Median IgG Levels Research Articles

Low Rates of Immunity among Medical Students and Residents in the Era of the Resurgence of Measles.

Measles is a highly contagious viral disease spread through respiratory droplets. The number of reported cases increased worldwide in 2023, particularly in the European Region. Italy reported 213 cases in the first quarter of 2024, with most of them in unvaccinated adults aged 15-64. Maintaining high vaccination coverage is essential to prevent outbreaks, especially in healthcare settings where measles transmission is a significant risk. In our study, we collected serological and demographic information from all Italian and foreign medical students and residents (850) who underwent a pre-training assessment at the Tor Vergata Occupational Medicine Service, Rome, between 3 April 2023 and 31 January 2024. Of the 850 students and residents analyzed, we found only 546 (64.2%) with a protective level of IgG antibodies against measles, with a median IgG level of 2.00 AI. A significant proportion of students and residents were serologically non-immune, raising concerns about the potential risk of hospital transmission. To manage this risk, it is important to assess serological levels, vaccinate those with inadequate levels, and promote vaccination in the general population.

Immunoglobulins As a Predictor of Chronicity in Pediatric Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder in children, but predictors of chronicity at the time of diagnosis remain largely unknown. Small studies have previously indicated predictive value of baseline immunoglobulin levels, but without definitive clinically applicable conclusions. We aim to further investigate the utility of immunoglobulin levels obtained at the time of diagnosis in predicting the development of chronic ITP (cITP) in children. Methods: We completed a retrospective review of patients aged 6 months - 21 years diagnosed with ITP at tertiary referral centers from 2015 - 2022 in accordance with IRB-approved protocols. Patients with immunoglobulin levels obtained within 3 months of ITP diagnosis and prior to any treatment were included in the study. cITP was defined as ITP duration >12 months. ITP resolution was defined as achieving a platelet count > 150 x 10 9/L on 2 occasions, or on 1 occasion in the presence of normalized MPV, absent of therapy. Patients who were lost to follow-up or had ongoing disease <1 year duration were excluded. Immunoglobulins were recorded by continuous variable as well as by age-related reference values. The two groups (“spontaneously resolved” and “cITP”) were compared using Pearson's Chi-squared test for nonparametric categorical variables, Fisher's exact test for parametric categorical variables, and Wilcoxon rank sum test for nonparametric categorical variables. A multivariable logistic regression model was built to determine independent associations between immunoglobulin levels and the development of cITP after adjusting for age. R (version 4.2.1) was used for analysis. A p-value <0.05 was considered to be statistically significant. Results: We identified 497 patients for inclusion in the study. Among these, 336 patients (67.6%) had ITP resolution prior to 12 months, while 161 patients (32.4%) developed cITP. Within the full cohort, 257 (51.7%) were male and 218 (43.9%) were Hispanic. Median age of diagnosis was 4.1 years among those with resolution, and 9.4 years among those with cITP. Patients were more likely to have secondary ITP in the cITP group vs the resolved group (37 patients [23.0%] vs 10 patients [6.2%]). Low and high IgG levels were more prevalent in cITP (5% vs 3% and 16% vs 5.7%, respectively). The median IgG level was higher in the cITP group (991 vs 838 mg/dL). Low IgA levels were more prevalent in cITP (7% vs 2.4%) and high IgA levels more prevalent in spontaneously resolving ITP (7.8% vs. 5.7%), although the median IgA level was higher in cITP (116 vs 88 mg/dL), likely attributable to older age in the cITP group. Both low and high IgM levels were more prevalent in cITP (8.9% vs 6.6% and 20% vs 16%, respectively), with the median IgM level being similar in both groups (89 vs 85 mg/dL). The age-adjusted multivariable logistic regression analysis demonstrated independent predictive value of IgG, IgA, and IgM for development of cITP (See Table, Figure). Each 100 mg/dL increase in IgG level was associated with a 17% increase in the odds of developing cITP (p=0.001); while each 100 mg/dL increase in IgA or IgM level was associated with decreased odds of developing cITP (37% [p=0.025] and 56% [p<0.001] decrease, respectively). Additionally, every 1-year increase in age was associated with a 16% increase in the odds of developing cITP (p<0.001). We also found that patients with a known secondary cause of ITP at the time of diagnosis had increased likelihood of developing cITP (p<0.001). Performance scores for the predictive model include a C-index of 0.72 and Nagelkerke R 2 of 0.21. Conclusions: We utilized pre-treatment immunoglobulin values obtained within 3 months of diagnosis from 497 children with ITP to investigate the predictive value of immunoglobulin measurements for the development of cITP. We found that IgG, IgA, and IgM values are predictive of cITP development after accounting for age. Increasing age was also associated with increased risk of cITP. In future work, we plan to evaluate the value of additional variables for predicting the development of cITP and then validate the predictions in an external cohort. Better defining the predictive value of clinical data available at the time of ITP diagnosis will allow hematologists to provide improved prognostication and individualized management much earlier in a patient's disease course, ultimately improving the quality of care for children with ITP.

