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.

Validation of dried blood spot sampling for detecting SARS-CoV-2 antibodies and total immunoglobulins in a large cohort of asymptomatic young adults.

BACKGROUND: Detecting antibody responses following infection with SARS-CoV-2 is necessary for sero-epidemiological studies and assessing the role of specific antibodies in disease, but serum or plasma sampling is not always viable due to logistical challenges. Dried blood spot sampling (DBS) is a cheaper, simpler alternative and samples can be self-collected and returned by post, reducing risk for SARS-CoV-2 exposure from direct patient contact. The value of large-scale DBS sampling for the assessment of serological responses to SARS-CoV-2 has not been assessed in depth and provides a model for examining the logistics of using this approach to other infectious diseases. The ability to measure specific antigens is attractive for remote outbreak situations where testing may be limited or for patients who require sampling after remote consultation. METHODS: We compared the performance of SARS-CoV-2 anti-spike and anti-nucleocapsid antibody detection from DBS samples with matched serum collected by venepuncture in a large population of asymptomatic young adults (N = 1070) living and working in congregate settings (military recruits, N = 625); university students, N = 445). We also compared the effect of self-sampling (ssDBS) with investigator-collected samples (labDBS) on assay performance, and the quantitative measurement of total IgA, IgG and IgM between DBS eluates and serum. RESULTS: Baseline seropositivity for anti-spike IgGAM antibody was significantly higher among university students than military recruits. Strong correlations were observed between matched DBS and serum samples in both university students and recruits for the anti-spike IgGAM assay. Minimal differences were found in results by ssDBS and labDBS and serum by Bland Altman and Cohen kappa analyses. LabDBS achieved 82.0% sensitivity and 98.2% specificity and ssDBS samples 86.1% sensitivity and 96.7% specificity for detecting anti-spike IgGAM antibodies relative to serum samples. For anti-SARS-CoV-2 nucleocapsid IgG there was qualitatively 100% agreement between serum and DBS samples and weak correlation in ratio measurements. Strong correlations were observed between serum and DBS-derived total IgG, IgA, and IgM. CONCLUSIONS: This is the largest validation of DBS against paired serum for SARS-CoV-2 specific antibody measurement and we have shown that DBS retains performance from prior smaller studies. There were no significant differences regarding DBS collection methods, suggesting that self-collected samples are a viable sampling collection method. These data offer confidence that DBS can be employed more widely as an alternative to classical serology.

Immune response following mRNA COVID-19 vaccination in patients with multiple sclerosis treated with the Bruton's tyrosine kinase inhibitor evobrutinib

Introduction: Evobrutinib is a highly selective, covalent Bruton's tyrosine kinase inhibitor (BTKi) being investigated for the treatment of relapsing multiple sclerosis (RMS). Previous analysis showed that patients with systemic lupus erythematosus receiving evobrutinib could mount a humoral response to seasonal influenza vaccination. However, the effects of BTKi on vaccine response in patients with MS are presently unknown. Objective(s): To examine the humoral response to mRNA COVID-19 vaccination in patients with RMS (PwRMS) receiving evobrutinib during the open-label extension (OLE) of a Phase II trial (NCT02975349). Method(s): A post hoc analysis of PwRMS who received evobrutinib 75 mg twice-daily and two doses of mRNA COVID-19 vaccination during the OLE (n=24). Immunoglobulin G (IgG) anti-S1 and anti-S2 specific antibodies to COVID-19 were measured using an indirect chemiluminescence immunoassay (DiaSorin Molecular LLC, USA;lower limit of quantification, 3.8 AU/mL;seronegative <15.0 AU/mL [n=19], seropositive >=15 AU/mL [n=5]). Result(s): Baseline mean (+/-SD) age of patients in the analysis was 44.6 (+/-10.1), 79.2% were female and mean/minimum evobrutinib exposure pre-vaccination was 105.8/97.6 weeks. All but one of the evobrutinib-treated patients developed or increased S1/S2 IgG antibody levels after two doses of mRNA vaccine (geometric mean [SD] pre-/post-vaccination: 6.7 [2.6]/209.1 [3.6] AU/mL;median pre-/post-vaccination: 3.8/185.0 AU/mL). Patients who were either S1/S2 IgG seronegative or seropositive pre-vaccination demonstrated a strong antibody response following vaccination (seronegative pre-/post-vaccination median: 3.8/167.0 AU/ mL;seropositive pre-/post-vaccination median: 26.2/715.0 AU/ mL). The majority of patients (n=22), whether seronegative or positive, had at least a 10-60-fold induction of S1/S2 IgG antibody levels from pre-to post-vaccination (median fold change of S1/S2 IgG antibody levels for total/seronegative/seropositive patients: 32.6/34.2/18.3). Conclusion(s): PwRMS treated with evobrutinib were able to mount an antibody response to two doses of mRNA COVID-19 vaccination. The marked increase in antibody response in seronegative and seropositive patients demonstrates a preserved response to novel and recall antigens in PwRMS undergoing BTKi with evobrutinib. This demonstration of a strong humoral response to vaccination during evobrutinib treatment is the first such evidence for any BTKi under investigation for the treatment of MS.

