LONG-TERM AND BOOSTER VACCINATION RESPONSES IN PATIENTS WITH GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA

BackgroundVaccination remains essential in preventing morbidity of SARS-CoV-2 infections. We previously showed that >10mg/day prednisolone and methotrexate use were associated with reduced antibody concentrations four weeks after primary vaccination in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) [1].ObjectivesHere, we performed a follow-up study to measure the decay of antibody concentrations over time and the immunogenicity of SARS-CoV-2 booster vaccination.MethodsGCA/PMR patients included in the primary vaccination (BNT162b2 or ChAdOx1) study were asked again to donate blood samples six months after primary vaccination (n=24) and one month after booster vaccination (n=46, BNT162b2 or mRNA1273). Data were compared to that of age-, sex-, and vaccine-matched controls (n=58 and n=42, respectively).ResultsAntibody concentrations decreased faster over time in GCA/PMR patients than in controls, but this decrease was not associated with treatment during primary vaccination. Post-booster antibody concentrations were comparable between patients and controls. Antibody concentrations post booster vaccination associated strongly with antibody concentrations post primary vaccination, but not with treatment during booster vaccination. However, the fold-change of post-booster vaccination showed a slight negative correlation with the post-primary vaccine antibodies.ConclusionThese results indicate that patients with impaired vaccine responses after primary vaccination, have slightly stronger increases in humoral immunity after booster vaccination, but this is not enough to reach a similar protection. The decrease in humoral immunity, and subsequent increase after booster vaccination, is likely not impacted by prednisolone or methotrexate treatment. Rather, these treatments put the patients at an immunogenic disadvantage during primary SARS-CoV-2 vaccination, which is not fully repaired by a single booster vaccination. This longitudinal study in GCA/PMR patients stresses the importance of repeat booster vaccination for patients that used >10mg/day prednisolone or methotrexate during primary vaccination.Reference[1]van Sleen Y, van der Geest, Kornelis SM, Reitsema RD, Esen I, Terpstra JH, Raveling-Eelsing E, et al. Humoral and cellular SARS-CoV-2 vaccine responses in patients with giant cell arteritis and polymyalgia rheumatica. RMD open 2022;8(2):e002479.Figure 1.Acknowledgements:NIL.Disclosure of InterestsYannick van Sleen: None declared, Kornelis van der Geest Speakers bureau: Speaker fees from Roche, Grant/research support from: Grant support from Abbvie, Annemarie Buisman: None declared, Maria Sandovici: None declared, Debbie van Baarle: None declared, Elisabeth Brouwer: None declared.

THE KINETICS OF HUMORAL AND CELLULAR RESPONSES AFTER THE BOOSTER DOSE OF COVID-19 VACCINE IN INFLAMMATORY ARTHRITIS PATIENTS

BackgroundImpaired immunogenicity of COVID-19 vaccinations in inflammatory arthritis (IA) patients results in diminished immunity. However, optimal booster vaccination regimens are still unknown, due to unstudied kinetics of the immune response after booster vaccinations.ObjectivesThis study aimed to assess the kinetics of humoral and cellular responses in IA patients after the COVID-19 booster.MethodsIn 29 IA patients and 16 healthy controls (HC) humoral responses (level of IgG antibodies) and cellular responses (IFN-γ production) were assessed before (T0), after 4 weeks (T1), and after more than 6 months (T2) from the booster vaccination with BNT162b2.ResultsIA patients, but not HC, showed lower anti-S-IgG concentration and IGRA fold change at T2 compared to T1 (p=0.026 and p=0.031). Furthermore, in IA patients the level of cellular response at T2 returned to the pre-booster level (T0). All immunomodulatory drugs, except IL-6 and IL-17 inhibitors for the humoral and IL-17 inhibitors for the cellular response, impaired the immunogenicity of the booster dose at T2. However, none of the immunomodulatory drugs affected the kinetics of both humoral and cellular responses (measured as the difference between response rates at T1 and T2).ConclusionOur study showed impaired kinetics of both humoral and cellular responses after the booster dose of the COVID-19 vaccine in IA patients, which, in the case of cellular response, did not allow the vaccination effect to be maintained for more than 6 months. Repetitive vaccination with subsequent booster doses seems to be necessary for IA patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

EVALUATION OF RESPONSE TO ADJUVANTED RECOMBINANT ZOSTER VACCINATION IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING UPADACITINIB: RESULTS FROM A RANDOMIZED TRIAL SUB-STUDY

