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Background. Vaccine-induced SARS-CoV-2 antibody responses are reduced in patients taking lymphocyte-depleting therapies, which are commonly prescribed for patients with idiopathic inflammatory myopathies (IIM). While a third vaccine dose (D3) augments the SARS-CoV-2 anti-spike response in some patients, there is a paucity of data on the humoral response following D3 in patients with IIM. Furthermore, the durability of antibody response is unknown. In this study, we evaluated serial antibody response for three months following a 3rd dose SARS-CoV-2 vaccination in IIM patients. Methods. Adults with a patient-reported diagnosis of idiopathic inflammatory myopathy who completed three-dose SARS-CoV-2 vaccination (two-dose BNT162b2 or mRNA-1273 followed by single mRNA or adenoviral vector dose) were recruited via social media campaign. Demographics and clinical characteristics were collected via patient report. Informed consent was provided electronically. Serial antibody responses were evaluated by the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay, which measures total antibody to the SARS-CoV-2 S-receptor binding domain (RBD) protein (range 0. 4-2500U/ mL;positive >0.8U/mL). Poor antibody response was defined as anti-RBD titer <500U/mL based on predicted correlates of protective plasma neutralizing capacity. Those with prior COVID-19 infection were excluded. Associations were evaluated using Fisher's exact and Wilcoxon rank-sum tests as appropriate. Results. We evaluated serial anti-RBD titers in 59 participants (Table I). Most (93%) were female with median (IQR) age of 51 (41-62) years. Mycophenolate mofetil was the most frequently prescribed medication (45.6%). Participants completed primary vaccination with two-dose BNT162b2(54%) or mRNA-1273(46%). Median pre-D3 anti-RBD titer (IQR) was 65.8U/mL (4.6,473) at 158 (136-183) days following primary vaccination. Dose 3 included BNT162b2(47%), mRNA-1273(47%) or Ad.26.COV2.S (6%). Most (89.9%) received homologous D3 vaccination. 39% of participants reported holding peri-D3 immunosuppression with mycophenolate mofetil being the most commonly held medication in the peri-D3 period. Repeat anti-RBD testing was performed at a median (IQR) 30 (28-32) days post-D3. A higher antibody titer was seen in 89.9% participants following D3 with median (IQR) titer of 2500 U/mL (92,2500). Thirty-seven percent remained <500U/mL following D3;a greater proportion of these participants reported use of rituximab and greater number of immunosuppressive therapies compared to those with anti-RBD >=500U (72.7% versus 5.4%, p<0.001;3 therapies versus 2 therapies, p=0.03). Furthermore, 13.5% (8/59) remained below the threshold of positivity following D3;7/8 reported use of rituximab, 5/8 mycophenolate mofetil, or combination of these agents (4/8). There was not a significant difference in antibody titers among recipients of homologous/heterologous vaccination (p=0.22). Dose 3 was well tolerated with only 2 (3.4%) participants reporting disease flare requiring treatment within one month of vaccination;neither required intravenous therapy or hospital admission. Thirty-four (57.6%) participants underwent repeat anti-RBD testing three months following D3 with median (IQR) 2500U/mL (456,2500);73.53% (25/34) remained above threshold of >=500U/mL. Limitations of this study include small sample size and absence of healthy control group. Diagnosis was based on participant report and we did not routinely collect information on disease activity. Conclusion. We observed an augmented humoral response in most IIM patients following 3rd dose SARS-CoV-2 vaccination;antibody response was durable at three months. Dose 3 was well tolerated. Over 1/3 participants failed to develop adequate response following D3, namely those on rituximab therapy and on higher number of immunosuppressive therapies. These patients should be prioritized for prophylactic therapies to enhance protection against COVID-19 infection.
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Purpose: We report the immunogenicity and safety of a third BNT162b2 vaccine in pediatric solid organ transplant recipients (pSOTRs). Method(s): Samples from pSOTRs (12-18 years) enrolled in our multicenter, observational study (COVID-19 Antibody Testing of Recipients of Solid Organ Transplants and Patients with Chronic Diseases) who received a third vaccine (V3) were analyzed for antibodies to SARS-CoV-2 spike protein receptor-binding domain, with a positive cutoff of >=0.8 and maximum titer of >2500 U/mL. Pre-V3 samples were 1-3 months after vaccine 2, and post-V3 were 1 month after vaccine 3. Result(s): Thirty-seven pSOTRs (46% heart, 24% liver, 27% kidney, 3% multi) received V3. Median (interquartile range [IQR]) age was 15 (14-16) years;42% were male and 78% white. pSOTRs were median (IQR) 9 (6-13) years from transplant. Four (11%) patients had prior SARS-CoV-2 infection. Antibody titers were positive in 26/37 (70%) patients pre-V3 and 32/37 (86%) post-V3 (Figure). Median (IQR) antibody titers were higher post-V3 (2500 [1581-2500] U/mL) than pre-V3 (211 [0.8-2500] U/mL) in paired analysis (p<0.001). 6/11 (55%) pSOTRs with negative pre-V3 titers seroconverted, with a post-V3 median (IQR) titer of 418 (132-1581) U/ mL. Transplant within 3 years was associated with negative post-V3 titer (p=0.037). Main side effects after V3 were pain (71%) and fatigue (50%). No patients reported allergic reaction, myocarditis, or rejection. One patient tested positive for SARSCoV- 2 between vaccines 2 and 3, with negative pre- and post-V3 titers. At time of first vaccine, this patient was transplanted a year ago, treated for rejection recently, and taking 3 immunosuppression agents including an antimetabolite. Conclusion(s): In this limited cohort, 86% of pSOTRs had a positive antibody response after three SARS-CoV-2 vaccines with no adverse events. Importantly, 55% of pSOTRs with prior negative response seroconverted post-V3, and 100% of pSOTRs with positive response increased their antibody titer or remained at maximum titer. Our preliminary results suggest the benefit of a third vaccine for adolescent pSOTRs based on antibody response;larger studies are needed to assess vaccine effectiveness.