Second SARS-CoV-2 Booster Vaccination Significantly Reduces Haemodialysis Patients' Susceptibility to Infection With Omicron Variant

Background: Patients requiring haemodialysis (HD) have disproportionately poorer outcomes from SARS-CoV-2 infection and vaccines afford an opportunity to improve this. However, the efficacy of booster doses on infection with emerging variants remains unclear in this population. Method(s): We report the real-world impact of SARS-CoV-2 booster vaccinations in an ethnically diverse urban cohort of 1172 patients receiving in-centre HD who were routinely screened for SARS-CoV-2 infection by weekly nasopharyngeal PCR between 1st December 2021 and 31st March 2022, during dominant UK prevalence of B.1.1.529 variant ("Omicron"). Where possible, genomic sequencing was performed as standard of care. Result(s): At the start of the observation period, 896 (76.5%) had received 3 doses of SARS-CoV-2 vaccine and only 87 (7.4%) were unvaccinated. By end of study 664 (59.5%) had received 4 vaccine doses. 305 patients had PCR positive SARS-CoV-2 infection, with Omicron variant confirmed in all but one of samples successfully tested. Clinical course of infection was mild: around half of patients asymptomatic, only 1 in 20 hospitalised, case fatality 3%. Three or more vaccine doses significantly associated with reduced risk of SARS-CoV-2 PCR positivity compared to unvaccinated status, together with White ethnicity and lower deprivation index (Cox regression p<0.03). However, 2 booster doses further reduced the risk of infection by around a third compared to 1 boost, independent of age, gender and comorbidity. Conclusion(s): A second SARS-CoV-2 booster vaccine further reduces the risk of Omicron infection in haemodialysis patients. As such, a double-boost policy could significantly reduce the burden and associated spread of SARS-CoV-2 infection in this vulnerable population.

FAECAL MICROBIOTA TRANSPLANT IN ULCERATIVE COLITIS (FMTUC) – A RANDOMISED CLINICAL TRIAL FEASIBILITY STUDY

Background Dysbiosis of the gut microbiota may be responsible for the pathogenesis of ulcerative colitis (UC). Restoration of gut microbiota diversity by means of faecal microbiota transplantation (FMT) is of increasing interest as a therapeutic option in the management of UC. The aims of this phase II feasibility study are to estimate the magnitude of treatment response to FMT in treatment-naïve patients with newly diagnosed UC, evaluate donor and patient recruitment rates and determine optimal study conditions for phase III study (ISRCTN 58082603). Methods Treatment-naïve patients with histologically confirmed UC below the sigmoid were recruited. Subjects were randomised to single FMT enema, five daily enemas and control group. All groups received antibiotic for 10 days and bowel preparation 48 hours before the interventions. They were followed up for 12 weeks with quality of life (QOL) scores (IBDex, CUCQ-32) and 16S RNA study on faecal samples. Endoscopic (Mayo score) and histological assessments were performed at the baseline and week 12. The primary endpoints were endoscopic remission of UC and rate of persistent microbial engraftment at 12 weeks. Secondary endpoints included QoL and mucosal cytokine profiling with IL-10. Clinical remission was defined as Mayo score ≤ 2 with an endoscopic Mayo score of 0. Results Eighteen UC patients were recruited between July 2016 and February 2020 until the COVID-19 pandemic, of those five achieved clinical remission. One subject from the control group withdrew at week 4 due to worsening symptoms. 72% improved Mayo and QOL scores, and 44% avoided medical treatment. Clinical remission was more observed among subjects with lower baseline QoL and mild-moderate disease, although this did not reach statistical significance (P=0.173). No correlation between FMT dose, frequency and clinical remission were observed. The 16S evaluation of the faecal samples demonstrated successful engraftment of FMT and showed a similar faecal microbiota profile amongst the intervention groups, which was markedly different from the control group. Coprococcus was found to be much more abundant amongst subjects who responded to the FMT intervention. This study also suggested an inverse correlation between IL-10 and the severity of UC. Conclusions FMT intervention protocols were well adhered and 94% completion rate, though the recruitment period was much longer than the original plan due to some unforeseen interruptions. Yet, this feasibility study demonstrated potential for employing this method for a larger multicentre RCT to further evaluate FMT dose and frequency effects. The correlation between IL-10 and IL-10 producing microorganisms should be sought in the future study.