BackgroundUpadacitinib (UPA) is an oral JAK inhibitor (JAKi) approved for the treatment of RA. JAKi have been associated with an elevated risk of herpes zoster (HZ) in patients (pts) with RA. The adjuvanted recombinant zoster vaccine (RZV, Shingrix) was shown to be well-tolerated and effective in preventing HZ in adults aged ≥ 50 years.[1] The efficacy and safety of RZV have not been studied in pts with RA while on UPA in combination with MTX.ObjectivesTo assess the immunogenicity of RZV in pts with RA receiving UPA 15 mg once daily (QD) with background MTX.MethodsEligible adults aged ≥ 50 years with RA enrolled in the ongoing SELECT-COMPARE phase 3 trial (NCT02629159) received two RZV doses, administered at the baseline and week (wk) 12 visits. Pts should have been on stable doses of UPA 15 mg QD and background MTX for ≥ 8 wks before the first vaccination and ≥ 4 wks after the second vaccination. Antibody titers were collected pre-vaccination (baseline), 4 wks post-dose 1 vaccination (wk 4), and 4 wks post-dose 2 vaccination (wk 16). The primary endpoint was the proportion of pts with a humoral response to RZV defined as ≥ 4-fold increase in pre-vaccination concentration of anti-glycoprotein E [gE] titer levels at wk 16. Secondary endpoints included humoral response to RZV at wk 4 and the geometric mean fold rise (GMFR) in anti-gE antibody levels at wks 4 and 16. Cell-mediated immunogenicity to RZV was an exploratory endpoint evaluated by the frequencies of gE-specific CD4+ [2+] T cells (CD4+ T cells expressing ≥ 2 of 4 activation markers: IFN-γ, IL-2, TNF-α, and CD40 ligand) measured by flow cytometry at wks 4 and 16 in a sub-cohort of pts.ResultsOf the 95 pts who received ≥ 1 RZV dose, 93 (98%) received both RZV doses. Pts had a mean (standard deviation) age of 62.4 (7.5) years. The median (range) disease duration was 11.7 (4.9–41.6) years and duration of UPA exposure was 3.9 (2.9–5.8) years. At baseline, all but 2 pts were receiving concomitant MTX and half (50%) were taking an oral corticosteroid (CS) at a median daily dose of 5.0 mg. One pt discontinued UPA by wk 16. Blood samples were available from 90/93 pts. Satisfactory humoral responses to RZV occurred in 64% (95% confidence interval [CI]: 55–74) of pts at wk 4 and 88% (81–95) at wk 16 (Figure 1). Age (50–< 65 years: 85% [95% CI: 75–94];≥ 65 years: 94% [85–100]) and concomitant CS (yes: 87% [77–97];no: 89% [80–98]) use at baseline did not affect humoral responses at wk 16. GMFR in anti-gE antibody levels compared with baseline values were observed at wks 4 (10.2 [95% CI: 7.3–14.3]) and 16 (22.6 [15.9–32.2]). Among the sub-cohort of pts, nearly two-thirds achieved a cell-mediated immune response to RZV (wk 4: n = 21/34, 62% [95% CI: 45–78];wk 16: n = 25/38;66% [51–81]). Within 30 days post-vaccination of either RZV dose, no serious adverse events (AEs) (Table 1) or HZ were reported. AEs that were possibly related to RZV were reported in 17% of pts. One death occurred more than 30 days after wk 16 due to COVID-19 pneumonia.ConclusionMore than three-quarters (88%) of pts with RA receiving UPA 15 mg QD on background MTX achieved a satisfactory humoral response to RZV at wk 16. In a subgroup of pts, two-thirds (66%) achieved a cell-mediated immune response to RZV at wk 16. Age and concomitant CS use did not negatively affect RZV response.Reference[1]Syed YY. Drugs Aging. 2018;35:1031–40.Table 1. Safety Results Through 30-Days Post-RZV Vaccination in UPA-Treated PatientsEvent, n (%)UPA 15 mg QD (N = 95)Any AE38 (40%)AE with reasonable possibility of being related to UPAa13 (14%)AE with reasonable possibility of being related to RZVa16 (17%)Severe AEb1 (1%)Serious AE0AE leading to discontinuation of UPA0Death0AE, adverse event;QD, once daily;RZV, adjuvanted recombinant zoster vaccine;UPA, upadacitinib.aAs assessed by the investigator.bHypersensitivity.AcknowledgementsAbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the . All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie.Disclosure of InterestsKevin Winthrop Consultant of: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Justin Klaff Shareholder of: AbbVie, Employee of: AbbVie, Yanxi Liu Shareholder of: AbbVie, Employee of: AbbVie, CONRADO GARCIA GARCIA: None declared, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Consultant of: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Alvin F. Wells Consultant of: AbbVie, Amgen, BMS, Eli Lilly, Novartis, Pfizer, and Sanofi, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Michael Chen Shareholder of: AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Anthony Cunningham Consultant of: GSK, Merck Sharp & Dohme, and BioCSL/Sequirus.

Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

POSSIBLE ROLE OF PEPTIDE EPITOPES OF COVID-19 BNT-162B2 MRNA VACCINE IN FOMENTING AUTOIMMUNITY: AN IN SILICO ANALYSIS

BackgroundFollowing the launch of the global COVID-19 vaccination campaign, there have been increased reports of autoimmune diseases developing de novo following vaccination. These cases include rheumatoid arthritis, autoimmune hepatitis, immune thrombotic thrombocytopenia, and connective tissue diseases. Nevertheless, COVID-19 vaccines are considered safe for patients with autoimmune diseases and are strongly recommended.ObjectivesThe aim of this in silico analysis is to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most commonly administered COVID-19 vaccines, that could elicit an aberrant adaptive immune response in predisposed individuals.MethodsThe FASTA sequence of the protein encoded by the BNT-162b2 vaccine was retrieved from http://genome.ucsc.edu and used as a key input to the Immune Epitope Database and Analysis Resource (www.iedb.org). Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC ligand assays without MHC restriction were searched and evaluated. HLA-disease associations were screened on the HLA-SPREAD platform (https://hla-spread.igib.res.in) by selecting only positive markers.ResultsA total of 183 epitopes were found, corresponding to 178 SARS-CoV-2 and 5 SARS-CoV spike epitopes, respectively. Results were obtained from 22 T-cell assays, 398 B-cell assays, and 2 MHC ligand assays. Complementary receptors included 1080 T-cell receptors and 0 B-cell receptors.Specifically, the IEDB_epitope:1329790 (NATNVVIKVCEFQFCNDPFLGVYY) was shown to bind to HLA-DRB1*15:02 and HLA-DRB1*15:03 alleles, whereas the IEDB_epitope:1392457 (TKCTLKSFTVEKGIYQTSNFRVQPT) was reported to bind to HLA-DRB1*07:01, HLA-DRB1*03:01, HLA-DRB3*01:01, and HLA-DRB4*01:01 alleles. The HLA alleles detected were found to be positively associated with various immunological disorders (Table 1).Table 1.MHC-restricted epitopes of the BNT-162b2 vaccine and potentially associated immunological conditionsEpitopeAssayMHC moleculeAssociated disease (population)NATNVVIKVCEFQFCNDPFLGVYY + OX(C10)cellular MHC/mass spectrometry ligand presentationHLA-DRB1*15:02Takayasu arteritis (Japanese) Arthritis (Taiwanese) Scleroderma (Japanese) Colitis (Japanese)HLA-DRB1*15:03Systemic lupus erythematosus (Mexican American)TKCTLKSFTVEKGIYQTSNFRVQPT + SCM(K2)as aboveHLA-DRB1*07:01Allergy, hypersensitivity (Caucasian)HLA-DRB1*03:01Type 1 diabetes (African) Sarcoidosis, good prognosis (Finnish)HLA-DRB3*01:01Graves' disease (Caucasian) Thymoma (Caucasian) Sarcoidosis (Scandinavian) Autoimmune hepatitis (Caucasian)HLA-DRB4*01:01Vitiligo (Saudi Arabian)ConclusionSimilar to the SARS-CoV-2 spike protein, the protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals. Genotyping for HLA alleles may help identify at-risk individuals. However, further research is needed to elucidate the underlying mechanisms and potential clinical implications.References[1]Vita R, Mahajan S, Overton JA et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 2019 Jan 8;47(D1):D339-D343. doi: 10.1093/nar/gky1006.[2]Dholakia D, Kalra A, Misir BR et al. HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed s. BMC Genomics 23, 10 (2022). https://doi.org/10.1186/s12864-021-08239-0[3]Parker R, Partridge T, Wormald C et al. Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells. Cell Rep. 2021 May 25;35(8):109179. doi: 10.1016/j.celrep.2021.109179.[4]Knierman MD, Lannan MB, Spindler LJ et al. The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein. Cell Rep. 2020 Dec 1;33(9):108454. doi: 10.1016/j.celrep.2020.108454.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

