Lower Ab Levels Research Articles

Lower magnitude and faster waning of antibody responses to SARS-CoV-2 vaccination in anti-TNF-α-treated IBD patients are linked to lack of activation and expansion of cTfh1 cells and impaired B memory cell formation

Patients with inflammatory bowel disease (IBD) and healthy controls received primary SARS-CoV-2-mRNA vaccination and a booster after six months. Anti-TNF-α-treated patients showed significantly lower antibody (Ab) levels and faster waning than α4β7-integrin-antagonist recipients and controls. This prospective cohort study aimed to elucidate the underlying mechanisms on the basis of circulating T-follicular helper cells (cTfh) and B memory cells. We measured SARS-CoV-2- Wuhan and Omicron specific Abs, B- and T-cell subsets at baseline and kinetics of Spike (S)-specific B memory cells along with distributions of activated cTfh subsets before and after primary and booster vaccination. Lower and faster waning of Ab levels in anti-TNF-α treated IBD patients was associated with low numbers of total and naïve B cells vs. expanded plasmablasts prior to vaccination. Along with their low Ab levels against Wuhan and Omicron VOCs, reduced S-specific B memory cells were identified after the 2nd dose which declined to non-detectable after 6 months. In contrast, IBD patients with α4β7-integrin-antagonists and controls mounted and retained high Ab levels after the 2nd dose, which was associated with a pronounced increase in S-specific B memory cells that were maintained or expanded up to 6 months. Booster vaccination led to a strong increase of Abs with neutralizing capacity and S-specific B memory cells in these groups, which was not the case in anti-TNF-α treated IBD patients. Of note, Ab levels and S-specific B memory cells in particular post-booster correlated with the activation of cTfh1 cells after primary vaccination. The reduced magnitude, persistence and neutralization capacity of SARS-CoV-2 specific Abs after vaccination in anti-TNF-α-treated IBD patients were associated with impaired formation and maintenance of S-specific B memory cells, likely due to absent cTfh1 activation leading to extra-follicular immune responses and diminished B memory cell diversification. These observations have implications for patient-tailored vaccination schedules/vaccines in anti-TNF-α-treated patients, irrespective of their underlying disease. The study was funded by third party funding of the Institute of Specific Prophylaxis and Tropical Medicine at the Medical University Vienna. The funders had no role in study design, data collection, data analyses, interpretation, or writing of report.

Immune response after SARS-CoV-2 vaccination in patients with inflammatory immune-mediated diseases receiving immunosuppressive treatment

BackgroundReal world data on the response to the SARS-CoV-2 vaccine in patients with immunomediated diseases (IMIDs) treated with immunesuppressants is of great interest because vaccine response may be impaired. The main aim was to study the humoral and cellular immune response after SARS-CoV-2 vaccination in patients with IMIDs treated with immunosuppressants. The secondary aim was to describe the frequency of SARS-CoV-2 infections after vaccination in these patients.Material and methodsThis is an observational study including 86 patients with IMIDs. All patients were treated with biologic or targeted synthetic disease-modifying antirheumatic drugs [b/tsDMARDs: TNF inhibitors (TNFi), rituximab, anti-interleukin 6 receptor (anti-IL6R) or JAK inhibitors (JAKi)]. Demographic and clinical information were collected. After 4–6 weeks of 2nd and 3rd vaccine doses, humoral response was assessed using the Thermo Scientific ELiA SARS-CoV-2-Sp1 IgG Test. Also, in patients with serum SARS-CoV-2 antibody levels under 100UI/ml, cellular response was analyzed using the QuantiFERON SARS-CoV-2 Starter Pack.ResultsA total of 86 patients under b/tsDMARDs and 38 healthy controls were included. Most patients received TNFi (45 with TNFi, 31 with rituximab, 5 with anti-IL6R and 5 with JAKi). SARS-CoV-2 antibodies (Ab) were present in an 86% of patients with IMIDs and in 100% healthy controls (p = 0.017). However, 12 (14%) patients had undetectable SARS-CoV-2 Ab levels, all treated with rituximab. In addition, SARS-CoV-2 Ab (IU/ml) were statistically lower in patients (Mdn (IQR): 59.5 (17–163) in patients vs 625 (405–932) in controls, p < 0.001). Patients treated with rituximab had lower Ab levels than those treated with TNFi and controls (p < 0.001). The cellular response to SARS-CoV-2 vaccine was evaluated in 30 patients. Eleven patients had a positive cellular response, being more frequent in patients treated with rituximab (p = 0.03). SARS-CoV-2 infection was reported in 43% of patients and 34% of controls after vaccination. Only 6 (7%) patients required hospitalization, most of whom treated with rituximab (67%).ConclusionSARS-CoV-2 antibody levels were lower in patients than in controls, especially in patients treated with rituximab. A cellular response can be detected despite having a poor humoral response. Severe infections in vaccinated patients with IMIDs are rare, and are observed mainly in patients treated with rituximab.