DEFINING IMMUNOGENIC PEPTIDES TARGETING SARS-CoV-2 VARIANTS of CONCERN

Background: Identifying Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) specific T-cell epitope-derived peptides that are also found within variants of concern (VOC) is critical for measuring the duration of cellular immunity induced by the virus and COVID-19 vaccines. Therefore, we assessed whether the peptides selected from topologically important regions of SARS-CoV-2 proteins avoid major mutations of VOC and induce T-cell immune response. Methods: We selected 32 peptides within topologically important regions of SARS-CoV-2 Spike (S) and Nucleocapsid (NC) proteins by applying an insilico pipeline to 607 viral sequences in 2019. To determine if these peptides avoid VOC mutations, we analyzed S and NC protein regions derived from 1.7 x 106 viral genomic sequences compiled from Mar 2020-Aug 2021. We identified α-, β-and δ-VOC mutations found within >1% of the S and NC protein sequences. These mutations were compared to the peptides. To determine T-cell immune response to these selected peptides as a pool, we assessed interferon-γ (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and CD107a/b (degranulation marker) production within peripheral blood mononuclear cell (PBMC) samples derived from COVID-19 post-recovery donors (n=23) by employing dual color FluoroSpot and intracellular cytokine staining (ICS). Results: We found 88% of S protein-derived peptides did not contain mutations of α-, β-and δ-VOC. All peptides from S protein (n=25) avoided known T-cell escape mutations. Of the 7 NC-derived peptides, three contained the L139F mutation found within α-and δ-VOC, however, this mutation was observed within <2% NC protein sequences. A peptide pool containing our 32 selected peptides elicited an immune response within PBMCs from 17/23 COVID-19 post-recovery donors. FluoroSpot analysis revealed IFN-γ and IL-2 production to our peptide pool was similar/higher compared to the commercial S and NC peptide pools. The response of CD4 and CD8 T-cells to our peptide pool was polyfunctional expressing ≥2 markers within most of the donors when ICS was performed, with IFN-γ and TNF-α being the main cytokines produced. Conclusion: Applying an immunoinformatics pipeline allowed us to select peptides from the S and NC proteins which avoid the majority of mutations found within the α-, β-and δ-VOC. Our peptide pool elicited a polyfunctional T-cell response making it an ideal candidate for assessing the duration of cellular immunity induced by SARS-CoV-2 variants and vaccines.

Telemedicine Use and Acceptability among Older Adults During the COVID Pandemic

Background: Telemedicine utilization has increased dramatically during the COVID pandemic. Few studies have evaluated the use and acceptability of telemedicine in older populations. This study examined the use and acceptability of telemedicine with older adults in an urban, geriatric practice. Methods: An anonymous survey was sent to patients seen at an urban, geriatric practice using MyChart in EPIC in March 2021. This population of patients is 55 years and older, 50% Black, 40% white, 3% Latino, 3% Asian and 4% other. This panel is comprised of 71% Medicare, 23% non-Medicare/non-Medicaid, and 6% Medicaid. The total panel of patients includes approximately 1400 patients. The percent of patients on MyChart at the time of the survey was 78%. Thus about 1092 patients received the survey. Results: 247 (22.6%) patients responded to the survey. 80.37% of respondents rated their overall experience with telemedicine as good or excellent. Theme areas emerged around the advantages and disadvantages of telemedicine as described in Table 1. 70.28% of respondents rated themselves as Somewhat Confident to Very Confident in use of telemedicine without family/friend assistance. 74.16% of respondents state they plan to use telemedicine again. Conclusions: This survey demonstrated the feasibility and acceptability of telemedicine in an urban, geriatric population. A limit to this study is that the survey was administered on-line, so that participants may be biased regarding use of on-line technology. However, this study showed that the vast majority of older adults were confident in using telemedicine as an alternative to in-person visits during the COVID pandemic and plan on using it again.