INTAKE OF ACETAMINOPHEN SUPPRESSES ANTIVIRAL HUMORAL IMMUNE RESPONSES IN PATIENTS WITH RA FOLLOWING VACCINATION WITH ANTI SARS-CoV-2 mRNA BASED VACCINES

BackgroundAcetaminophen (APAP = paracetamol) may potentially impact vaccine-associated immune responses as the intake of APAP has been associated with a worse outcome in tumor patients receiving checkpoint inhibitors.[1]Different DMARD regimen have been shown to impair the humoral immune response to mRNA SARS-CoV-2 vaccines in patients with rheumatoid arthritis but the effect of paracetamol has not been explored thus far.ObjectivesTo analyse whether the intake of APAP may interfere with antiviral humoral immune responses following two doses of an anti-SARS-CoV-2 mRNA based vaccine in patients with rheumatoid arthritis (RA) on DMARD therapy.MethodsThe RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) was a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 healthy controls (HC). We performed a posthoc analysis of blood samples taken before the first vaccine dose (T0), two (T1) and three (T2) weeks after the first and second vaccine dose, and at 12 (T3) weeks. APAP intake was measured using ELISA. The antibody response (anti-S) to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The neutralizing activity NT50 at week 12 was assessed using an HIV-based pseudovirus neutralization assay against Wuhan-Hu-1.ResultsBaseline characteristics of participants are detailed in Table 1. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein at baseline). APAP was detected in serum samples from 34/73 (25%) RA patients and in 7/21 (33%) HC (least at one timepoint T0, T1 and/or T2). APAP intake in HC did not affect levels of anti-S at any timepoint and all HC developed potent neutralizing activity (NT50 ≥ 250) at week 12. RA patients, who tested positive for APAP at T1, showed comparable anti-S levels at T1, T2 and T3 compared to RA patients not exposed to APAP. The detection of APAP at T2 corresponded to lower anti-S levels at T2 (Figure 1 A, B). The detection of APAP at T2 was associated with a significantly lower SARS-CoV-2 neutralizing activity at week 12 compared to patients without perivaccination APAP exposure (p =0.04) (Figure 1 C).ConclusionA decrease of antiviral humoral immune responses was observed in RA patients (but not in HC) who were exposed to APAP at the time of the second mRNA vaccine dose compared to patients in whom APAP was not detected. Our data suggest that the use of paracetamol within the time period around vaccination may impair vaccine-induced immune responses in patients with an already higher risk for blunted immune responses.Reference[1]Bessede A et al. Ann Oncol 2022;33: 909-915Table 1.Baseline characteristics: RA patients and HC with/without APAP exposureRA APAP – n = 37RA APAP + n = 36p-valueHC APAP – n = 8HC APAP + n = 13p-valueAge (yrs), mean (± SD)62 (13)67 (10)0.07 (NS)45 (12)44 (14)0.90 (NS)Female sex, n (%)24 (65)19 (53)0.29 (NS)2 (25)5 (38)0.53 (NS)Vaccination type/schedulemRNA-1273, n (%)4 (11)8 (22.2)0.19 (NS)0 (0)0 (0)BNT162b2, n (%)33 (89)28 (77.8)0.19 (NS)8 (100)13 (100)RA disease characteristicsACPA ± RF, n (%)17/37 (46)19/36 (53)0.56 (NS)NANANARA disease duration (yrs ± SD)9.2 (9.8)10.2 (8.1)0.67 (NS)NANANADMARD therapycsDMARD-mono, n (%)13/37 (35)9/36 (25)0.35 (NS)NANANAbDMARD-mono/combo, n (%)16/37 (43)16/36 (44)0.92 (NS)NANANAtsDMARDs-mono/combo, n (%)8/37 (22)11/36 (31)0.38 (NS)NANANAPrednisone, n (%)15/37 (41)12/36 (33.3)0.52 (NS)NANANAMean daily dose prednisone (mg ± SD)4.6 ± 1.13.9 ± 2.30.39 (NS)NANANA* APAP = acetaminophenFigure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

PROSPECTIVE EVALUATION OF THE EFFECT OF THE VACCINE AGAINST SARS-COV-2 IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: DATA FROM SAFER STUDY

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease, which presents an immune disorder that leads to the production of autoantibodies with potential involvement of multiple organs. Infections are one of the most frequent causes of hospitalization and death in lupus patients, and SARS-CoV-2 infection has been a global threat since March 2020. Immunization of these patients has been strongly recommended, although vaccine evaluation studies have not included this profile of patients.ObjectivesTo evaluate the immunogenicity and safety after 2 doses of the vaccine against SARS-CoV2 in patients with SLE.MethodsSubgroup of SLE patients from the prospective multicenter cohort of patients with immune-mediated diseases "SAFER” – Safety and Efficacy on COVID-19 Vaccine in Rheumatic Disease, a phase IV study. Vaccination against SARS-CoV-2 took place with vaccines approved by Brazilian regulatory bodies CoronaVac (Inactivated SARS-CoV-2 Vaccine), ChadOx-1 (AstraZeneca) and BNT162b2 (Pfizer-BioNTech) and this project followed in line with the guidelines of the National Immunization Plan in Brazil. Patients aged 18 years or older with a previous diagnosis of SLE (according to the 2019 ACR/EULAR criteria) were included. Patients were evaluated by telephone contact and in a face-to-face visit on the 28th day after each dose. Patients were followed up by means of blood collection for measurement of IgG antibody against SARS-COV-2 by chemiluminescence and disease activity assessed using SLEDAI-2K score.ResultsA total of 367 individuals with SLE were included, of whom 207 received 2 doses of CoronaVac, 128 received 2 doses of ChadOx-1 and 32 received 2 doses of BNT162b2. 90% of the subjects were female with a mean age of 37 years. About 42% (154) of the individuals included did not have any other associated comorbidity. 50% (182) of patients were using oral glucocorticoids and azathioprine was the most frequent immunosuppressive therapy. Regarding disease activity parameters, 38% (140) of patients had zero SLEDAI-2K at baseline and 41% (147) had zero SLEDAI-2K 28 days after the 2nd dose. Anti-DNA positivity was 30.7% (16/52) at inclusion and 32.6% (17/52) 28 days after the 2nd dose. Complement consumption was present in 18% (10/55) at inclusion and in 14.5% (8/55) 28 days after the 2nd vaccine dose. The geometric mean titers of IgG antibodies against SARS-COV-2 increased in the different vaccine groups, log 2.27 BAU/mL at inclusion and log 5.58 BAU/mL 28 days after the 2nd dose. Antibody titers after second dose varied between different vaccines, 4.96 BAU/mL CoronaVac, 6.00 BAU/mL ChadOx-1 and 7.31 BAU/mL BNT162b2 vaccine, p < 0.001. Only 3.54% (13/367) patients had covid-19 infection after the 15th day of the second dose of immunization, 9 of them having received 2 doses of CoronaVac, 4 of them of ChadOx-1 and none of them receiving BNT162b2, with p-value of 0.63.ConclusionThis study suggests that vaccines against SARS-COV-2 are safe in SLE patients. Induction of immunogenicity occurred in different vaccine regimens. Only 3.5% of individuals had COVID-19 infection with no difference between the types of vaccines evaluated. Future analyzes to explore the association of the effect of immunosuppressive medication, as well as the impact of booster doses and longer follow-up on clinical outcome will be performed.References[1]Mason A, et al. Lupus, vaccinations and COVID-19: What we know now. Lupus. 2021;30(10):1541-1552.[2]Furer V, Eviatar T, Zisman D, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: A multicentre study. Ann Rheum Dis. 2021;80(10):1330-1338.[3]Izmirly PM, Kim MY, Samanovic M, et al. Evaluation of Immune Response and Disease Status in SLE Patients Following SARS-CoV-2 Vaccination. Arthritis Rheumatol. Published online 2021.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

