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Introduction: Immune responses following SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) are not well characterised, and limited data is available regarding the humoral immune response related to the underlying bowel disease and serum concentrations of biologics and thiopurine metabolites. Aims & Methods: This prospective, observational study included adult patients with ulcerative colitis (UC) and Crohn's disease (CD), and healthy controls. Sera were analysed for antibodies binding the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, and anti-RBD >=70 AU/ml was defined as serologic response. Anti-RBD and serum concentrations of the ongoing immunosuppressive medications were measured prior to, and 2-5 weeks after the second vaccine dose. The aims of this study were to explore the serologic response associated with the underlying bowel disease and immunosuppressive medications including serum concentrations of biologics and thiopurine metabolites. Result(s): The study included 958 IBD patients (380 UC, 578 CD), median age 40 (Q1;Q3 29;52), and 323 healthy controls, age 44 (33;56). The type and frequency of ongoing immunosuppressive therapy was comparable between the UC and CD patients. The median (Q1;Q3) anti-RBD level (AU/ml) was lower in patients (618 (192;4370)) compared to controls (3355 (896;7849)) post vaccination (p<0.001), and the antibody levels were lower in CD (439 (174;3304)) compared to UC (1088 (251;5975)) (p<0.001). No association between serum concentration and serologic response was demonstrated in patients treated with tumor necrosis factor inhibitor (TNFi) monotherapy, TNFi + thiopurines, vedolizumab, and ustekinumab. Patients treated with TNFi + thiopurines with low 6-thioguanine nucleotides (6-TGN) levels (<3.5 pmol/8x108RBC) demonstrated a higher response rate (93%) than patients who had 6-TGN levels within the therapeutic range (>=3.5 pmol/8x108RBC) (53%) (p=0.003). In the multiple regression model, UC as compared to CD, higher BMI, and mRNA-1273 vaccine were associated with higher odds for serologic response (Table). Older age and patients on treatment with TNFi + thiopurines were associated with lower odds ratios for a serologic response (Table). Treatment with TNFi monotherapy, disease activity (CRP, calprotectin, disease indices) gender and smoking were not associated with serologic response. Conclusion(s): No association between serum drug concentrations for any biologics and the humoral immune response to SARS-CoV-2 vaccines were demonstrated. However, TNFi in combination with thiopurines were associated with an attenuated serologic response, and the serologic response in general was significantly reduced in CD compared to UC patients. Our results indicate that SARS-CoV-2 vaccines can be provided without consideration to the timing of biologic doses in IBD patients and will aid decision-making regarding re-vaccinations and tailoring of medication in order to keep vulnerable IBD patients protected against serious SARSCoV-2 infection.
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Introduction: Limited data is available regarding long-term effectiveness of SARS-CoV-2 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy. Whether the persistence of vaccine-induced humoral immunity differs between IMID patients and the general public is currently unknown. Aims & Methods: IMID patients on immunosuppressive medication and healthy controls were enrolled in the prospective, observational Nor-vaC study. Serum samples were collected at two time points following two dose SARS-CoV-2 vaccination (first assessment within 6-48 days and second within 49-123 days). Sera were analysed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Anti-RBD <200 BAU /ml were defined as low levels. The estimated percent reduction in anti-RBD standardised to 30 days was calculated and factors associated with reduction were identified in multivariable regression models. The aims of the study were to compare the persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses between IMID patients and healthy controls, and to identify predictors of antibody decline. Result(s): A total of 1097 patients (190 Crohn's disease, 129 ulcerative colitis, 400 rheumatoid arthritis, 189 psoriatic arthritis, 189 spondyloarthritis) (median age 54 years [IQR 43-64];56% women) and 133 controls (age 45 years [35-56];83% women) provided blood samples within the defined intervals (median 19 days [IQR 15-24] and 97 days [86-105] after second vaccine dose). Of the patients, 464 used tumor necrosis factor inhibitor (TNFi) monotherapy, 259 TNFi + metabolite inhibitor(s), 212 methotrexate monotherapy, 42 interleukin inhibitors, 34 vedolizumab, 29 rituximab, and 23 janus kinase