Assessment of antibody levels to SARS-CoV-2 in patients with idiopathic inflammatory myopathies receiving treatment with intravenous immunoglobulin

Antibodies to Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) have been reported in pooled healthy donor plasma and intravenous immunoglobulin products (IVIG). It is not known whether administration of IVIG increases circulating anti-SARS-CoV-2 antibodies (COVID ab) in IVIG recipients. COVID ab against the receptor binding domain of the spike protein were analyzed using a chemiluminescent microparticle immunoassay in patients with idiopathic inflammatory myopathies (IIM) both receiving and not receiving IVIG (IVIG and non-IVIG group, respectively). No significant differences in COVID ab levels were noted between IVIG and non-IVIG groups (417 [67–1342] AU/mL in IVIG vs 5086 [43–40,442] AU/mL in non-IVIG, p = 0.11). In linear regression models including all post-vaccination patient samples, higher number of vaccine doses was strongly associated with higher COVID ab levels (2.85 [1.21, 4.48] log AU/mL, regression coefficient beta [95% CI], p = 0.001), while use of RTX was associated with lower ab levels (2.73 [− 4.53, − 0.93] log AU/mL, beta[95%CI], p = 0.004). In the IVIG group, higher total monthly doses of IVIG were associated with slightly higher COVID ab levels (0.02 [0.002–0.05] log AU/mL, p = 0.04). While patients on IVIG did not have higher COVID ab levels compared to the non-IVIG group, higher monthly doses of IVIG were associated with higher circulating levels of COVID ab in patients receiving IVIG, particularly in patients concomitantly receiving RTX. Our findings suggest that IIM patients, especially those at increased risk of COVID infection and worse COVID outcomes due to RTX therapy may have protective benefits when on concurrent IVIG treatment.

Neutralizing Antibody Responses Against Sars-Cov-2 in Patients with Plasma Cell Disorders Who Are on Active Treatment after Two Doses of mRNA Vaccination