Infection Risk and Use of Prophylaxis with Anti-BCMA Bispecific T Cell Engagers and Belantamab Mafodotin for Patients with Relapsed and Refractory Multiple Myeloma

Introduction: BCMA targeted therapies have demonstrated single agent efficacy for patients with triple class exposed or refractory multiple myeloma (RRMM). Teclistamab and Belantamab Mafodotin (Belamaf) are currently approved for RRMM in Europe with several Bispecific T Cell Engagers (TCE) under investigation. However, whilst TCEs have higher response rates and progression free survival to Belamaf, adverse events, particularly infections may influence treatment choice particularly for frailer patients. Intravenous Immunoglobulin (IVIg) is recommended to prevent infections once IgG levels fall <4g/L or even as prophylaxis with anti-BCMA TCEs. Methods: This was a retrospective review of MM patients treated with anti-BCMA monotherapies at University College London Hospitals between 28/07/2015 and 15/06/2023. IVIg was given according to UK guidelines: IgG of <3g/L and recurrent infections/ one severe infection, despite 6 months of prophylactic antibiotics. IgG levels between 3-4g/L also required failure of a vaccine challenge. IVIg for asymptomatic patients was not permitted. Statistics was performed using GraphPad Prism. Results: 55 patients were treated with anti-BCMA monotherapies: 21 with TCE and 34 with Belamaf. The median age was 61 years (range 45-79), 43% female, 80% white and 5.6% Black. The median time from diagnosis to treatment was 5.8 years with a median of 5 prior lines (range 2-15). 51.9% of patients had high risk cytogenetics. Patients were a median of 59 years for TCE (range 47-73) vs 64 years (range 45-79) with Belamaf. Both groups had a median of 5 prior lines and a median Charlson co-morbidity index of 2, but 40% of TCE were classified frail by modified IMWG score vs 61.8% with Belamaf. CD38 exposure was 100% for TCE patients and 76% Belamaf. Severe hypogammaglobulinemia (<4g/L) at baseline prior to anti-BCMA treatment was present in 75% of TCE and 53% of Belamaf patients. Further significant reductions in median IgG levels occurred during treatment (TCE: 3.04g/L to 1.06g/L, p=0.01; Belamaf: 3.9g/L to 1.9g/L p=0.002). Nadir IgG levels were significantly lower with TCE than Belamaf (p=0.047). All patients received aciclovir prophylaxis, PJP prophylaxis (co-trimoxazole/ azithromycin) was given in 100% with TCE and 82% with Belamaf, with anti-fungal prophylaxis in 1 TCE patient. IVIg was used prior to anti-BCMA treatment in 3 patients (2 TCE, 1 Belamaf). Whilst on anti-BCMA treatment, IVIg was used in 38% for TCE and 5.9% for Belamaf. The risk for all grade infection per patient was 3.7 times higher for TCE vs Belamaf (increased risk TCE vs Belamaf: G1-2: 3.3, G3: 2.1, G4: 2.1). There was a total of 104 infection episodes, 57% with TCE, 43% with Belamaf (see Figure). The median time to first infection was 45 days for TCE and 34 days for Belamaf. Most infections were low grade with 20 patients having ≥1 infection (10/21 (48%) TCE, 10/34 (29%) Belamaf). At Grade 1-2, there were 1.8 infections per patient for TCE vs 0.7 for Belamaf. For G3-5, 1.0 infections per patient vs 0.6 for Belamaf. There was 1 grade 5 infection with TCE, 0 for Belamaf. Respiratory infections predominated (TCE: 80% vs Belamaf: 73%) followed by urinary (TCE: 5% vs Belamaf 16%), blood (TCE 10% vs Belamaf 5.4%) and GI (TCE 3% vs Belamaf 5%). 96/ 104 infections were identified, most were viral (TCE 71% vs Belamaf 62%) with few fungal infections (6% vs 4%). More bacterial infections occurred with Belamaf possibly due to lower antibacterial prophylaxis and IVIg use (TCE: 23% vs Belamaf: 35%). Since commencing IVIg, 5 of 8 (63%) TCE patients had at least 1 infection, mainly viral. A median of 1 further infection (range 0-14) occurred over a median of 3.2m (range 0.6-28.3m) of monthly IVIg infusions. Routine blood viral PCR monitoring for CMV, EBV & Adenovirus was performed in 30% of patients. 13 (65%) of TCE patients had 197 blood viral PCR tests performed of which 3 patients (23%) tested positive (2x adenovirus and 1 CMV). Of these 2 (both adenovirus) had symptoms requiring intervention. Of the 8.8% of Belamaf patients tested, 0 were positive. Conclusions: Patients treated with Belamaf were frailer than those receiving TCE. Hypogammaglobulinemia was more profound with TCE and the per patient risk of infections was higher. IVIg use was substantially higher for TCE than Belamaf. Blood viral PCR monitoring for TCE patients only detected symptomatic reactivations in 2 out of 13 patients suggesting this was an infrequent event.