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Purpose: Kidney transplant recipients taking belatacept (KTR-B) have poor immune response to two-dose SARS-CoV-2 vaccination. We sought to characterize the impact of an additional vaccine dose on plasma neutralizing capacity and cellular responses as compared to that of KTRs controls (KTR-C) not taking belatacept. Method(s): Within an observational cohort, we tested 26 KTR-Bs and 27 KTR-Cs for anti-spike antibody responses before and after a third SARS-CoV-2 vaccine dose (D3) using two clinical assays (Roche Elecsys anti-S Ig and EUROIMMUN anti-S1 IgG). For a subset of 5 KTR-Bs and for all KTR-Cs we used a research assay (Meso Scale Diagnostics V-Plex [MSD]) to further assess anti-spike and RBD IgG, as well as surrogate plasma neutralizing activity (% ACE2 inhibition) versus the ancestral and delta variants. For 3 KTR-Bs, post D3 T cell response was assessed via IFN-y ELISpot and deemed positive if spot forming units > 20 per million PBMC and stimulation index > 3. Result(s): KTR-Bs had significant lower clinical anti-spike seroconversion than KTR-Cs (31% vs 74%, p=0.001) after D3 despite similar demographics, clinical factors, and vaccines administered (Table 1). No KTR-B (0/5) was seropositive by MSD anti-spike or anti-RBD IgG (Figure 1). % ACE2 inhibition versus the ancestral variant was significantly lower in KTR-Bs than in KTR-Cs (Median [IQR] 5.2 [2.8, 6.5] vs 12.5 [7.7, 23.9], p<0.01);all KTR-Bs were below a level consistent with detectable neutralizing antibody. All tested KTR-Bs (3/3) had a negative ELISpot, consistent with negligible cellular response. Conclusion(s): These results suggest minimal humoral or cellular immunogenicity of additional vaccine doses for KTR-Bs and indicates the need for alternative strategies to improve vaccine response such as immunosuppression alteration or use of passive immunoprophylaxis with monoclonal anti-spike antibody to improve protection versus SARS-CoV-2.
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Purpose: Understanding the dynamics of antibody response to a third dose (D3) of anti-SARS-CoV-2 vaccine in solid organ transplant recipients (SOTRs) is important to inform booster strategies. Method(s): We studied the the dynamics of anti-RBD (Roche, <0.8 to >2500 U/dL) and anti-S (Euroimmun, 0.1 to >8.9 AU) antibody levels in a cohort of SOTRs at 2 weeks, 1 month and 3 months after D3. We compared the proportion of seroconversion at 1 month or 3 months after D3 between mRNA and Ad.26.COV2.S D3 recipients, using Poisson regression with robust standard error, adjusting for age and numbers of immunosuppressants. Result(s): Among 928 SOTRs with 2-week (n=655), 1-month (n=651) or 3-month (n=404) post-D3 titer, 78%, 82% and 86% tested positive for antibodies. The median (IQR) anti-RBD at the three timepoints were >2500 (73, >2500), 2494 (49, >2500) and 1234 (59, >2500) U/mL (Figure 1A, blue), and there were 61% (n=436), 60% (n=491) and 53% (n=313) with anti-RBD> 1000 u/mL, respectively. The median (IQR) anti-S at the three timepoints were 3.2 (0.3, 8.4), 8 (2, >8.9) and 7.4 (2, >8.9) AU (Figure 1B, blue), and there were 47% (n=218), 61% (n=161) and 64% (n=91) who developed anti-S>4 AU. Among patients with no or minimal immune response at 2 weeks post-D3 (n=102), 3/41 (7%) had increased anti-RBD by 1 month while 11/18 (61%) had increased anti-S (Fisher exact p<0.001). 6/29 (21%) had increased anti-RBD by 3 months while 12/20 (60%) had increased anti-S (p<0.01) (Figure 1A&B, yellow). 27/102 (27%) of them seroconverted at 1 or 3 months after D3. Having received Ad.26.COV2.S as D3 is associated with 3.9X increased proportion of seroconversion at 1 month or 3 months among patients with no or minimal immune response at 2 weeks after D3 (aIRR=2.223.926.92, p<0.001). Conclusion(s): Among SOTRs who received a booster anti-SARS-CoV-2 vaccination, dynamics of Anti-RBD and Anti-S antibodies differed substantially. Anti-RBD titers on average declined only slightly after 14 days post-D3, while anti-S increased up through 30-60 days post-D3. After the peak, average titer values for both antibodies declined slightly through three months post-D3.