BackgroundPatients (Pts) with multiple myeloma (MM) experience prolonged immunosuppression due to the incurable nature of the disease and corresponding treatment modalities. Due to this many MM pts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require hospitalization, with an increased mortality rate over healthy adults. Two mRNA vaccines against (SARS-CoV-2): BNT162b2 & mRNA-1273 were approved under an emergency use authorization (EUA) by the Food and Drug Administration (FDA) due to the high efficacy in preventing SARS-CoV-2. The aim of this study was to analyze the antibody (Abs) response in all pts with plasma cell disorders (PCD) including MM, AL-Amyloidosis, and smoldering myeloma (SMM) who are on active treatment.Patients & MethodsAll pts (MM, AL-Amyloidosis, and SMM) on active treatment who received SARS-CoV-2 mRNA vaccine were identified at the University of Kansas Health System between January 2021 to July 2021and reviewed retrospectively. Descriptive analyses were performed on available data for patient characteristics. Abs against SARS-CoV-2 were measured using methodology approved by the FDA (enzyme-linked immunosorbent assay; cPass SARS-CoV-2 Neutralizing Antibody Detection Kit; GenScript, Piscataway, NJ). We stratified pts into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL), and non-responders (<50 IU/mL)ResultsA total of 118 pts were identified in our analysis and are described in Table 1. Of the total pts, 102 (86%) had MM, 13 (11%) pts had AL-Amyloidosis, and 3 (3%) pts had SMM. Median age was 69 years (45-95), 96 pts (81%) were Caucasian, and 57 (48%) were male. Median lines of prior treatment was 2 (1-13). Active PCD patients were treated with single-agent therapy in 60 pts (51%), doublet-based therapy in 5 pts (4%), and triplet-based therapy in 51 pts (43%). Daratumumab based therapy was utilized in 59 pts (50%). All pts included received two doses of either BNT162b2 or mRNA-1273. At the time of abs testing 82 patients (69%) were in a very good partial response (VGPR) or better, 29 pts (25%) were in partial response, while 7 pts (6%) had stable disease. Five pts (4%) had COVID-19 infection prior to the vaccine. The median time between thesecond dose of the vaccine and testing for Abs was 100 days (34-190). Only 46 pts (39%) developed an adequate response, 36 pts (30.5%) had a partial response, while 36 (30.5%) did not respond to the vaccine. Low Ab levels were seen in all PCD subtypes with the following mean levels: SMM :25.4 (5.4- 36.9) IU/mL, MM 148 (0- >250) IU/mL, and AL- Amyloidosis 92.35 (range 0- >250) IU/mL. Among the 5 pts with COVID-19 infection prior to the vaccination, full Abs response was observed in 4 pts, and 1 patient had no Abs response. Type of treatment did not affect the response to treatment in any clinically meaningful way. The odds ratio of achieving a clinically relevant Abs response was higher in pts with absolute lymphocyte counts>0.5 K/uL (p=0.01) and IgG levels> 400 mg/dL (p=0.04) and lower in pts receiving treatments with daratumumab combinations or anti-BCMA therapy (p<0.0001). Higher levels of anti-SARS-CoV-2 Abs were observed in pts with ≥ VGPR (mean≈147 IU/mL) compared to <VGPR (mean≈ 119 IU/mL). However, in this dataset, this difference was not statistically significant (p=0.17).ConclusionmRNA vaccine Ab response is lower in PCD pts getting active treatment compared with the general population. For PCD patients on active treatment, mRNA vaccine produced full antibody responses and partial responses in 39% and 30.5% of pts, respectively. anti-SARS-CoV-2 abs are especially low for patients on daratumumab combinations or anti-BCMA therapy, low lymphocytes, and low IgG levels at the time of vaccination. Some PCD may not develop anti-SARS-CoV-2 abs despite vaccination and/or previous COVID-19 infection. Therefore, checking anti-SARS-CoV-2 abs may be clinically useful in identifying patient's response. Further prospective studies should ascertain the value of a 3 rd vaccine dose in this population. [Display omitted] DisclosuresMahmoudjafari: Omeros: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Astelllas Pharma: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Pluristem Therapeutics: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding. Atrash: Jansen: Research Funding, Speakers Bureau; AMGEN: Research Funding; GSK: Research Funding.

Antibody response to first and second dose of BNT162b2 in a cohort of characterized healthcare workers

BackgroundVaccine-induced population immunity is a key global strategy to control coronavirus disease 2019 (COVID-19). The rapid implementation and availability of several COVID-19 vaccines is now a global health-care priority but more information about humoral responses to single- and double-dose vaccine is needed. Methods163 health care workers (HCW) of the Padua University Hospitals, who underwent a complete vaccination campaign with BNT162b2 vaccine were asked to collect serum samples at 12 (t12) and 28 (t28) days after the first inoculum to allow the measurement of SARS-CoV-2 Antibodies (Ab) using chemiluminescent assays against the spike (S) protein and the Receptor Binding Domain (RBD) of the virus, respectively. ResultsSignificant differences were found at t12 for infection-naïve and subjects with previous-natural infection who present higher values of specific antibodies, while no significant differences have been found between t12 and t28. No statistically significant difference was found between male and female, while lower Ab levels have been observed in subjects older than 60 years at t12 but not at t28. ConclusionsOur study confirms observed differences in vaccine responses between infection-naïve and subjects with previous natural infection at t12 but not for a longer time. The influence of sex and age deserves further studies, even if the relationship with age seems particularly significant.