inhibitors. Antibody levels were significantly lower in patients compared to controls at both assessments, with median anti-RBD 1468 BAU/ml [IQR 500-5062] in patients and 5514 BAU/ml [2528-9580] in controls (p<0.0001) and 298 BAU/ml [IQR 79-500] in patients and 715 BAU/ ml [28-2870] in controls (p<0.0001), at first and second assessment respectively. At the second assessment, anti-RBD antibody levels decreased below 200 BAU/ml in 452 (41%) patients and in 1 (0.8%) control (p<0.0001) (Table). The percentage change in anti-RBD levels were -86 % in patients and -77 % in controls (p<0.0001). In the multivariable regression analyses, patients had a greater decline in anti-RBD levels compared to controls beta -3.7 (95% CI -6.0, -1.4) (p<0.001). Use of TNFi in mono- or combination therapy was associated with the greatest decline compared to controls, beta -6.1 (95% CI -8.1, -4.1) and beta -6.4 (-8.4, -4.2) respectively (p<0.001). Conclusion(s): Within four months after the second vaccine dose, anti-Spike antibody levels declined considerably in both IMID patients and controls. Patients had lower antibody levels at the first assessment and a more pronounced decline compared to controls, and were consequently more likely to have low antibody levels four months after the second vaccine dose. Our results support that IMID patients lose humoral protection and need additional vaccine doses sooner than healthy individuals. (Table Presented).
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Introduction: Humoral vaccine responses to SARS-Cov-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID). Concerns have been raised regarding their protection against severe COVID-19 disease. Knowledge regarding efficacy and safety of repeated vaccination in this large patient group is currently lacking. Aims & Methods: The prospective observational Nor-vaC study (NCT04798625) enrolled adult patients on immunosuppressive therapy for inflammatory bowel-and joint diseases. Healthy controls were health care workers from participating hospitals. All participants received standard vaccines according to the national vaccination program with three doses in patients and two doses in controls. The third dose was offered to IMID patients >4 weeks after the second dose. Anti-Spike antibodies were assessed 2-4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2-4 weeks following three-and two-dose vaccination in patients and controls, respectively. Levels were compared across groups by Mann-Whitney U test. Factors associated with anti-Spike antibody level following the third dose were assessed by uni-and multivariable linear regression adjusted for time between vaccine and sampling. The aim of the study was to evaluate humoral immune responses and safety of repeated vaccination in IMID patients. Result(s): Overall, 1100 patients (156 ulcerative colitis, 217 Crohn's disease, 366 rheumatoid arthritis, 177 spondyloarthritis, and 184 psoriatic arthritis;median age 54 [IQR 42-64];602 women [55%]) and 303 controls (median age 43 [IQR 33-55];226 women [75 %]) were included. Immunosuppressants were tumor necrosis factor inhibitor (TNFi) monotherapy (n=461), TNFi with concomitant immunomodulator (n=254), methotrexate (n=220), vedolizumab (n=46), janus kinase inhibitors (n=33), and other (n=86). Vaccine series were Pfizer BNT162b2 (54% patients, 54% controls), Moderna mRNA-1273 (17% patients, 23% controls), or combination of vaccines (29% patients, 23% controls)). Patients received the third vaccine dose a median of 126 (IQR 105-154) days after the second dose. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/ml (2138-8732) compared to 4495 (1591-6639) in controls receiving two doses, p=0.27. In patients, anti-Spike antibody levels increased by a median of 1932 BAU/ ml (IQR 150-4978) from the second to the third dose, p<0.001. Factors associated with response were a greater interval between the second and third vaccine dose (>5 months) (p=0.03), vaccination with mRNA-1273 (p<0.001), and a combination of vaccines (p<0.001). Antibody levels had a slower decline-rate following the third vaccine dose, as compared to after the second dose, with a significant difference (p<0.001). Adverse events were reported by 488 (53%) and 464 (47%) patients after second and third dose, respectively, and by 196 (68%) controls. Disease flares were reported by 50 (5%) and 70 (7%) patients following the second and third dose. Conclusion(s): This large observational study shows that additional vaccine doses to IMID patients contributes to strong and sustained immune-responses comparable to healthy persons vaccinated twice. This study highlights the importance of repeated vaccination of IMID patients to ensure a stronger and more durable protection from severe COVID-19.