Dynamics of IgG antibody response against Plasmodium antigens among Nigerian infants and young children.

Plasmodium falciparum malaria is a leading cause of child mortality in Nigeria. Neonates are born with maternal antibodies from placental transfer which may protect against malaria infection in the first months of life. The IgG dynamics of the transition from passively transferred antimalarial antibodies to actively acquired IgG from natural exposure have not been well elucidated. Blood samples collected during a 2018 Nigeria nationwide HIV/AIDS household survey were available for 9,443 children under 5 years of age, with a subset of infants under 2 months of age having maternal samples available (n=41). Samples were assayed for the P. falciparum HRP2 antigen and anti-malarial IgG antibodies. LOESS regression examined the dynamics in IgG response in the first 5 years of life. Correlation with maternal IgG levels was assessed for mother/child pairs. Consistent decreases were observed in median IgG levels against all Plasmodium spp. antigen targets for the first months of life. At a population level, P. falciparum apical membrane antigen-1 (AMA1) and merozoite surface protein-1 19kD (PfMSP1) IgG decreased during the first 12 months of life before reaching a nadir, whereas IgGs to other targets only declined for the first 4 months of life. Seropositivity showed a similar decline with the lowest seropositivity against AMA1 and PfMSP1 at 10-12 months, though remaining above 50% during the first 2 years of life in higher transmission areas. No protective association was observed between IgG positivity and P. falciparum infection in infants. Maternal antibody levels showed a strong positive correlation with infant antibody levels for all P. falciparum antigens from birth to 2 months of age, but this correlation was lost by 6 months of age. Maternally transferred anti-malarial IgG antibodies rapidly decline during the first 6 months of life, with variations among specific antigens and malaria transmission intensity. From 3-23 months of age, there was a wide range in IgG levels for the blood-stage antigens indicating high individual variation in antibody production as children are infected with malaria. Non-falciparum species-specific antigens showed similar patterns in waning immunity and correlation with paired mother's IgG levels compared to P. falciparum antigens.

