis, 79 spondyloarthritis) on immunosuppressive therapy (Table 1) received a 2nd and a 3rd booster dose. In total, 239/371 (64%) of patients responded to questionnaires asking for adverse events within two weeks following the 2nd booster, and 141/371 (38%) following the 3rd booster dose. A total of 47/239 (20%) vs 17/141 (12 %) reported any adverse event after a 2nd booster dose (bivalent), compared to the 3rd booster (monovalent) (p=0.07). The most frequent adverse events following the 3rd booster were pain at injection site (5%, n=7), fever (4%, n=6) and flu-like symptoms (4%, n=6). However, these adverse events were less frequent compared to after the 2nd booster (pain at injection site (13 %, n=30, p=0.02), fever (5 %, n=11, p=1.00) and flu-like symptoms (10 %, n=23, p=0.07)). In total (4 %, n=6) of patients reported a disease flare after receiving the 3rd, monovalent booster, compared to (6 %, n=14) after the 2nd, bivalent booster (p=0.63). No new safety signals emerged.
Conclusion:
There were less adverse events overall following the monovalent, 3rd booster, compared to the bivalent, 2nd booster, although not significant, indicating that the XBB.1.5 vaccine is safe in patients with inflammatory joint diseases.
REFERENCES:
[1] Syversen S.W. et al Arthritis Rheumatol 2022. [2] Bjørlykke K.H. et al Lancet Rheumatol 2022.
Acknowledgements:
We thank the patients who have participated in the Norwegian study of vaccine responses to COVID-19, and the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff at the clinical departments involved.
Disclosure of Interests:
Hilde S. Ørbo: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Ingrid E. Christensen: None declared, Joe Sexton: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Espen A. Haavardsholm Pfizer, UCB, Novartis, Abbvie, Pfizer, Eli Lilly, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.
Objectives To assess incidence, severity and predictors of COVID-19, including protective post-vaccination levels of antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD), informing further vaccine strategies for patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive medication. Methods IMIDs on immunosuppressives and healthy controls (HC) receiving SARS-CoV-2 vaccines were included in this prospective observational study. COVID-19 and outcome were registered and anti-RBD antibodies measured 2–5 weeks post-immunisation. Results Between 15 February 2021 and 15 February 2023, 1729 IMIDs and 350 HC provided blood samples and self-reported COVID-19. The incidence of COVID-19 was 66% in patients and 67% in HC, with re-infection occurring in 12% of patients. Severe COVID-19 was recorded in 22 (2%) patients and no HC. No COVID-19-related deaths occurred. Vaccine-induced immunity gave higher risk of COVID-19 (HR 5.89 (95% CI 4.45 to 7.80)) than hybrid immunity. Post-immunisation anti-RBD levels <6000 binding antibody units/mL were associated with an increased risk of COVID-19 following three (HR 1.37 (95% CI 1.08 to 1.74)) and four doses (HR 1.28 (95% CI 1.02 to 1.62)), and of COVID-19 re-infection (HR 4.47 (95% CI 1.87 to 10.67)). Conclusion Vaccinated patients with IMID have a low risk of severe COVID-19. Hybrid immunity lowers the risk of infection. High post-immunisation anti-RBD levels protect against COVID-19. These results suggest that knowledge on COVID-19 history, and assessment of antibody levels post-immunisation can help individualise vaccination programme series in high-risk individuals. Trial registration number NCT04798625 .
Background SARS-CoV-2 vaccination in rheumatoid arthritis (RA) patients treated with B cell-depleting drugs induced limited seroconversion but robust cellular response. We aimed to document specific T and B cell immunity in response to vaccine booster doses and breakthrough infection (BTI). Methods We included 76 RA patients treated with rituximab who received up to four SARS-CoV-2 vaccine doses or three doses plus BTI, in addition to vaccinated healthy donors (HD) and control patients treated with tumor necrosis factor inhibitor (TNFi). We quantified anti-SARS-CoV-2 receptor-binding domain (RBD) Spike IgG, anti-nucleocapsid (NC) IgG, 92 circulating inflammatory proteins, Spike-binding B cells, and Spike-specific T cells along with comprehensive high-dimensional phenotyping and functional assays. Findings The time since the last rituximab infusion, persistent inflammation, and age were associated with the anti-SARS-CoV-2 RBD IgG seroconversion. The vaccine-elicited serological response was accompanied by an incomplete induction of peripheral Spike-specific memory B cells but occurred independently of T cell responses. Vaccine- and BTI-elicited cellular immunity was similar between RA and HD ex vivo in terms of frequency or phenotype of Spike-specific cytotoxic T cells and in vitro in terms of the functionality and differentiation profile of Spike-specific T cells. Interpretation SARS-CoV-2 vaccination in RA can induce persistent effector T-cell responses that are reactivated by BTI. Paused rituximab medication allowed serological responses after a booster dose (D4), especially in RA with lower inflammation, enabling efficient humoral and cellular immunity after BTI, and contributed overall to the development of potential durable immunity.
Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapies have attenuated humoral vaccine responses and are prone to more severe infections. Assessing the persistence of cellular and humoral immunity following repeated SARS-CoV-2 vaccine doses and infection is important to evaluate the need for booster vaccine doses.
Objectives:
To assess the cellular and humoral responses to 4th (original) and 5th (updated BA.1 or BA.4/5) SARS-CoV-2 vaccine doses and to COVID-19 following a 4th vaccine dose (hybrid immunity) in IMID patients on tumour necrosis factor inhibitors (TNFi).
Methods:
The ongoing observational Nor-vaC study includes IMID patients receiving multiple SARS-CoV-2 vaccines. In the present analyses, patients using TNFi who were eligible for a 5th vaccine dose and/or undergoing COVID-19 following a 4th vaccine dose, provided serum and peripheral blood mononuclear cells (PBMCs) 2-4 weeks and 4-11 months following infection, and before, 2-4 weeks, and 6 months after their 5th vaccination. CD4 and CD8 T cell responses to SARS-CoV-2 spike, nucleocapsid and membrane peptides, and also IgG anti-spike antibodies, were analysed. T cell responses were measured by flow cytometry (≥0.01% increase in responding CD4 or CD8 cells compared to unstimulated cells).
Results:
Between December 17th, 2021, and June 20th, 2023, 394 IMID patients (86 rheumatoid arthritis, 72 psoriatic arthritis, 97 spondyloarthritis, 86 Crohn's disease, 53 ulcerative colitis) on TNFi received a 4th and 5th vaccine dose, and/or had COVID-19 following a 4th vaccine dose. (Table 1). Infection induced a small increase in spike-specific CD4 T cell responses in individuals who had already received a 4th dose (median (IQR) frequencies); four vaccine doses vs. hybrid immunity, 0.068% (0.034-0.16) vs. 0.11% (0.080-0.17), p=0.048). CD4 T cell responses after hybrid immunity waned over 4-11 months (0.035% (0.026-0.072), (hybrid immunity at 2-4 weeks vs. 4-11 months, p=0.0008). CD8 T cell responses following 4th vaccine dose (0.040 % (0.010-0.14) remained stable after infection (0.054% (0.025-0.17) p=0.57), and also in the next 4-11 months (0.038% (0.013-0.17) p=0.63). (Figure 1) A 5th vaccine dose restored CD4 T cell responses to the level seen 2-4 weeks after infection (0.089% (0.046-0.15), p=0.0093) compared with levels prior to 5th vaccine dose. CD8 T cell responses to a 5th vaccine dose did not significantly differ from those post-infection (0.057% (0.016-0.21) p=0.63). After infection, 32/36 (89%) patients had nucleocapsid-specific CD4 T cell responses and 23/36 (64%) had membrane-specific CD4 T cell responses. Similarly, 30/36 (83%) and 22/36 (61%) patients had nucleocapsid- and membrane-specific CD8 T cell responses. These responses decreased over time and were not boosted by vaccination. Patients with hybrid immunity had higher IgG anti-spike antibody levels than patients receiving only 4th dose (median 23159 IU/mL (IQR 14588-44529) vs 7242 (3220-17259) p<0.001. This humoral response waned prior to the 5th dose but increased following the 5th vaccine dose, median 9109 (3603-19839) vs. 31198 (13976-51224), p<0.001).
Conclusion:
CD8 T cell responses after four immunisations showed no significant benefit of further boosting, suggesting long-lived cellular responses that could be clinically protective. CD4 T cell and humoral responses wane following both four vaccinations and infection but are restored by vaccine boosters, indicating that also IMID patients with hybrid immunity could benefit from a booster vaccine to maintain high levels of circulating antibodies and spike-specific T cells. Table 1. Patient characteristics
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, Asia-Sophia Wolf: None declared, Taissa M. Kasahara: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Ingrid Jyssum: None declared, Joe Sexton: None declared, Anne Therese Tveter: None declared, Guri Solum: None declared, Ingrid Fadum Kjønstad: None declared, Ingrid E. Christensen: None declared, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Grete B. Kro: None declared, 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, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Gunnveig Grødeland Bayer, Sanofi, ThermoFisher, Pfizer, Vitusapotek, GSK, Siri Mjaaland: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.
T cells are critical for control of viral infection with SARS-CoV-2, but knowledge is lacking on cellular immune responses following repeated vaccination and breakthrough infection in immunosuppressed patients.