Intensity of the immunity against measles in employees of the maternity unit in Moscow

Measles remains an urgent problem in Russian healthcare. Despite the ongoing vaccination, thereis an increase in the incidence of measles. Prevention of measles is particularly important in high-risk groups,as well as among healthcare professionals to prevent hospital-acquired outbreaks of infection. The duration ofpost-vaccination immunity during the elimination of measles has not been sufficiently studied, so often people whohave had measles in childhood or have 1-2 vaccinations against the disease lose their protective antibodies withage in the absence of natural boosterization.Goals and objectives. To study the intensity of specific immunity to measles in employees of the maternity unit. The study involved 271 employees of the maternity unit aged 21 to 93 years (262 serumsamples). The level of IgG antibodies (Ab) to the measles virus in the blood serum was studied by ELISA using a standard set of reagents for the quantitative determination of IgG by «VECTOR-BEST». The result was considered negative if the concentration of IgG to the measles virus in tested sample was ≤ 0.18 IU/ml and positive - if &gt; 0.18 IU/ml.Results. The number of seronegatives ranged from 0% to 30.8% in female employees with its maximum at ageof 31-35 years. The lowest proportion of seronegative and the highest proportion of seropositive women wereobserved among the elderly, &gt; 60 years. There is a marked tendency for an increase of the proportion of persons with average Ab levelswith age and a decrease of the proportion of persons with low Ab levels. The percentage of seronegative womenamong employees exceeded the recommended level, which makes it possible for an nosocomial outbreak whenan infection is introduced. The authors recommend that serological testing for the intensity of the immune response againstmeasles should be included in the standard of the pre-vaccination screening for adults.

Age-associated defects impair the optimal development of a protective immune response to Clostridium difficile in the context of infection in a novel aged murine model

Abstract Clostridium difficile infections (CDI) is a major source of mortality in the US, especially among the elderly. Protection against CDI is mediated by anti-toxin host antibodies (Ab). Although it is known that elderly mount an impaired anti-toxin response, it is yet to be determined whether their lower Ab levels are due to defective germinal center (GC) priming during acute CDI that leads to defective B cell proliferation and maturation. To test our hypothesis, we developed an antibiotic mucosal spore challenge CDI model and infected young (4mo.) and aged (&amp;gt;18mo.) mice with UK1 hypervirulent C. diff spores. By day 4 post-infection 100% of the aged had succumbed to infection compared to only 10% of young mice. Following a sublethal spore challenge a significant decrease of total PD1+CXCR5+ Tfh cells was detected in aged compared to young at Day 12 and 21 PI (p&amp;lt; 0.05 and p&amp;lt; 0.03, respectively). We also observed a marked decline of total and antigen-specific CD19+PNA+CXCR5+ B cells in our aged cohort (p&amp;lt; 0.05). We re-challenged with a lethal dose 1 month later. Only 50% of the aged vs 100% of the young survived. At Day 7 post re-challenge (D37) there was a decrease in total GC B cells (M= 7.2% SD+/−1.8 in aged vs M=15.8% SD+/−3.3 in young) and no change in Tfh cells (M= 7.5% SD+/−0.7 in old vs M=8.2% SD+/−2.1 in young). Further, the frequency of anti-toxin-specific B cells was significantly decreased in the aged (p= 0.02). The frequency of toxin-specific IgG, IgM and IgA ASC, and serum and mucosal toxin-specific Ab were markedly reduced in the aged. Our data suggests aged mice are more susceptible to CDI due to a defect in early GC formation, leading to an impaired antigen-specific Ab response. Overcoming this could prevent age-associated recurrence and severe CDI.

Influence of Intermittent Preventive Treatment on Antibodies to VAR2CSA in Pregnant Cameroonian Women.