HUMORAL AND CELLULAR IMMUNOGENICITY INDUCED BY THIRD BOOSTER OF SARS-CoV-2 VACCINES IN PATIENTS WITH RHEUMATIC MUSCULOSKELETAL DISEASES

BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefited most people worldwide. While healthy people can acquire sufficient humoral immunity against COVID-19 even in the elderly by vaccination with three doses of vaccine., recent studies have shown that complex factors other than age, including the type of vaccines and immunosuppressive drugs, are associated with immunogenicity in patients with rheumatic musculoskeletal disease (RMD). Identifying factors that contribute to the vulnerability of those patients to acquire not only humoral but also cellular immunity to SARS-CoV-2 despite multiple vaccinations is crucial for establishing an appropriate booster vaccine strategy.ObjectivesTo assess humoral,and T cell immune responses after third doses of mRNA vaccines against SARS-CoV-2.MethodsThis prospective observational study included consecutive RMD patients treated with immunosuppressant who received three doses of mRNA vaccines including BNT162b2 and mRNA-1273. Blood samples were obtained 2-6 weeks after second and third dose of mRNA vaccines. We measured neutralizing antibody titres, which against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 and seroconversion rates to evaluate the humoral responses. We also assessed T-cell immunity responses using interferon releasing assay against SARS-CoV-2.ResultsA total of 586 patients with RMD treated with mmunosuppressive treatments were enrolled. The mean age was 54 years, and 70% of the patients were female. Seroconversion rates and neutralizing antibody titres after third vaccination of SARS-CoV-2 were significantly higher compared to those after second vaccination (seroconversion rate, 94.5% vs 83.6%, p<0.001;titres of neutralizing antibody, 48.2 IU/mL vs 11.0 IU/mL, p<0.001, respectively). Interferon releasing assay after third vaccinations demonstrated that T cell reaction against SARS-CoV-2 was also increased from that of second vaccination (interferon for antigen 1, 1.11.9 vs 0.61.9, p=0.004,interferon for antigen 2, 1.72.6 vs 0.82.3, p=0.004). Humoral and cellular immunogenicity did not differ between the types of third vaccination including full dose of BNT162 and half dose of mRNA1273.(neutralizing antibody titers, 47.8±76.1 IU/mL vs 49.0±60.1 IU/mL, p<0.001;interferon for antigen 1, 1.12.0 vs 1.01.5, p=0.004, respectively). Attenuated humoral response to third vaccination was associated with BNT162b2 as second vaccination age (>60 years old), glucocorticoid (equivalent to prednisolone > 7.5 mg/day), and immunosuppressant use including mycophenolate, and rituximab. On another front, use of mycophenolate and abatacept or tacrolimus but not rituximab were identified as negative factors for T-cell reactions against SARS-CoV-2. Although 53 patients (9.0%) who had been immunised with third-vaccination contracted COVID-19 during Omicron pandemic phase, no one developed severe pulmonary disease that required corticosteroid therapy.ConclusionOur results demonstrated third mRNA vaccination booster of SARS-CoV-2 contributed to restore both humeral and cellular immunity in RMD patients with immunosuppressants. We also identified that certain immunosuppressive therapy with older RMD patients having BNT162b2 as a second vaccination may need additional booster vaccination.Reference[1]Furer V, Eviatar T, Freund T, et al. Ann Rheum Dis. 2022 Nov;81(11):1594-1602. doi: 10.1136/ard-2022-222550.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

FREQUENCY OF DISEASE FLARE AND ITS RISK FACTORS FOLLOWING TWO-DOSE OF COVID-19 VACCINATION IN PATIENTS WITH RHEUMATOID ARTHRITIS

BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefitted most people worldwide. However, the safety of vaccine has not been established in patients with rheumatic arthritis (RA). Previous studies reported that flares of underlying RA following SARS–CoV-2 vaccination were not so frequent, and there was no report of severe flare. However, those reports did not assess patients' disease activity with validated disease activity measures and described only simple self-reported questionnaires. Hence, the effect of vaccination on disease activity in patients with RA is still unclear. Understanding the association between arthritis flare in patients in RA and vaccination is important to overcome vaccine hesitancy.ObjectivesTo clarify the effect of SARS-CoV-2 vaccination on disease activity in patients with RA and identify risk factors associated with RA flares following the vaccination.MethodsThis is a prospective cohort study in patients with rheumatic musculoskeletal disease including RA who received the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273 from March 16, 2021, at Keio University Hospital. The disease activity was evaluated with disease activity score for 28 joints using C-reactive protein (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI) before vaccination and after second vaccination (within two months). RA flare was defined as ΔDAS28-CRP>0.6with requirement of treatment intensification. All analysis in this study was carried out with JMP.ResultsWe enrolled 318 patients with RA in this analysis. The mean age was 61 years old, and 283 (89%) were female. The mean DAS28-CRP before vaccination and after 2nd dose of vaccination were 1.70±0.71 and 1.78±0.81, respectively (p=0.84). The increase in DAS28-CPR after vaccination > 0.6 was observed in 53 patients (16.7%), and among them, 23 patients (8.2%) needed treatment intensification. The types of SARS-CoV-2 vaccine, humoral immunogenicity including neutralizing antibody titer and its adverse effects including systemic reaction (fever or general fatigue) were not different between the flare and non-flare groups (9.8 vs 9.1 IU/mL, p=0.88;31.2% vs 18.7%, p=0.32, respectively). In the flare group, swollen joint counts (SJC), hourly erythrocyte sedimentation rates, DAS28-CRP, and SDAI were significantly higher than those in the non-flare group (0.5 vs 0.0, p<0.000;13 vs 11 mm/h, p=0.01;1.57 vs 1.45, p<0.001;3.9 vs 2.4, p=0.02, respectively). Multivariable logistic regression analysis revealed that the number of swollen joints before vaccination contributed RA exacerbation after SARS-CoV-2 vaccination significantly (odds ratio 1.3, 95% confidence interval 1.06-1.65, p=0.01). The receiver operating curve analysis identified that having two or more swollen joint counts predicts RA flares after vaccination with an area under the curve of 0.64, a sensitivity of 42.3%, and a specificity of 86.9%.ConclusionDisease flare with requirement of treatment intensification is observed in 8.2% of patients with RA. Patients with higher disease activity, especially having two or more swollen joint counts are at high risk of flare following mRNA SARS-CoV-2 vaccination.Reference[1]Connolly CM, Ruddy JA, Boyarsky BJ, et al. Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination. Arthritis Rheumatol. 2022;74(1):28-32. doi: 10.1002/art.41924. Epub 2021 Dec 3.Figure 1.Risk factors associated with RA flares after vaccination[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.

COMPARISON OF HOMOLOGOUS AND HETEROLOGOUS BOOSTER SARS-CoV-2 VACCINATION IN AUTOIMMUNE RHEUMATIC AND MUSCULOSKELETAL PATIENTS

BackgroundVaccine-induced immunity is very important for controlling the COVID-19 infection. The vaccination supports humoral and cellular immunity, and this is one of the main strategy for us. Various vaccines approved in the countries have been shown to reduce infection rates, severity, and mortality.ObjectivesWe aimed to compare humoral and cellular immune responses after homologous or heterologous vaccination among patients with aiRMDs at their third vaccination with BNT162b2 or with two vaccinations followed by COVID-19 infection. We detected the anti-SARS-CoV2 antibody levels and measured the SARS-CoV-2 reactive B-, or T-cell mediated immunity in aiRMDs receiving homologous (Hom.), heterologous (Het.) vaccines or became infected (Inf.).MethodsA single center observational study evaluated immunogenicity and safety of the third dose vaccines or after two-dose regimen of vaccine and COVID infection in patients with aiRMDs. Neutralizing anti-RBD antibodies and specific T-cell response were measured.ResultsWe showed that following 4 months of the booster vaccination with the third dose of mRNA-based vaccine or after COVID infection, the positive (>21.8 BAU/mL) neutralizing anti-RBD IgG antibody response was outstanding in all three patient groups, 95.5%, 100% and 100% of the homologous and heterologous as well as the SARS-CoV-2 infected groups. Taken together booster vaccinations or SARS-CoV-2 infection after completing 2 doses of the vaccination can lead to the production of neutralizing antibodies still protective in RMD cases after 4 months of the third antigen exposition. The booster vaccination reduces the frequency of hospital admissions and mortality with ai RMDs. The vaccinations are effective independently from the type of vaccine, the SARS-CoV-2 specific memory B-cell populations showed a statistically not significant but lower frequency in the infection group. Clinical activity of aiRMDs was not increased following booster vaccination.ConclusionPatients, who received a heterologous booster vaccine had a higher level of peripheral memory B-cells compared to those who had COVID-19 infection. Biologic therapy decreased the level of B-cells. Patients with a disease duration of more than 10 years had higher level of CD8+TNF-α+ and CD8+IFN-γ+ T-cells compared to patients who were diagnosed less than 10 years ago. The third booster mRNA-based vaccine was as much effective as in the homologous and heterologous patients groups compared who had COVID infection.References[1] Szebeni, G.J.;Gemes, N.;Honfi, D.;Szabo, E.;Neuperger, P.;Balog, J.A.;Nagy, L.I.;Szekanecz, Z.;Puskas, L.G.;Toldi, G.;et al. Humoral and Cellular Immunogenicity and Safety of Five Different SARS-CoV-2 Vaccines in Patients With Autoimmune Rheumatic and Musculoskeletal Diseases in Remission or With Low Disease Activity and in Healthy Controls: A Single Center Study. Front. Immunol. 2022, 13, 846248.[2]Honfi, D.;Gémes, N.;Szabó, E.;Neuperger, P.;Balog, J.Á.;Nagy, L.I.;Toldi, G.;Puskás, L.G.;Szebeni, G.J.;Balog, A. Comparison of Homologous and Heterologous Booster SARS-CoV-2 Vaccination in Autoimmune Rheumatic and Musculoskeletal Patients. Int. J. Mol. Sci. 2022, 23, 11411Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Challenges in the manufacture, storage, distribution and regulation of traditional and novel vaccines

Since the onset of the COVID-19 pandemic, there has been a significant surge in interest of COVID-19 vaccines in particular, and other traditional vaccines in general. This strong interest is expected to continue as the industry strives to manufacture safer and more effi cacious vaccines against COVID-19 and other infectious diseases. Vaccines are a unique class of products, being biologicals that are administered to healthy individuals to prevent diseases. The equitable distribution and availability of safe, efficacious and good quality vaccines are of utmost importance in preventing and controlling infections and safeguarding public health. The continued existence of poor- quality vaccines suggests a lack of control of manufacturing, storage, distribution, and possibly, their associated regulation. Nonetheless, all these situations - whether positive or negative, present opportunities for improvements. As regulatory authorities step up efforts in regulating existing traditional vaccines, advancements in vaccine research and development churn out novel vaccines that pose further manufacturing and regulatory challenges. This manuscript provides an overview of vaccines, both traditional and novel, and strives to identify challenges in the manufacture, storage, distribution, handling and their associated regulation. It also evaluates whether current regulatory frameworks are adequate, and where applicable, recommends areas for improvements. International harmonization and convergence of national regulatory framework with the view to facilitate quicker approval of safe, efficacious and good quality vaccines, that are accessible and affordable to patients worldwide, are also explored.