Objectives
To examine longitudinal T cell responses across diagnoses, following vaccine series and COVID-19 in patients on tumor necrosis factor inhibitors (TNFi).
Methods
The prospective, observational Nor-vaC study included patients with arthritis (spondyloarthritis, rheumatoid arthritis, psoriatic arthritis) or inflammatory bowel disease (IBD) (ulcerative colitis, Crohns disease) on immunosuppressive therapies [1]. Here, we included patients on TNFi mono- or combination therapy immunised with up to four SARS-CoV-2 vaccine doses with or without breakthrough infection, collecting peripheral blood mononuclear cells (PBMCs) 2-4 weeks after each immunisation. Samples were incubated with SARS-CoV-2 spike, nucleocapside or membrane peptides. The percentage of responding T cells was measured by flow cytometry (2) (≥0.01% increase in responding CD4 cells, ≥0.001% increase in responding CD8 cells, compared to baseline).
Results
Between February 2021 and December 2022, 144 patients on TNFi (monotherapy n=86 (60%), combination with methotrexate or azathioprine n=58 (40%)) were included (median age 48 years [IQR 33-57]; 51% women) (Table 1). The proportions of arthritis vs IBD patients with CD4 responses after 2 vaccine doses were 75% (12/16 patients) vs 86% (25/29), and after 3 doses 83% (10/12) vs 93% (28/30). In total, 80% (4/5) of arthritis patients showed further increases in CD4 responses after a 4th vaccine dose. Conversely, 81% (13/16) of arthritis patients vs. 55% (16/29) of IBD patients had CD8 T cell responses after two doses, and 67% (8/12) vs. 62% (18/29) after three doses. A 3rd and 4th dose induced higher CD8 responses compared to the previous dose in 55% (6/11) and 100% (5/5) of arthritis patients. Arthritis patients had lower T cell responses than IBD patients after the 3rd dose; median CD4 response 0.024% [IQR 0.009-0.036] vs 0.098% [IQR 0.040-0.182], p=0.0004; median CD8 response 0.003% [IQR 0.001-0.016] vs 0.044% [IQR 0.009-0.140], p=0.0032 (Figure 1). This difference remained robust after adjusting for age and sex, p<0.001, but was no longer detected after the 4th vaccine dose. Breakthrough infection elicited increased T cell responses across all diagnoses to spike (p<0.0001), and to nucleocapsid (p=0.002) and membrane proteins (p=0.001) compared to unstimulated T cells. Also, Spike-specific T cell responses increased compared to the 3rd dose (median CD4 T cell response 0.18% vs. 0.06%, p=0.003; CD8 T cell response 0.08% vs. 0.01%, p<0.0001), but to a lesser extent compared to the 4th dose (median CD4 response 0.18% vs. 0.12%, p=0.05; CD8 response 0.08% vs. 0.05%, p=0.26). There were no differences in cellular response between patients on TNFi mono- or combination therapy (p=0.93).
Conclusion
Patients on TNFi show improved cellular responses following each immunisation, with infection generating a strong and broad T cell response. Arthritis patients had significantly lower CD4+ responses compared to IBD patients after three vaccine doses, but with no difference after the 4th dose. These results support giving a 4th vaccine dose to TNFi-treated patients, with particular benefit for arthritis patients.
References
[1]Syversen S.W et al Arthritis Rheumatol. 2022 [2]Kared H et al Nature Communications. 2022
Acknowledgements
We thank the patients and health-care workers who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff involved at the departments involved, particularly Synnøve Aure, Margareth Sveinsson, May Britt Solem, Elisabeth Røssum-Haaland, and Kjetil Bergsmark.
Disclosure of Interests
Hilde Ørbo: None declared, Asia -Sophia F. M. Wolf: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Speakers bureaus for Janssen-Cilag, Sarah Josefsson: None declared, Guri Solum: None declared, Ingrid Fadum Kjønstad: None declared, Ingrid Jyssum: None declared, Ingrid E. Christensen: None declared, Anne Therese Tveter: None declared, Joseph Sexton: None declared, Grete B. Kro: None declared, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi, ThermoFisher, Consultant of: AstraZeneca, Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, Jørgen Jahnsen Speakers bureau: AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, Consultant of: AbbVie/Abbott, Pfizer, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Roche, Sandoz, Takeda, Grant/research support from: Boehringer-Ingelheim, John Torgils Vaage: None declared, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Sella Aarrestad Provan: None declared, Hassen Kared: None declared, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Kristin Kaasen Jørgensen Speakers bureau: Bristol-Myers Squibb, Roche, Silje Watterdal Syversen: None declared, Siri Mjaaland: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott, Galapagos, Pfizer, UCB, Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.
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