Faecal Microbiota Transplant in Ulcerative Colitis (FMTUC) - A randomised clinical trial feasibility study

Background: Dysbiosis of the gut microbiota may be responsible for the pathogenesis of ulcerative colitis (UC). Restoration of gut microbiota diversity by means of faecal microbiota transplantation (FMT) is of increasing interest as a therapeutic option in the management of UC. The aims of this phase II feasibility study are to estimate the magnitude of treatment response to FMT in treatment-naïve patients with newly diagnosed UC, evaluate donor and patient recruitment rates and determine optimal study conditions for phase III study (ISRCTN 58082603). Methods: Treatment-naïve patients with histologically confirmed UC below the sigmoid were recruited. Subjects were randomised to three arms;single FMT enema, five daily enemas and control. All groups received antibiotic for 10 days and bowel preparation 48 hours before the interventions. They were followed up for 12 weeks with quality of life (QOL) scores (IBDex, CUCQ-32) and 16S RNA study on faecal samples. Endoscopic (Mayo score) and histological assessments were performed at the baseline and week 12. The primary endpoints were endoscopic remission of UC and rate of persistent microbial engraftment at 12 weeks. Secondary endpoints included QoL and mucosal cytokine profiling with IL-10. Clinical remission was defined as Mayo score ≤ 2 with an endoscopic Mayo score of 0. Results: Eighteen UC patients were recruited between July 2016 and February 2020 until the COVID-19 pandemic, of those five achieved Clinical remission. One subject from the control group withdrew at week 4 due to worsening symptoms. 72% improved Mayo and QOL scores, and 44% avoided medical treatment. Clinical remission was more observed among subjects with lower baseline QoL and mildmoderate disease, although this did not reach statistical significance (P=0.173). No correlation between FMT dose, frequency and clinical remission were observed. The 16S evaluation of the faecal samples demonstrated successful engraftment of FMT and showed a similar faecal microbiota profile amongst the intervention groups, which was markedly different from the control group. Coprococcus was found to be much more abundant amongst subjects who responded to the FMT intervention. This study also suggested an inverse correlation between IL-10 and the severity of UC. Conclusion: FMT intervention protocols were well adhered and achieved 94% completion rate, though the recruitment period was much longer than the original plan due to unforeseen interruptions. Yet, this feasibility study demonstrated potential for employing this method for a larger multicentre RCT to further evaluate FMT dose and frequency effects. The correlation between IL-10 and IL-10 producing microorganisms should be sought in the future study.

Validation of a combined ELISA to detect IgG, IgA and IgM antibody responses to SARS-CoV-2 in mild or moderate non-hospitalised patients.

BACKGROUND: Frequently SARS-CoV-2 results in mild or moderate disease with potentially lower concentrations of antibodies compared to those that are hospitalised. Here, we validated an ELISA using SARS-CoV-2 trimeric spike glycoprotein, with targeted detection of IgG, IgA and IgM (IgGAM) using serum and dried blood spots (DBS) from adults with mild or moderate disease. METHODS: Targeting the SARS-CoV-2 trimeric spike, a combined anti-IgG, IgA and IgM serology ELISA assay was developed using 62 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 624 COVID-19 negative samples. The assay was validated using 73 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 359 COVID-19 negative serum samples with an additional 81 DBSs. The assay was further validated in 226 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 426 COVID-19 negative clinical samples. RESULTS: A sensitivity and specificity of 98.6% (95% CI, 92.6-100.0), 98.3% (95% CI, 96.4-99.4), respectively, was observed following validation of the SARS-CoV-2 ELISA. No cross-reactivities with endemic coronaviruses or other human viruses were observed, and no change in results were recorded for interfering substances. The assay was stable at temperature extremes and components were stable for 15 days once opened. A matrix comparison showed DBS to correlate with serum results. Clinical validation of the assay reported a sensitivity of 94.7% (95% CI, 90.9-97.2%) and a specificity of 98.4% (95% CI, 96.6-99.3%). CONCLUSIONS: The human anti-IgGAM SARS-CoV-2 ELISA provides accurate and sensitive detection of SARS-CoV-2 antibodies in non-hospitalised adults with mild or moderate disease. The use of dried blood spots makes the assay accessible to the wider community.