THE IMPACT OF IMMUNOMODULATING TREATMENT ON THE SEROLOGICAL IMMUNOGENICITY FOLLOWING THREE DOSES OF COVID-19 VACCINE AND PERSISTENCE OF IMMUNOGENICITY OF TWO VACCINE DOSES IN PATIENTS WITH INFLAMMATORY RHEUMATIC DISEASES - A SWEDISH STUDY (COVID19-REUMA)

BackgroundData on serological immunity after three doses and the long-term immunogenicity (persistence) of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with different immunomodulating drugs are still limited.ObjectivesTo elucidate if 1) a third dose COVID-19 vaccine improves antibody responses, compared to two doses, in patients with IRD treated with biologic or targeted synthetic DMARD (b/tsDMARDs) treatment given as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) compared to controls, and 2) the persistence of antibody response after two doses of COVID-19 vaccine in IRD patients.MethodsAntibody levels to two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confirm previous COVID-19 infection) were measured in serum samples collected 2-12 and 21-40 weeks after the second vaccine dose and 2-12 weeks after the third dose using a multiplex bead-based serology assay. A sufficient antibody response (seropositivity) was defined as having antibodies over the cut-off level for both spike antigens (1). WT (wild type) anti-Spike IgG and omicron BA.1 and BA.2 variants were measured. Patients with IRD receiving immunomodulating treatment, regularly followed at a rheumatology department and a group of controls were recruited from five Swedish region.ResultsIn total, 323 of 414 patients with IRD and 36 controls who received three vaccine doses participated in this part of the study. Following treatment groups were included: rituximab (n=118;68% female;mean age 67 years), abatacept (n=18;72% female;mean age 64 years), IL6r inhibitors (n=60;73% female;mean age 64 years), JAK-inhibitors (n=44;80% female, mean age 52 years), TNF-inhibitors (n=59;70% female;mean age 47 years;), IL12/23/17 inhibitors (n=24;46% female;mean age 54 years) and controls (n=36;75% female, mean age 51 years). b/ts DMARD treatment was given as monotherapy or in combination with csDMARD, methotrexate (MTX) being the most frequently used csDMARD (32.5%). Compared to results after two vaccine doses, proportion (%) of seropositivity after three vaccine doses increased significantly in groups rituximab +/- DMARD (p=0.003 and p=0.004, respectively), IL6r inhibitors +DMARD (p=0.02), and abatacept+DMARD (p=0.01). However, the proportion of seropositivity after three vaccine doses was still significantly lower in rituximab treated patients (52%) compared to other treatment groups or controls (p<0.001) (Figure 1A/B). Antibody response to WT, omicron sBA.1 and sBA.2 showed similar pattern with the lowest levels among patients treated with rituximab.When antibody response was compared between 2-12 weeks and 21-40 weeks after second dose, the proportion of seropositive rituximab treated patients decreased from 34.9 % to 32.6%. All patients with JAK inhibitors and with JAK-inhibitors and IL6r-inhibitors seropositive 21-40 weeks after the second vaccine dose. Patients treated with other bDMARDs were not included in this analysis due to limited number participants.ConclusionIn this Swedish study including IRD patients receiving different b/t DMARDs, a sufficient immunogenicity of the third dose of COVID-19 vaccine was observed in all treatments with exception for rituximab. However, the increased proportion of seropositivity after the third COVID-19 vaccine doses in rituximab and other patients with insufficient response to two doses including response to the omicron variants, supports the current recommendations on additional booster doses. The immunogenicity of two vaccine doses was preserved to 40 weeks in majority of patients treated with different immunomodulating treatment with exception for rituximab.Figure 1.AcknowledgementsThe study has been supported by the independent research grants from Roche.Disclosure of InterestsMartina Frodlund: None declared, Per Nived: None declared, Katerina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer., Grant/research support from: Research grand from Galapagos, Anna ödergren: None declared, Eva Klingberg: None declared, Monika Hansson: None declared, Elisa Pin: None declared, Lars Klareskog: None declared, Meliha C Kapetanovic Grant/research support from: independent research grants från Pfizer and Roche.

Animal Pre-Clinical Study of an Inactivated SARS-CoV-2 Vaccine candidate (Osvid-19 ): Immunogenicity, Protective, and Safety Aspects

Background: This study aimed to evaluate the outcomes of preclinical studies on the safety and immunogenicity of an inactivated COVID-19 vaccine candidate to warrant further clinical evaluation. Method(s): SARS-CoV-2 positive nasopharyngeal swab specimens were confirmed by real-time polymerase chain reaction and next-generation sequencing. The safety and immunogenicity tests of the COVID-19 vaccine were carried out in rats and Rhesus monkeys, and Balb/C mice and Rhesus monkeys, respectively. Result(s): The candidate vaccine was well tolerated and induced promising levels of SARS-CoV-2- specific IgG1, IgG2a, and Granzyme B in Balb/C mice, and anti-SARS-CoV-2 spike IgG and neutralizing antibodies in Rhesus monkeys. Based on cVNT results, the inactivated vaccine in 0.5 and 1 microg/100 microL doses was able to induce a neutralizing effect against the SARS-CoV-2 virus up to a dilution of 1:512 and 1:1000. The protective efficacy of the vaccine candidate was challenged with 2 x108 PFU of live viruses and confirmed by lung CT scan and histopathological evaluations compared to the control group. Repeated intramuscular injection of the candidate vaccine was generally well-tolerated in Rats and Rhesuses. No significant side effects were observed in rats injected with ten full human doses and in the Rhesus monkeys with three full human doses. Conclusion(s): Based on the findings presented in this study, it is recommended that this vaccine be moved into human testing commencing with a phase I clinical trial.Copyright © 2021 Muslim OT et al.