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Purpose: Liver transplant (LT) recipients have a decreased response to 2 doses of SARS-CoV-2 vaccine compared to the general population, so we aimed to understand response to a third dose to inform vaccination strategies. Method(s): LT recipients in our observational cohort who received 3 homologous mRNA vaccines and available antibody levels pre- and post-dose 3 (D3) were identified. Those who reported a prior COVID-19 diagnosis or used belatacept were excluded. The peak anti-spike antibody level collected between the second (D2) and third dose (D3), was compared to the antibody level at 1 month post-D3. Samples were tested with Roche Elecsys Anti-Sars-CoV-2 enzyme immunoassay (EIA) (positive >=0.8 U/mL) or EUROIMMUN EIA (positive >=1.1 AU). Result(s): 146 participants completed 3 homologous doses of BNT162b2 (53%) or mRNA-1273 (47%) vaccines between 5/15/2021 - 11/8/2021. The median (IQR) time of peak pre-D3 antibody collection was 89 (31, 104) days post-D2. The median time of 1-month post-D3 antibody collection was 30 (23, 33) days. The median time between D2 and D3 was 168 (149-188) days. Overall, 125/146 (86%) were seropositive pre-D3, and 139/146 (95%) were seropositive post-D3 (Figure 1). There were no seroreversions post D3, and among the 21 seronegative recipients pre-D3, 14 (67%) seroconverted post-D3. Risk factors significantly associated with persistent seronegativity post-D3 were less time since LT (1.3 vs 6 years, p=0.042), mycophenolate use (100% vs 37%, p=0.001), BNT162b2 series (100% vs 50%, p=0.01), and pre-D3 seronegative status (86% vs 10%, p<0.001). Conclusion(s): Most LT recipients have excellent responses to a third homologous mRNA vaccine dose, greater than that seen in other transplant recipients. Persons seronegative after D2, however, show weaker response and may remain at high risk for SARS-CoV-2 infection despite D3.
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Purpose: Humoral response to COVID-19 vaccines is attenuated in many solid organ transplant recipients (SOTRs), necessitating additional primary and booster vaccinations. The omicron variant demonstrates substantial immune evasion, and it is not known if boosters increase neutralizing capacity versus omicron among SOTRs. We therefore investigated SOTR antibody response and neutralization versus variants of concern (VOC) including omicron to a 4th vaccine dose (D4). Method(s): Within a national, prospective observational cohort, 25 SOTRs underwent anti-SARS-CoV-2 spike and receptor binding domain (RBD) IgG testing using the Meso Scale Discovery platform before and 2-4 weeks after D4. Surrogate neutralization (%ACE2 inhibition [%ACE2i], range 0-100% with >20% correlating with live virus neutralization), was measured versus full spike proteins of the ancestral ("vaccine") strain and 5 VOCs including delta and omicron. Change in IgG level and %ACE2i were compared using paired Wilcoxon rank-sum testing. Result(s): Demographics are outlined in Table 1, including median (IQR) age 59 (45- 55) years, 64% kidney recipients, and D4 receipt (60% Moderna, 40% Pfizer) median (IQR) 93 days (28-134) post D3. Two participants had SARS-CoV-2 exposure per anti-nucleocapsid testing, including one incident infection. Overall, anti-RBD (92%- >100%) and anti-spike (84%->92%) seropositivity increased after D4, as did median (IQR) anti-spike IgG 42.3 (4.9-134.2)->228.9 (115.4-655.8) WHO binding antibody units (p<0.05). Median (IQR) %ACE2i significantly increased after D4 vs the vaccine strain 5.8% (0-16.8)->20.6% (5.8-45.9) and delta variant 9.1% (4.9-12.8)->17.1% (10.3-31.7) (both p<0.001). In contrast, no SOTR showed neutralization vs omicron before or after D4: median (IQR) %ACE2i 4.1% (0-6.9)->0.5% (0-5.7) (p=0.11). Conclusion(s): Although a 4th vaccine dose increased anti-spike IgG and neutralizing capacity vs some VOC, there was no omicron variant neutralization among SOTRs. SOTRs may remain at high risk for SARS-CoV-2 infection despite boosting, thus additional protective interventions should be urgently explored. (Figure Presented).
