Durable Immune Response and Long-term Efficacy of COVID-19 Vaccination in Children With Inflammatory Bowel Disease.

BACKGROUND: Children with inflammatory bowel disease (IBD) may have diminished serologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and increased risk for subsequent severe coronavirus disease 2019 (COVID-19) infection. We sought to describe outcomes among those who developed SARS-CoV-2 infection following vaccination, characterize SARS-CoV-2 antibodies 1 year post-vaccination, and identify factors associated with durable serologic response. METHODS: We recruited children with IBD who received ≥2 doses of SARS-CoV-2 vaccine and prospectively collected data on (1) demographics, IBD characteristics, and therapy and (2) SARS-CoV-2 vaccination, testing, and infection symptoms. Serum was obtained for measurement of anti-receptor-binding domain IgG antibodies following a 2-part immunization at 12 and 52 weeks. RESULTS: We enrolled 298 participants (mean age 11.9 ±â€…3.82, 50% female, 67% Crohn's disease). Symptomatic COVID-19 infection after vaccination occurred in half of the participants, although only 2 (1%) required hospitalization. Anti-tumor necrosis factor alpha (TNF-α) was associated with higher likelihood of symptomatic COVID-19 infection, with an adjusted hazard ratio of 2.7 (95% CI, 1.5-5.0; P = .001). Nearly all participants (99%) had detectable antibody at Week 52. Children aged 1-5 years had lower 52-week antibody level compared to older children (P = .04), as did those on anti-TNF-α therapy (P = .007) and those who received only 2 vaccine doses prior to Week 52 (P < .001). CONCLUSIONS: SARS-CoV-2 vaccination provides lasting serologic response and protection against severe COVID-19 for most children with IBD, despite the use of lower vaccine doses in younger children and wide-ranging classes of immunosuppressive therapies.

We demonstrate high rates of durable antibody response and low rates of coronavirus disease 2019-related hospitalization 1 year following severe acute respiratory syndrome coronavirus 2 vaccination in children with inflammatory bowel disease. Anti-tumor necrosis factor alpha therapy, young age, and fewer vaccine doses were associated with lower 52-week antibody level.

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

OBJECTIVES: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS: A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). CONCLUSIONS: In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

BACKGROUND: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). METHODS: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. RESULTS: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 µg/mL [P = .49]; adalimumab: 11.1 vs 10.5 µg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 µg/mL [P < .01]; adalimumab: 9.1 vs 12.3 µg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). CONCLUSIONS: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

For children with Crohn's disease treated with biologic medications, with and without low-dose methotrexate, the role of drug levels on treatment failure in a recent prospective trial is unclear. These data suggest patients on infliximab with therapeutic drug levels are more likely to continue any therapy, and the effect on patients treated with adalimumab requires more investigation.

Quantitative SARS-CoV-2 Spike Receptor-Binding Domain and Neutralizing Antibody Titers in Previously Infected Persons, United States, January 2021-February 2022.

We studied SARS-CoV-2 binding and neutralizing antibody titers among previously infected persons in the United States over time. We assayed SARS-CoV-2 spike protein receptor-binding domain and neutralizing antibody titers for a convenience sample of residual clinical serum specimens that had evidence of prior SARS-CoV-2 infection gathered during January 2021-February 2022. We correlated titers and examined them by age group (<18, 18-49, 50-64, and >65 years) across 4 different SARS-CoV-2 variant epochs. Among selected specimens, 30,967 had binding antibody titers and 744 had neutralizing titers available. Titers in specimens from children and adults correlated. In addition, mean binding antibody titers increased over time for all age groups, and mean neutralization titers increased over time for persons 16-49 and >65 years of age. Incorporating binding and neutralization antibody titers into infectious disease surveillance could provide a clearer picture of overall immunity and help target vaccination campaigns.

Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Higher and Sustained Cell-Mediated Immune Responses After 3 Doses of mRNA COVID-19 Vaccine in Patients With Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy.