Intermittent preventive treatment (IPT) and insecticide-treated bed nets are the standard of care for preventing malaria in pregnant women. Since these preventive measures reduce exposure to malaria, their influence on the antibody (Ab) response to the parasite antigen VAR2CSA was evaluated in pregnant Cameroonian women exposed to holoendemic malaria. Ab levels to full-length VAR2CSA (FV2), variants of the six Duffy binding like (DBL) domains, and proportion of high avidity Ab to FV2 were measured longitudinally in 92 women before and 147 women after IPT. As predicted, reduced exposure interfered with acquisition of Ab in primigravidae, with 71% primigravidae being seronegative to FV2 at delivery. Use of IPT for > 13 weeks by multigravidae resulted in 26% of women being seronegative at delivery and a significant reduction in Ab levels to FV2, DBL5, DBL6, proportion of high avidity Ab to FV2, and number of variants recognized. Thus, in women using IPT important immune responses were not acquired by primigravidae and reduced in a portion of multigravidae, especially women with one to two previous pregnancies. Longitudinal data from individual multigravidae on IPT suggest that lower Ab levels most likely resulted from lack of boosting of the VAR2CSA response and not from a short-lived Ab response.

Parainfluenza virus type 3 Ab in allogeneic hematopoietic cell transplant recipients: factors influencing post-transplant Ab titers and associated outcomes.

Parainfluenza virus type 3 (PIV-3) can cause severe respiratory illness among hematopoietic cell transplantation (HCT) recipients. Factors associated with PIV-3-specific Ab level, and the association between PIV-3 Ab levels and clinical outcomes in HCT recipients who acquire PIV-3 infection, are unknown. We evaluated PIV-3-specific hemagglutination inhibition Ab levels and clinical outcomes among 172 patients with PIV-3 infection following HCT. In a multivariable linear regression model, high post-transplantation Ab levels were independently associated with higher pre-transplantation recipient titer (mean difference 0.38 (95% confidence interval (CI), 0.26, 0.50), P<0.001). Significant associations between pre-HCT Ab titers in both patients and donors and occurrence of lower respiratory tract disease (LRD) after HCT were not observed. In conclusion, low pre-transplantation titers are associated with low Ab levels after HCT. The relationship between PIV-3 Ab levels and outcomes remain uncertain. Further study is needed to prospectively evaluate the dynamics of PIV-3-specific Ab responses and the relative contribution of PIV-3-specific Ab to protection from infection acquisition and progression to LRD.

Total IgE and allergen-specific IgE and IgG antibody levels in sera of atopic dermatitis affected and non-affected Labrador- and Golden retrievers

Canine atopic dermatitis (CAD) is an allergic skin disease associated with IgE and IgG antibodies (Ab) to environmental allergens. The aim of this study was to determine which other factors influence serum Ab levels in CAD-affected and non-affected dogs as this has only been poorly investigated in dogs so far.Total and allergen-specific IgE levels and Dermatophagoides farinae (DF)-specific IgG1 and IgG4 were measured by ELISA in sera of 145 CAD-affected and 271 non-affected Labrador- and Golden retrievers. A multivariable logistic regression analysis including the factors age, breed, gender, castration, clinical CAD status and allergen-specific immunotherapy (ASIT) was performed.Golden retrievers had more frequently total (OR=1.87, 95% CI=1.26–2.87, p<0.01) and specific IgE levels above the threshold value than Labrador retrievers, suggesting that genetic factors influence IgE levels in dogs. Castration was generally associated with low Ab levels (OR=0.43–0.65, p<0.05). Surprisingly, dogs with CAD did not have increased odds for high IgE against any of the allergens tested. ASIT with DF was associated with high DF-specific IgG1 (OR=4.32, 95% CI 1.46–12.8, p<0.01) but was not associated with DF-specific IgG4 or decreased IgE levels.Further studies are needed to understand the role of allergen-specific IgE in CAD and of IgG1 in ASIT.