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Purpose: Solid organ transplantation decreased during the SARS-CoV-2 pandemic largely due to temporary shutdowns. The pandemic revealed significant gaps in medical knowledge among the public;disinformation, distrust, and the advent of SARS-CoV-2 may have lingering effects on transplantation rates. We hypothesize that the SARS-CoV-2 pandemic has influenced interest in living kidney donation (LKD) among members of the public. Method(s): We surveyed 900 US adults (ages 25-65) in June 2021 about LKD knowledge, attitudes, perceived barriers/facilitators, and impact of the pandemic on their interest in LKD. We evaluated the relationships between self-reported characteristics and interest in LKD using Chi-square tests. Result(s): The experience of the SARS-CoV-2 pandemic increased interest in LKD for 12% of participants, decreased interest for 9%, and had no impact for 79%. Increased interest in LKD was significantly associated with White race (White only vs. Asian only: 12.4% vs. 9.4%, p=0.005), younger age (25-34 vs. 55-65: 16.7% vs. 6.1%, p<0.0001 and 35-44 vs. 55-65: 15.9% vs. 6.1%, p<0.0001), male gender (16.3% vs. 8.5%, p= 0.001), higher income ($100,000-149,000 vs. <$50,000: 18.9% vs. 7.5%, p=0.0008), and higher educational attainment (4-year degree vs. some college: 14.4% vs. 6.07%, p=0.0012 and post-graduate degree vs. some college: 21.5% vs. 6.1%, p= <0.0001). Conclusion(s): The SARS-CoV-2 pandemic only impacted 21% of participants' interest in LKD, highlighting an unexpected externality of the pandemic. These findings unveil new opportunities for community engagement and population groups to target in future education and outreach campaigns.
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Purpose: nti-spike antibody response to SARS-CoV-2 vaccination is diminished in LT recipients compared to the general population so understanding durability for those that do respond is critical to mitigating risks of infection. We measured serial antibody titers in LT recipients for 6 months after two-dose mRNA vaccine series to describe kinetics and sero-reversion rates. Method(s): LT recipients without known prior COVID-19 had anti-spike antibody testing at 1, 3, and 6 months after the second dose of mRNA vaccine (D2) using two commercial assays (Roche Elecsys anti-receptor binding domain immunoassay (EIA) [positive >=0.8 U/mL] or EUROIMMUN anti-S1 EIA [positive >=1.1 AU]). We compared titer distributions over time and identified factors associated with sero-reversion. Result(s): 180 LT recipients received BNT162b2 (48%) or mRNA-1273 (52%) 2-dose series between 1/7/2021-5/7/2021. At 1 month post-D2 (n=173), 146 (84%) had positive antibody levels at a median (IQR) of 30 (28, 32) days post-D2. At 3 months post-D2 (n=164), 149 (91%) had positive levels at a median of 92 (90, 96) days post-D2. At 6 months post-D2 (n=73), 62 (85%) had positive levels at a median of 180 (176, 185) days post-D2. Among the 66 seropositive at 1 or 3 months post-D2, 58 (88%) remained seropositive by 6 months post-D2. Neither age, years since transplant, vaccine type, nor mycophenolate (MMF) use were associated with sero-reversion, though there was a trend toward more triple immunosuppressive use (25% vs 3%, p=0.07). Of those Roche-tested, the median anti-RBD levels were >=250 U/mL (14, >=250;n=120) at 1 month post-D2, >=250 U/mL (58, >=250;n=113) at 3 months, and >=250 U/mL (30, >=250;n=49) at 6 months . Of those EUROIMMUN-tested, the median anti-S1 levels were 7.25 AU (4.31, 8.71;n=53) at 1 month, 5.71 AU (1.27, 7.90;n=51) at 3 months, and 1.73 AU (0.76, 6.01;n=25) at 6 months. Conclusion(s): Overall, most LT recipients demonstrated 6 month durability of anti-spike antibody following vaccination, but a subset did sero-revert, potentially associated with heavier immunosuppression. Further investigation into clinical consequences of waning antibody levels is key to guide timing of additional vaccine doses.