INTRODUCTION: Studies suggest that the generation of durable T-cell immunity following coronavirus disease 2019 (COVID-19) vaccination protects against severe disease. The aim of this study was to measure cell-mediated immune response (CMIR) 1-2 months and 6 months after a third dose of a COVID-19 mRNA vaccine. METHODS: This prospective study (HumoRal and CellULar initial and Sustained immunogenicity in patients with inflammatory bowel disease [IBD]) evaluated CMIR at 28-65 days (t 1 ) after dose 2, 28-65 days (t 2 ) (n = 183) and 6 months (±45 days) (t 3 ) (n = 167) after a third dose of an mRNA COVID-19 vaccine. A small cohort had blood sample available 28-65 days (t 4 ) (n = 55) after a fourth dose. Primary outcomes were CMIR at (t 2 ) and (t 3 ). Secondary outcomes included the effect of immunosuppressing IBD medications on CMIR and response at (t 4 ). RESULTS: All patients had measurable CMIR at all time points. CMIR increased at t 2 compared with that at t 1 (median 1,467 responding cells per million (interquartile range [IQR] 410-5,971) vs 313 (94-960) P < 0.001). There was no significant waning in t 2 vs t 3 or significant boosting at t 4 . Those on anti-tumor necrosis factor monotherapy had a higher CMIR compared with those not on this therapy at t 2 (4,132 [IQR 1,136-8,795] vs 869 [IQR 343-3,221] P < 0.001) and t 3 (2,843 [IQR 596-6,459] vs 654 [IQR 143-2,067] P < 0.001). In univariable analysis, anti-tumor necrosis factor monotherapy was associated with a higher CMIR at t 2 ( P < 0.001) and t 3 ( P < 0.001) and confirmed in a multivariable model ( P < 0.001). DISCUSSION: A third dose of a COVID-19 vaccine boosts CMIR, and the response is sustained in patients with IBD.

SARS-CoV-2 neutralizing antibody titers in maternal blood, umbilical cord blood, and breast milk.

OBJECTIVE: We quantified neutralizing SARS-CoV-2 antibody against spike protein (nAb) levels after vaccination and SARS-CoV-2 infection in maternal serum, cord blood, and breast milk and determined whether they correlate with levels of spike protein binding antibody. STUDY DESIGN: Women (n = 100) were enrolled on admission for delivery. Previous SARS-CoV-2 infection was defined by anti-nucleocapsid antibodies. Levels of nAb and binding antibodies against spike receptor binding domain were measured in maternal blood, cord blood, and milk. RESULTS: Maternal nAb levels were higher after vaccine and infection than vaccine alone but waned rapidly. Levels of nAb in cord blood and milk correlated with maternal levels and were higher in cord blood than maternal. Spike protein binding antibody levels correlated with nAb. CONCLUSION: SARS-CoV-2 vaccination near delivery may boost antibody-mediated immunity in the peripartum period. Neutralizing antibodies are passed transplacentally and into milk. Spike protein binding antibody may be a feasible proxy for nAb.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Persistence of Antibodies Six Months after Three COVID-19 mRNA Vaccine Doses in Patients with Inflammatory Bowel Disease.

We evaluated antibody concentrations 6 months after a third coronavirus disease 2019 messenger RNA vaccine dose in patients with inflammatory bowel diseases. Almost all patients had an antibody response, and those with a previous SARS-CoV-2 infection had higher antibody concentrations.

Low Rates of Breakthrough COVID-19 Infection After SARS-CoV-2 Vaccination in Patients With Inflammatory Bowel Disease.

We demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.

Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance.

BACKGROUND: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance. AIMS: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients. METHODS: The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non-linear mixed effects modelling. For the evaluation of the exposure-response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole-genome metagenomic sequencing was conducted at baseline and week 2. RESULTS: A two-compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 µg/ml) and before infusion 4 (20 µg/ml) best predicted steroid-free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate-producing species and pathways that were associated with an infusion 4 trough concentration >20 µg/ml. CONCLUSIONS: This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.

Humoral Immune Response and Safety of SARS-CoV-2 Vaccination in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5-17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 µg/mL (SD 67) and a median of 22 µg/mL (interquartile range 12-38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Higher Cell-Mediated Immune Responses in Patients With Inflammatory Bowel Disease on Anti-TNF Therapy After COVID-19 Vaccination.