SAFETY AND IMMUNOGENICITY OF TWO HETEROLOGOUS VACCINE SCHEDULES AGAINST SARS-CoV-2 IN PATIENTS WITH RHEUMATOID ARTHRITIS: BRAZILIAN MULTICENTER STUDY

BackgroundPatients with immune-mediated rheumatic diseases (IMRDs) have been prioritized for COVID-19 vaccination to mitigate the infection severity risks. Patients with rheumatoid arthritis (RA) are at a high risk of severe COVID-19 outcomes, especially those under immunosuppression or with comorbidities associated. However, few studies in the literature assessed the safety and immunogenicity of the COVID-19 heterologous vaccine schedules in patients with RA.ObjectivesEvaluate the safety and immunogenicity of two heterologous vaccine schedules against SARS-CoV-2 in patients with RA.MethodsThese data are from the study "SAFER - Safety and Efficacy on COVID-19 Vaccine in Rheumatic Diseases,” a Brazilian multicentric prospective phase IV study to evaluate COVID-19 vaccine in IMRDs in Brazil. Immunogenicity and adverse events (AEs) in patients with RA of all centers were assessed after two doses of ChAdOx1 plus additional dose of BNT162b2 or after two doses of inactivated SARS-CoV-2 vaccine CoronaVac plus additional dose of BNT162b2. The titers of neutralizing antibodies against the receptor-biding domain of protein spike (S) of SARS-CoV-2 (anti-RBD) were measured by chemiluminescence test after each dose of immunizers. Proportions between groups were compared using the chi-square and Fisher's exact tests for categorical variables. Clinical Disease Activity Index (CDAI) before and after vaccination was assessed using the McNemar test.ResultsA total of 107 patients with RA were include in the study, most of them female, with a mean age of 46 years. Biological disease modifying anti-rheumatic drugs (DMARDs) were used by 50 % of the patients and conventional synthetics DMARDs in 48 %. Two doses of CoronaVac plus additional dose of BNT162b2 was used in 66 patients and two doses of ChAdOx1 plus additional dose of BNT162b2 in 41. Only mild AEs were observed, mainly after the first dose. The most common AEs after all doses, regardless of the immunizer type, were pain at the injection, headache, arthralgia and myalgia. ChAdOx1 had a higher frequency of pain at the injection (66% vs 32 %, p < 0,001) and arthralgia (68% vs 15%, p < 0,001) compared to CoronaVac. No patients had flare after the vaccination. The titers of anti-RBD after two doses of ChAdOx1 were higher compared to two doses of CoronaVac (6,03 BAU/mL vs 4,67 BAU/mL, p < 0,001). However, after the additional dose of BNT162b2, the anti-RBD titers were similar in both groups (7.28 BAU/mL vs 7.06 BAU/mL, p = 0.56). Only two cases of COVID 19, with mild symptoms, were reported, one in each group.Figure 1.ConclusionChAdOx1, CoronaVac, and BNT162b2 vaccines are safe in RA patients. The frequency of local adverse effects, particularly pain at the injection site, is high. AEs are more frequent with ChAdOx1, especially after the first dose. The use of the immunizers does not change the degree of inflammatory activity of the disease. The immunogenicity of the two heterologous regimens analyzed was similar.References[1]Marques C, Kakehasi AM, Gomides APM, Paiva EDS, Dos Reis Neto ET, Pileggi GCS, et al. A Brazilian Cohort of Patients With Immuno-Mediated Chronic Inflammatory Diseases Infected by SARS-CoV-2 (ReumaCoV-Brasil Registry): Protocol for a Prospective, Observational Study. JMIR Res Protoc.[2]Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, Yuki EFN, Pedrosa T, Fusco SRG, et al. Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial. Nat Med. 2021;27(10):1744-1751.[3]Machado PM, Lawson-Tovey S, Strangfeld A, Mateus EF, Hyrich KL, Gossec L, et al. Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry. Ann Rheum Dis. 2022;81(5):695-709.[4]Tavares ACFMG, Melo AKG, Cruz VA, Souza VA, Carvalho JS, Machado KLLL, et al. Guidelines on COVID-19 vaccination in patients with immunemediated rheumatic diseases: a Brazilian Society of Rheumatology task force. Adv Rheumatol. 2022;62:3.Acknowledg ments:NIL.Disclosure of InterestsNone Declared.

CELLULAR AND HUMORAL IMMUNOGENICITY OF THE NEOANTIGEN S1 FROM SARS-COV-2 VACCINES IN PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASES

BackgroundData on cellular and humoral immunogenicity triggered by SARS-CoV-2 vaccines in patients with autoimmune rheumatic diseases (ARDs) are limited. While current vaccine efforts have focused on the induction of neutralizing antibodies against SARS-CoV-2, T-cell immunity may also provide protection against infection. Experimental data suggest that CD8+ T cell responses may have a protective role in the presence of decreasing or sub protective antibody titers [1].ObjectivesThe aim of this project is to describe the serological and T cell responses to the third dose of vaccine (either with BNT162b2 mRNA or ChAdOx1 nCoV-19 replication-deficient adenoviral vector vaccines) in a cohort of patients with ARDs (rheumatoid arthritis and spondyloarthropathies) treated with biologic therapies, to describe the impact of these treatments on vaccine response in this patient population. As a second objective, we will describe the characteristics of patients who did not present an adequate immunogenic response.MethodsCase-control study. We studied in 79 patients with ARDs and in 31 healthy controls, anti-SARS-CoV-2 specific interferon-gamma (IFN-γ) production measured by IGRA between 8-12 weeks after the third dose of anti-SARS-CoV-2 vaccine. In addition, humoral response was measured by anti-S1 IgG antibody production measured by chemiluminescent microparticle immunoassay. Statistical comparison between categorical variables was performed by Fisher's or χ2 test. For quantitative variables by Kruskal-Wallis test or Mann-Whitney test.Results79 patients with ARDs (48 women, 31 men;mean age 58±11.4) 43 (54%), with rheumatoid arthritis and 36 (45.6%) with spondyloarthropathies. 32 (49.5%) of them were on glucocorticoid treatment (mean dose 4.92 mg/day), 25 (31.6%) on methotrexate and 56 (70.9%) on anti-TNF. Post-vaccination results showed positive T-cell immune responses in 68 of 79 (86.1%) ARDs patients with mean IFN- γ anti-SARS-CoV-2 titers of 1,606.85 mUI/ml. 7 (8.9%) of ARDs patients showed negative IFN-γ SARS-CoV-2 levels, while 4 (5%) had borderline titers. 100% of patients with previous COVID 19 disease had positive cellular responses. Within the group of negative or borderline cellular responses, 7 of 10 were men (70%), with no significant differences in terms of diagnosis, comorbidities or immunosuppressive treatments used. In the control group, 100% presented positive cellular responses. Anti-Spike IgG antibodies were detectable in all patients with ARDs as in the control group.ConclusionOur preliminary data show that most patients with ARD were able to generate an adequate specific cellular response after vaccination against SARS-CoV-2, emphasizing the relevance of vaccination in this group. Specific antibody responses secondary to anti-SARS-CoV-2 vaccination were detected in all patients with ARD. Our data could support the relevance of these immune responses to personalize prevention, vaccination decision-making and treatment in this subgroup of patients.References[1]Sieiro Santos C, Calleja Antolin S, Moriano Morales C, Garcia Herrero J, Diez Alvarez E, Ramos Ortega F, et al. Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases. RMD Open. 2022 Jan 5;8(1).Figure 1.Specific anti-SARS-CoV-2-IFN- γ responses measured by IGRA. Dotted lines represent positivity cut-off: ≥200mUI/ml. HC: Healthy controls. AIRDs: Autoimmune rheumatic diseases.[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.