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Purpose: Heart and lung transplant (HT/LT) recipients have impaired humoral responses to SARS-CoV-2 vaccination compared to other solid organ transplant recipients (SOTRs). The purpose of this study is to describe antibody titer kinetics and durability among HT and LT recipients. Method(s): HT or LT recipients (> 18 years) with no known COVID-19 infection were included. Demographics and clinical characteristics were collected via survey. Serologic testing was performed on the Roche Elecsys anti-SARS-CoV-2 enzyme immuno-assay (EIA) or the EUROIMMUN EIA pre- and post-dose 2 (D2). Result(s): Among 93 HT recipients, 59 (63%) were seropositive 1 month and 66 (71%) 3 months post-D2 (Table 1). Seropositive HT recipients had a higher median length of time from transplant to vaccination. 7/66 (11%) had delayed seroconversion (were negative for antibodies 1-month post-D2). Median(IQR) anti-RBD was 81 (8, 250) 1-month post-D2 (n=38) and 231 (48, 438) U/mL 3-months post-D2 (n=43) (Figure 1). Among 68 LT recipients, 29/68 (43%) were seropositive 1-month and 30 (44%) 3-months post-D2. Seronegative LT recipients were more likely to younger (18-39 years old, 15% vs 3%), or older (> 60 years, 74% vs. 50%, p=0.01). Seronegative LT recipients were more likely to be on anti-metabolite therapy (79% vs. 53%, p=0.04) and had a lower median length of time from transplant to vaccination. Among seropositive LT recipients at 3-months, 3 (10%) had delayed seroconversion. Median (IQR) anti-RBD was 61 (4, 233) U/mL 1-month post-D2 (n=26) and 45(11, 299) U/mL 3-months post-D2. Conclusion(s): HT and LT recipients develop a delayed and variable antibody response to mRNA SARS-CoV-2 vaccination. HT recipients more frequently seroconverted, and had higher anti-RBD levels, than LT recipients. Persistent negative and low antibody titers may place LT recipients at the highest risk of breakthrough SARSCoV- 2 infection among SOTRs.
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Purpose: Some solid-organ transplant recipients (SOTRs) with low or negative antibody levels after a 2-dose mRNA vaccine series against SARS-CoV-2 experience boosting after a third dose (D3), but long-term antibody durability after D3 is unknown. We describe six-month SARS-CoV-2 antibody kinetics and durability in 31 SOTRs who received D3. Method(s): 31 SOTRs without prior COVID-19 were identified within our national observational study. Serologic testing was performed a median of 30 (IQR 27-40) days after D3 and repeated at a median of 166 (148-184) days after D3. Semiquantitative anti-spike serologic testing using the Roche Elecsys anti-S enzyme immunoassay (EIA) or EUROIMMUN anti-S1 EIA was performed. Result(s): Over 6 months of follow-up, antibody levels increased in 16/27(59%), remained stable in 6/27(22%) (one negative, the others above the assay limit), and decreased in 5/27(19%). One-month post-D3, 24/31(77%) were seropositive and 7/31(23%) were seronegative. Six-months post-D3, 29/31(94%) were seropositive and 2/31(6%) remained seronegative. Both nonresponders received the BNT-162b2 primary series;one received Ad.26.CoV2.S and the other mRNA-1273 for D3. This difference in seroconversion after D3 was not statistically significant (Fisher exact = 0.49, between primary series). There were no reported cases of COVID-19 during the study period. Conclusion(s): We observed a very high rate of seroconversion after D3 in SOTRs, with marked heterogeneity in timing and strength of response depending on baseline antibody level and vaccine platform received. These results are encouraging evidence for the durable immunogenicity of additional vaccine doses in most SOTRs, and demonstrate the need for dedicated analysis of heterologous boosting strategies.