BACKGROUND: Some patients with inflammatory bowel disease (IBD) on immunosuppressive therapies may have a blunted response to certain vaccines, including the messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines. However, few studies have evaluated the cell-mediated immune response (CMIR), which is critical to host defense after COVID-19 infection. The aim of this study was to evaluate the humoral immune response and CMIR after mRNA COVID-19 vaccination in patients with IBD. METHODS: This prospective study (HERCULES [HumoRal and CellULar initial and Sustained immunogenicity in patients with IBD] study) evaluated humoral immune response and CMIR after completion of 2 doses of mRNA COVID-19 vaccines in 158 IBD patients and 20 healthy control (HC) subjects. The primary outcome was the CMIR to mRNA COVID-19 vaccines in patients with IBD. The secondary outcomes were a comparison of (1) the CMIR in patients with IBD and HC subjects, (2) CMIR and humoral immune response in all participants, and (3) correlation between CMIR and humoral immune response. RESULTS: The majority (89%) of patients with IBD developed a CMIR, which was not different vs HC subjects (94%) (P = .6667). There was no significant difference (P = .5488) in CMIR between immunocompetent (median 255 [interquartile range, 146-958] spike T cells per million peripheral blood mononuclear cells) and immunosuppressed patients (median 377 [interquartile range, 123-1440]). There was no correlation between humoral and cell-mediated immunity after vaccination (P = .5215). In univariable analysis, anti-tumor necrosis factor therapy was associated with a higher CMIRs (P = .02) and confirmed in a multivariable model (P = .02). No other variables were associated with CMIR. CONCLUSIONS: Most patients with IBD achieved CMIR to a COVID-19 vaccine. Future studies are needed evaluating sustained CMIR and clinical outcomes.

Antibody and T cell responses to coronavirus disease 2019 vaccines in patients with inflammatory bowel disease do not correlate. Most patients with inflammatory bowel disease mount a T cell response despite being on biologic therapies, those on anti-tumor necrosis factor may have a higher T cell response. Anti-tumor necrosis factor therapy has been associated with a lower antibody response to coronavirus disease 2019 vaccines, but the T cell response is augmented.

Anti-Carbamylated Protein (Anti-CarP) Antibodies in Patients Evaluated for Suspected Rheumatoid Arthritis.

(1) Background: Anti-carbamylated protein (CarP) antibodies have been studied as novel markers to aid in the diagnosis and prognosis of rheumatoid arthritis. (2) Methods: A total of 265 samples were included in the evaluation, for which 98 had results for anti-cyclic citrullinated peptide (CCP), 86 for rheumatoid factor (RF), and 212 for 14-3-3 eta protein. Anti-CarP antibodies were measured using a fetal calf serum-based single-step assay (research use only, Inova Diagnostics, San Diego, CA). (3) Results: Anti-CarP antibodies were significantly higher and more frequent in anti-CCP3.1+ (p = 0.0025), RF+ (p = 0.0043) and 14-3-3 eta+ (p = 0.028) samples compared to the negative counterpart group. In addition, isolated anti-CarP positivity occurred in samples negative for anti-CCP3.1, RF, or 14-3-3 eta. When anti-CarP antibodies were compared to each of the RF, anti-CCP3.1, and 14-3-3 eta by receiver operating characteristic (ROC) analyses, the area under the curve (AUC) values of 0.71 (RF), 0.68 (anti-CCP3.1), and 0.59 (14-3-3 eta), respectively, demonstrated a moderate correlation. Using an UpSet plot, we determined that 10.6% of the samples with available results for anti-CCP3.1, RF, and anti-CarP showed triple positivity. (4) Conclusions: Anti-carbamylated protein (anti-CarP) antibodies can be detected in anti-CCP, RF and 14-3-3 eta-positive and -negative patients, potentially identifying specific subsets of patients.

SARS-CoV-2 Convalescent Sera Binding and Neutralizing Antibody Concentrations Compared with COVID-19 Vaccine Efficacy Estimates against Symptomatic Infection.

Previous COVID-19 vaccine efficacy (VE) studies have estimated neutralizing and binding antibody concentrations that correlate with protection from symptomatic infection; how these estimates compare to those generated in response to SARS-CoV-2 infection is unclear. Here, we assessed quantitative neutralizing and binding antibody concentrations using standardized SARS-CoV-2 assays on 3,067 serum specimens collected during 27 July 2020 to 27 August 2020 from COVID-19-unvaccinated persons with detectable anti-SARS-CoV-2 antibodies. Neutralizing and binding antibody concentrations were severalfold lower in the unvaccinated study population compared to published concentrations at 28 days postvaccination. In this convenience sample, ~88% of neutralizing and ~63 to 86% of binding antibody concentrations met or exceeded concentrations associated with 70% COVID-19 VE against symptomatic infection; ~30% of neutralizing and 1 to 14% of binding antibody concentrations met or exceeded concentrations associated with 90% COVID-19 VE. Our study not only supports observations of infection-induced immunity and current recommendations for vaccination postinfection to maximize protection against COVID-19, but also provides a large data set of pre-COVID-19 vaccination anti-SARS-CoV-2 antibody concentrations that will serve as an important comparator in the current setting of vaccine-induced and hybrid immunity. As new SARS-CoV-2 variants emerge and displace circulating virus strains, we recommend that standardized binding antibody assays that include spike protein-based antigens be utilized to estimate antibody concentrations correlated with protection from COVID-19. These estimates will be helpful in informing public health guidance, such as the need for additional COVID-19 vaccine booster doses to prevent symptomatic infection. IMPORTANCE Although COVID-19 vaccine efficacy (VE) studies have estimated antibody concentrations that correlate with protection from COVID-19, how these estimates compare to those generated in response to SARS-CoV-2 infection is unclear. We assessed quantitative neutralizing and binding antibody concentrations using standardized assays on serum specimens collected from COVID-19-unvaccinated persons with detectable antibodies. We found that most unvaccinated persons with qualitative antibody evidence of prior infection had quantitative antibody concentrations that met or exceeded concentrations associated with 70% VE against COVID-19. However, only a small proportion had antibody concentrations that met or exceeded concentrations associated with 90% VE, suggesting that persons with prior COVID-19 would benefit from vaccination to maximize protective antibody concentrations against COVID-19.