EFFICACY AND SAFETY OF ANTI-SARS-CoV-2 VACCINATION IN PEOPLE WITH RMDs: RESULTS FROM A SYSTEMATIC LITERATURE REVIEW

BackgroundAs the third year of the pandemic begins, over 13 billion doses of anti-SARS-CoV-2 vaccines have been administrated worldwide and growing evidence on their efficacy and safety in people with RMDs has accrued.ObjectivesTo update our previous systematic literature review (SLR)[1] on efficacy and safety of anti-SARS-CoV-2 vaccination in people with rheumatic and musculoskeletal diseases (RMDs)MethodsA literature search according to the PICO framework was conducted on July 22, 2022 to identify references in seven databases published after June 1, 2021 (end date of previous SLR). Title and s were independently screened by 3 investigators (AA, AN and FK). Eligibility criteria were stricter in terms of requirement of the inclusion of control group or undertaking a multivariable analysis. However, for some outcomes (e.g., RMD flares), descriptive studies were also included due to the paucity of data. Data extraction and risk of bias (RoB) assessment were performed as in the previous SLR.ResultsOf 1583 references, 219 were included for full text assessment and 30 fulfilled the eligibility criteria. Recent studies confirmed that a full vaccination cycle was generally immunogenic, though the seroconversion rate and the anti-spike antibody (Ab) titre were lower in patients with RMDs compared to healthy controls. Vaccination was also able to induce neutralising antibodies (NAb) but the seroconversion rate and the neutralising activity were lower than in controls. Glucocorticoids, mycophenolate mofetil, rituximab and abatacept were negatively associated with Ab and NAb seroconversion. Two studies specifically investigating RTX-treated RMD patients identified an association between lower dose and longer period of time after the last RTX infusion before vaccination and higher likelihood of Ab seroconversion. The majority of breakthrough infections (B-INFs) were asymptomatic and, if symptomatic, mild to moderate. A higher number of vaccine doses was associated with a lower incidence and severity of B-INFs, although B-INF incidence rate was generally higher in the post-delta variant period. Higher disease activity was associated with higher likelihood of severe/critical B-INFs. Regarding safety, in general, patients with RMDs showed higher rates of mild AEs compared to the general population, however severe AEs were rare, if any. Disease flares have been observed in/reported by less than 10% of patients in the various cohorts and although often requiring treatment with glucocorticoids or change of the ongoing immunosuppressive therapy, hospitalization was generally not needed. Pre-vaccination colchicine prophylaxis seemed useful to prevent gout flares in the post-vaccination trimester.ConclusionOverall anti-SARS-CoV-2 vaccination is immunogenic and safe in patients with RMDs. However, careful and individualised assessment of the ongoing therapy and disease activity when planning the vaccination schedule is necessary to minimise the risk of reduced immunogenicity, post-vaccination disease flares and breakthrough infections.Reference[1]Kroon FPB, Najm A, Alunno A, Schoones JW, Landewé RBM, Machado PM, Navarro Compán V. Ann Rheum Dis. 2022;81(3):422-432Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Long-acting vaccine delivery systems.

Bolus vaccines are often administered multiple times due to rapid clearance and reduced transportation to draining lymph nodes resulting in inadequate activation of T and B lymphocytes. In order to achieve adaptive immunity, prolonged exposure of antigens to these immune cells is crucial. Recent research has been focusing on developing long-acting biomaterial-based vaccine delivery systems, which can modulate the release of encapsulated antigens or epitopes to facilitate enhanced antigen presentation in lymph nodes and subsequently achieve robust T and B cell responses. Over the past few years, various polymers and lipids have been extensively explored to develop effective biomaterial-based vaccine strategies. The article reviews relevant polymer and lipid-based strategies used to prepare long-acting vaccine carriers and discusses their results concerning immune responses.

Humoral immunogenicity of COVID-19 vaccines in patients with inflammatory rheumatic diseases under treatment with Rituximab: a case-control study (COVID-19VacRTX).

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRDs) treated with the anti-CD20 mAb rituximab (RTX) have been identified as high-risk for severe COVID-19 outcomes. Additionally, there is increased risk due to reduced humoral immune response, induced by therapeutic B cell depletion. This study sought to quantify humoral response after vaccination against SARS-CoV-2 in patients with IRD treated with RTX. It also sought to elucidate the influence of the time frame between the last RTX dose and the first vaccination, or the status of B cell depletion on antibody titre. METHODS: In this case-control study, patients with IRDs previously treated with RTX were examined for humoral immune response after completing the first series of vaccinations with approved vaccines [BNT162b2 (Biontech/Pfizer), RNA-1273 (Moderna), AZD1222 (AstraZeneca/Oxford), Ad26.COV2.S (Janssen/Johnson & Johnson)]. Antibody levels were quantified using the Euroimmun Anti-SARS-CoV-2 QuantiVac ELISA (EI-S1-IgG-quant). Blood samples were taken just before the next infusion with RTX after the vaccination. The interval between the last RTX infusion and the first vaccination against SARS-CoV-2 and other possible factors influencing the antibody levels were evaluated. RESULTS: A total of 102 patients were included. Of these, 65 (64%) showed a negative antibody level (<24 IU (international unit)/ml) after the vaccination. The comparative univariate analysis of the antibody levels achieved a significant result (P = 0.0008) for the time between the last RTX infusion and first vaccination against SARS-CoV-2. No CD19+ peripheral B-cells could be detected in 73 of the patients (72%). CONCLUSION: The study confirms the negative impact of RTX on antibody level after vaccination against SARS-CoV-2. A clear relationship exists between the antibody titre and the interval between the last RTX infusion and the first vaccination, the number of peripheral B-cells, and immunoglobulin quantity. Improved understanding of the effect of these parameters can help guide synchronization of vaccination in relation to the RTX therapy regimen.