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Purpose: While SARS-CoV-2 vaccination has dramatically reduced COVID-19 severity in the general population, fully vaccinated solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates. Furthermore, a third vaccine dose only increases antibody and T cell responses in a proportion of SOTRs. We sought to investigate the underlying mechanisms resulting in varied humoral responses in SOTRs. Method(s): Within a longitudinal prospective cohort of SOTRs, anti-spike IgG, total and spike-specific B cells were evaluated in 44 SOTR participants before and after a third vaccine dose using high dimensional flow cytometry to assess immunologic and metabolic phenotypes. B cell phenotypes were compared to those of 10 healthy controls who received a standard two-dose mRNA series. Result(s): Notably, even in the absence anti-spike antibody after two doses, spikespecific B cells were detectable in most SOTRs (76%). While 15% of participants were seropositive before the third dose, 72% were seropositive afterward. B cells, however, were differentially skewed towards non-class switched B cells in SOTRs as compared to healthy control B cells. Expansion of spike-specific class-switched B cells in SOTRs following a third vaccine dose correlated with increased classswitched (IgG) antibody titers. Antibody response to a third vaccine dose was associated with expanded populations of germinal center-like (CD10+CD27+) B cells, as well as CD11c+ alternative lineage B cells with specific upregulation of CPT1a, the rate limiting enzyme of fatty acid oxidation and a preferred energy source of germinal center B cells. Conclusion(s): This analysis defines a distinct B cell phenotype in SOTRs who respond to a third SARS-CoV-2 vaccine dose, specifically identifying fatty acid oxidation as pathway that could be targeted to improve vaccine response such as through targeted immunosuppressive modulation. (Figure Presented).
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Purpose: Mycophenolate mofetil (MMF) use is associated with decreased antibody response to the SARS-CoV-2 mRNA vaccine series in heart and lung transplant recipients (HLTRs). Higher MMF doses have been associated with poor immunogenicity in kidney transplant recipients, but limited data exist on HLTRs. We evaluated the relationship between daily MMF dose and vaccine-induced antibody response in HLTRs. Method(s): HLTRs (n= 212) from an observational cohort were categorized by daily MMF doses (None, Low: <1000mg, Moderate: 1000-2000mg, High: >=2000mg). Semi-quantitative antibody testing was performed at 1, 3, and 6-months post-dose 2 (D2) using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (EIA), testing for antibodies to SARSCoV2 spike protein receptor binding domain, and the EUROIMMUN EIA, testing for S1 domain of SARS-CoV-2 spike protein. Multivariable Poisson regression was used to estimate the risk of a negative antibody response with increasing MMF dose. Result(s): At the time of vaccination, 94 (44.3%) HLTRs reported receiving no MMF, 33 (15.6%) reported a low dose, 54 (25.7%) reported a moderate dose, and 31 (14.8%) reported a high dose regimen. There were statistically significant differences in the number of participants on mTOR inhibitors and Triple immunosuppression among the groups but the participants in all 4 dose categories were otherwise comparable (Table 1) The risk ratio of a negative post-D2 titer with low, moderate and high dose regimens compared to no MMF was 0.65 1.15 2.05 (p=0.63), 1.34 2.043.10 (p=0.001) and 1.83 2.77 4.21 (p<0.001) after adjusting for age, sex, vaccine type, time since transplant, and corticosteroid use. Conclusion(s): HLTRs taking MMF >1000mg/day are at higher risk of remaining seronegative after mRNA vaccination, with evidence of a dose-nonresponse effect. The findings support the exploration of whether targeted MMF reduction strategies in HLTRs increase SARS-CoV-2 vaccine immunogenicity. (Table Presented).
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Purpose: To compare antibody response to a third dose (D3) of SARS-CoV-2 vaccine in solid organ transplant recipients (SOTRs) with negative or low-positive antibody levels after 2-dose mRNA vaccination across D3 platforms. Method(s): From our observational study, 532 SOTRs who developed suboptimal antibody responses to 2-dose mRNA vaccination (Roche<50 U/mL or EUROIMMUN <1.1 AU) were selected. Belatacept recipients and persons with any COVID-19 diagnosis were excluded. We compared post-D3 antibody levels among SOTRs who received an mRNA vaccine for D3 (n=487) versus Ad.26.COV2.S for D3 (n=45). Poisson regression with robust standard error was used to study the association between vaccine platform and seroconversion, adjusting for immunosuppression, age, time since transplant, and liver transplant status. Result(s): Pre-D3, 342 SOTRs (64%) were seronegative, of whom 107 (31%) developed high-positive antibody levels post-D3. In contrast, of the 190 (36%) with low-positive pre-D3 antibody levels, 172 (91%) were high-positive post-D3 (Figure 1). Among SOTRs seronegative pre-D3, 1.8x more Ad.26.COV2.S D3 recipients seroconverted compared to mRNA D3 recipients (49.7% vs 27.8%, Fisher's exact=0.014) (Figure 2). Among the pre-D3 seronegative group, there was a 2x higher chance of developing high-positive post-D3 levels with Ad.26.COV2.S compared to mRNA D3 (IRR =1.42.02.9, p<0.001). This was despite the Ad.26. COV2.S D3 group having fewer younger patients and liver transplant recipients, factors that are associated with higher odds of positive antibody response. 165 SOTRs (31%) remained seronegative after D3 (22% of Ad.26.COV2.S recipients vs 32% of mRNA recipients). Conclusion(s): Heterologous boosting with Ad.26.COV2.S may be a promising vaccination option for SOTRs with poor response to the 2-dose mRNA series, particularly among those who are seronegative. (Table Presented).