Humoral Immunogenicity of 3 COVID-19 Messenger RNA Vaccine Doses in Patients With Inflammatory Bowel Disease.

Herein, we evaluated the humoral immunogenicity of a third coronavirus disease 2019 messenger RNA vaccine dose in patients with inflammatory bowel diseases. All patients displayed a humoral immune response, and median antibody concentrations were higher after the third dose than after completion of the 2-dose series.

Strong Response to SARS-CoV-2 Vaccine Additional Doses Among Patients With Inflammatory Bowel Diseases.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has disrupted health care and has resulted in high mortality rates.1 Vaccination is an international priority to mitigate the risks of SARS-CoV-2. The initial trials for development of SARS-CoV-2 vaccines excluded individuals with immunocompromising conditions.2.

Factors Affecting Initial Humoral Immune Response to SARS-CoV-2 Vaccines Among Patients With Inflammatory Bowel Diseases.

INTRODUCTION: Although an additional coronavirus disease 2019 vaccine dose for immunocompromised persons has been recommended in some countries, further data to guide vaccination strategies for patients with inflammatory bowel disease (IBD) are urgently needed. We sought to identify factors affecting initial humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among patients with IBD. METHODS: In this prospective cohort of SARS-CoV-2 immunized patients with IBD, we evaluated associations between participant age, sex, vaccine type, medication use, and the presence of a detectable antireceptor binding domain antibody and quantitative antibody level. RESULTS: In total, 1,909 participants were included (1,123, 692, and 94 received BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively) of whom 96% achieved a positive antibody response. On multivariable analysis, factors associated with lack of antibody response were older age (P = 0.043), BNT162b2 vs mRNA-1273 (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.0-3.9), and combination therapy with anti-TNF and 6MP, azathioprine, or methotrexate (OR 4.2, 95% CI 2.4-7.3). The use of 5-aminosalicylate or sulfasalazine (OR 0.3, 95% CI 0.1-0.8) and ustekinumab (OR 0.2, 95% CI 0.05-0.8) was associated with decreased odds of lacking antibody response. DISCUSSION: Most patients with IBD mount an initial response to SARS-CoV-2 vaccination; however, older patients and those treated with anti-TNF and immunomodulator have blunted responses and may benefit the most from an additional vaccine dose. Patients treated with other classes of immunosuppressive medications have more robust initial immune responses to vaccination. These data should inform key decisions about patient selection for additional coronavirus disease 2019 vaccine doses in patients with IBD.

Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease.

BACKGROUND: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. AIMS: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn's disease cohort with 1-year follow-up. METHODS: This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. RESULTS: ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23-1828). Maximum ATI concentration was <200 ng/mL in 73.6% (39/53). Median clearance in ATI patients was higher (with higher clearance if loss of response), compared to no-ATI patients (P < 0.001). Neutrophil CD64 ratio >6 and starting dose <7.5 mg/kg independently predicted ATI in multivariable regression, while HLA-DQA1*05 presence did not. Dose adjustment resolved ATI in 37.5% (12/32) patients with concomitant infliximab concentration and clearance recovery. A maximum ATI level of ≤99 ng/mL predicted ATI resolution (area under the receiver operating curve 0.80 [95% CI 0.64-0.96]). CONCLUSIONS: In this real-world cohort, ATI as low as 23 ng/mL impacted drug clearance. Our data suggest that dose optimisation for low-level ATI can improve infliximab clearance and prevent loss of response.