CSF biomarker and PIB-PET–derived beta-amyloid signature predicts metabolic, grey matter and cognitive changes in nondemented subjects

Beta-amyloid (Ab) is a histopathological hallmark of Alzheimer’s disease dementia, but high levels of Ab in the brain can also be found in a substantial proportion of nondemented subjects. Here we investigated which 2-year rate of brain and cognitive changes are present in nondemented subjects with high and low Ab levels, as assessed with cerebrospinal fluid and molecular positron emission tomography (PET)--based biomarkers of Ab. In subjects with mild cognitive impairment, increased brain Ab levels were associated with significantly faster cognitive decline, progression of gray matter atrophy within temporal and parietal brain regions, and a trend for a faster decline in parietal Fludeoxyglucose (FDG)PET metabolism. Changes in gray matter and FDG-PET mediated the association between Ab and cognitive decline. In contrast, elderly cognitively healthy controls (HC) with high Ab levels showed only a faster medial temporal lobe and precuneus volume decline compared with HC with low Ab. In conclusion, the current results suggest not only that both functional and volumetric brain changes are associated with high Ab years before the onset of dementia but also that HC with substantial Ab levels show higher Ab pathology resistance, lack other pathologies that condition neurotoxic effects of Ab, or accumulated Ab for a shorter time period.

Adsorption to aluminum hydroxide promotes the activity of IL-12 as an adjuvant for antibody as well as type 1 cytokine responses to HIV-1 gp120.

A series of protocols were tested to examine the adjuvant effects of IL-12 on humoral and type 1 cytokine responses elicited in mice by recombinant gp120 envelope protein from HIV-1. This Ag fails to induce detectable Ab responses when administered s.c. alone, but stimulates low Ab levels when combined with aluminum hydroxide (alum). Moreover, when i.p. injected rIL-12 was included in the immunization, no increase in Ab production was observed. Importantly, optimal gp120 Ab responses were achieved by immunizing mice s.c. with gp120 and rIL-12 simultaneously coadsorbed to alum. These animals displayed a highly polarized, type 1 cytokine profile, with the emergence of anti-gp120 Ig belonging to the IgG2 and IgG3 isotypes. In addition, a major increase occurred in Ab of the IgG1 subclass. The superior adjuvant activity of alum-adsorbed IL-12 compared with that of the free cytokine correlated with the prolonged detection of IFN-gamma in the sera of animals immunized using the former procedure. In related experiments, in vitro neutralization of IL-12 was shown to inhibit IFN-gamma production by spleen cells from mice immunized with gp120 plus alum, but not by splenocytes from mice primed in the presence of IL-12, suggesting that the latter protocol induces a stable type 1 phenotype. These studies demonstrate that presentation of IL-12 on alum enhances its immunomodulatory effects and establish a protocol for the use of the cytokine as an adjuvant for simultaneously promoting both humoral Ab and type 1 cytokine responses.

Inhibition of complement, evoked antibody, and cellular response prevents rejection of pig-to-primate cardiac xenografts.

Complement (C) inhibition alone using a recombinant soluble form of complement receptor type 1 (sCR1) prevents hyperacute rejection but not subsequent irreversible accelerated acute rejection of discordant pig-to-cynomolgus monkey cardiac xenografts, which occurs within 1 week. To inhibit accelerated acute rejection, which is associated with a rise in serum xenoreactive antibody (Ab) and a cellular infiltrate, triple therapy with standard immunosuppressive agents (cyclosporine, cyclophosphamide, and steroids [CCS]) was combined with continuous C inhibition using sCR1. Each of two monkeys that received sCR1 + CCS showed minimal evidence of rejection when killed on days 21 and 32 in comparison to a monkey that received sCR1 + subtherapeutic CCS (rejected at 11 days) and a control that received CCS alone (rejected at 38 min). Prolonged xenograft survival was associated with low Ab levels and a minimal cellular infiltrate, suggesting that combined inhibition of C, xenoreactive Ab responses, and cellular immunity may be a useful approach in overcoming the immune barriers to discordant xenotransplantation.