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Background: Patients with immune-mediated infammatory diseases (IMIDs) on immunosuppressive therapy have an inadequate serologic response following two-dose SARS-CoV-2 vaccination, and a standard vaccination strategy of three doses for this patient group is currently under implementation in several countries. However, the serological response and safety of this strategy has not been evaluated. Objectives: To assess serological response and safety of a three-dose vaccination strategy in IMID patients on immunosuppressive therapy as compared to standard two-dose vaccination of healthy controls. Methods: The prospective observational Nor-vaC study (NCT04798625) enrolled adult patients on immunosuppressive therapy for infammatory joint-and bowel diseases. Healthy controls were health care workers from participating hospitals. All participants received standard vaccines according to the national vaccination program with three doses in patients and two doses in controls. The third dose was offered to IMID patients >4 weeks after the second dose. Analyses of antibodies binding the receptor-binding domain of the SARS-CoV-2 Spike protein were performed prior to, and 2-4 weeks after the second and third vaccine doses. Levels were compared across groups by Mann-Whitney U tests and multi-variate linear regression was used to identify predictors of response. Results: Overall, 961 patients (315 rheumatoid arthritis, 156 spondyloarthritis, 171 psoriatic arthritis, 132 ulcerative colitis and182 Crohn's disease) (median age 54 years [IQR 43-64];56 % women) and 227 controls (median age 44 years [IQR 32-55];83 % women) were included in the present analyses. TNFi mon-otherapy was used by 399 patients, 229 used TNFi in combination with other immunomodulators, 189 methotrexate monotherapy, 39 vedolizumab, 32 JAKi and 73 patients used other drugs. Patients on rituximab were not included. Patients were vaccinated with Pfzer BNT162b2 (54% patients, 14% controls), Moderna mRNA-1273 (16% patients, 40% controls) or a combination of vaccines (30% patients, 46% controls). Patients received the third vaccine dose a median of 120 (IQR 102-143) days after the second dose. After two doses, median antiSpike antibody levels were signifcantly lower in patients (861 BAU/ml (IQR 418-4275) than controls (6318 BAU/ml (IQR 2468-9857)), p<0.001 (Figure 1). Following the third dose, patients achieved antibody levels comparable to the two-dose vaccinated controls (median 5480 BAU/ml (IQR 1081-12069), p=0.28) (Figure 1). In the patients anti-Spike antibody levels increased by a median of 2685 BAU/ml (IQR 265-9129) from the second to the third dose. Main factors associated with increased antibody level after the third dose were younger age (β-87.7 (p=0.002)), and vaccine status (mRNA-1273 vaccine (β 5549 (p<0.001)) or a combination of vaccines (β 4367.3 (p<0.001)). Adverse events were reported by 438 (48%) of patients after the third dose as compared to 471 (54%) after the second dose and 193 (78 %) of controls. Disease fares were reported by 42 (5%) and 69 (8%) patients after the second and third dose, respectively. Conclusion: This study suggests that a third vaccine dose for immunosup-pressed patients closes the gap in serological response between patients and the healthy population. Antibody levels following the three-dose regimen in IMID patients were comparable to healthy controls vaccinated twice, and no new safety issues emerged. This fnding was consistent across all diagnoses and treatment groups, supporting the implementation of a three-dose vaccine regimen as standard in the IMID population.