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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: 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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Background: An attenuated humoral response to SARS-CoV-2 vaccination has been observed in some patients with rheumatic and musculoskeletal diseases (RMD) (1). We sought to identify clinical factors associated with poor humoral response following primary (two-dose mRNA or single adenoviral vector dose) SARS-COV-2 vaccination in patients with RMD on immunosuppression. Objectives: To identify clinical predictors of an attenuated antibody response to primary SARS-CoV-2 vaccination in RMD patients on immunosuppression. Methods: We included patients ≥18 years old with RMD on immunosuppres-sion who received either two-dose mRNA or single dose Janssen/Johnson and Johnson (J&J) vaccination. Demographics, diagnoses, and therapeutic regimens were collected via participant report;those with prior COVID-19 infection were excluded. One month after vaccination, participants underwent SARS-CoV-2 antibody testing on the semi-quantitative Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay, which measures antibody to the SARS-CoV-2 S-recep-tor binding domain (RBD) protein (ceiling >250U/mL later expanded to >2500U/mL). Associations were evaluated using Fisher's exact and Wilcoxon rank sum tests. Logistic regression analyses were performed to evaluate for clinical factors associated with antibody response. We adapted survival methods to address right-truncation of titers;this methodology was used to calculate medians. Participants provided informed consent electronically and the study was approved by the local Institutional Review Board. Results: We studied 1138 RMD participants on immunosuppression;most were female (93%) and white (91%) (Table 1). One-hundred and ffteen (10%) had anti-RBD response in the negative range at a median (IQR) of 29 days (28-34) following completion of vaccine series. A greater proportion of participants with negative response were non-white, received J&J vaccine, reported use of myco-phenolate, rituximab, or glucocorticoids. Antibody response differed by immuno-suppressive regimen, with those receiving rituximab having poorest response (Figure 1). Use of mycophenolate (aOR 9.92, p=0.001), rituximab (aOR 56.99, p=0.001), glucocorticoids (aOR 2.99, p=0.001) or receipt of J&J (aOR 3.13, p=0.039) were associated with negative antibody response. Conclusion: Use of mycophenolate, glucocorticoids, rituximab and receipt of J&J vaccine were the strongest predictors of an attenuated antibody response to primary SARS-CoV-2 vaccination;these data support use of an additional primary dose in RMD patients.
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Purpose: The response to SARS-CoV-2 may be blunted in transplant recipients, impacting reinfection risk, treatment selection, and vaccine protocols. We quantified antibody response and durability after COVID-19 in solid organ transplant recipients (SOTRs). Methods: SOTRs with PCR-confirmed COVID-19 were recruited through the EMR August 21-October 15, 2020. Participants underwent at-home blood sampling with the TAPTM Blood Collection Device, Second Edition (7SBio, Medford, MA). Serum samples were screened using Elecsys® anti-SARS-CoV-2 immunoassay (Roche), which uses a recombinant protein representing the nucleocapsid antigen. Confirmatory testing was performed using EUROIMMUN anti-SARS-CoV-2 enzyme-linked immuosorbent assay (ELISA) for semi-quantitative detection of IgG antibodies to spike protein (anti-S1-IgG), a likely correlate of neutralizing immunity. Results: Eighteen SOTRs were studied, for whom COVID-19 occurred at a median of 6 years (IQR 2-9) post-transplant. Median age was 56 years (IQR 42-63);56% were female;33% were Black and 11% were Hispanic. Most participants (89%) had experienced COVID-19 symptoms;72% were hospitalized. Among those hospitalized, 15% were admitted to the ICU and 8% were mechanically ventilated. COVID-19 convalescent plasma (CCP) was administered to 3 kidney and 2 lung recipients. At median 98 days (IQR 55-147) after COVID-19 diagnosis, 78% had reactive screening immunoassays (Table 1). Of the four patients with non-reactive immunoassays, 2 were the lung recipients treated with CCP and 1 was the kidney recipient receiving IVIg. Of those who screened positive, anti-S1-IgG was detectable in 83%. SOTRs who received CCP and/or IVIg were less likely to develop anti-S1- IgG and had lower antibody levels. Conclusions: We found antibody levels suggestive of neutralizing immunity in the majority of participants. However, those who were administered CCP and/or IVIg were less likely to mount a durable immune response. This raises the possibility that exogenous antibody preparations may blunt durable antibody formation. We observed a significant association between more severe disease and higher antibody levels. Seropositivity might decline over time;however, we were unable to distinguish between impaired production or rapid decrement. Our findings are important for individuals with compromised immune systems, whether deliberately for conditions like organ transplantation and cancer, or naturally in the elderly, frail, and autoimmune populations.