Subcutaneous immunoglobulin 20% (Ig20Gly) treatment regimens in pediatric patients with primary immunodeficiencies – real-world data from the IG TATRY study

ABSTRACT Background Subcutaneous administration of immunoglobulins is associated with fewer systemic adverse events and easier infusion compared to intravenous administration. Ig20Gly is a 20% immunoglobulin formulation effective and safe in patients with primary immune deficiency diseases (PIDDs). Real-world data are scarce, therefore our study aimed to examine the real-life treatment regimen and clinical outcomes of Ig20Gly in Polish children with PIDDs. Researchdesign We retrospectively analyzed the medical documentation of 75 pediatric patients aged 0–17 years (mean 9.9) who received Ig20Gly (Cuvitru®; Baxalta US, Inc.; part of Takeda, MA, U.S.A.). Results The median exposure to treatment of the study population was 22.3 months. At the end of the study, 59 (78.7%) were still on Ig20Gly. The median monthly dose was 0.40 g/kg. The median treatment interval was 7.7 days. Most patients (96%) used one infusion site. The median infusion rate increased with patient age. The median IgG level in the study population, 8.0 g/L, was stable. There was one case of serious bacterial infection. Conclusion This is the largest, long-term real-world study to date on the treatment patterns of Ig20Gly in pediatric patients with PIDDs. The results of this study support the feasibility and tolerability of Ig20Gly usage in PIDD patients across the pediatric age spectrum. Trial registration The trial is registered at ClinicalTrials.gov (NCT04636502).

Immunological responses and adverse reactions of the heterologous second booster dose of BNT162b2 after two-dose CoronaVac for COVID-19 vaccination in healthcare workers of Faculty of Medicine, Naresuan University

BackgroundThe first COVID-19 vaccination campaign in Thailand began in April 2020, with healthcare workers receiving two doses of inactivated COVID-19 vaccine (CoronaVac). However, the emergence of the delta and omicron variants raised concerns about vaccine effectiveness. The Thai Ministry of Public Health provided the first booster dose (third dose) and second booster dose (fourth dose) of the mRNA vaccine (BNT162b2) for healthcare workers. This study investigated the immunity and adverse reactions elicited by a heterologous second booster dose of BNT162b2 after a two-dose CoronaVac vaccination for COVID-19 in healthcare workers of the Faculty of Medicine, Naresuan University. MethodsIgG titres against the SARS-CoV-2-spike protein were measured four and 24 weeks after the second booster dose of BNT162b2 in the study participants. Adverse reactions were recorded during the first three days, four weeks and 24 weeks after the second booster dose of BNT162b2. ResultsIgG against the SARS-CoV-2-spike protein was positive (>10 U/ml) in 246 of 247 participants (99.6 %) at both four and 24 weeks after the second booster dose of BNT162b2. The median specific IgG titres at four and 24 weeks after the second booster dose of BNT162b2 were 299 U/ml (min: 2, max: 29,161) and 104 U/ml (min: 1, max: 17,920), respectively. The median IgG level declined significantly 24 weeks after the second booster dose of the BNT162b2 vaccine. Of the 247 participants, 179 (72.5 %) experienced adverse reactions in the first three days after the second booster dose of BNT162b2. Myalgia, fever, headache, injection site pain and fatigue were the most common adverse reactions. ConclusionThis study demonstrated that a heterologous second booster dose of BNT162b2 after two doses of CoronaVac induced elevated IgG against the SARS-CoV-2-spike protein and caused minor adverse reactions in healthcare workers of the Faculty of Medicine, Naresuan University.This study was registered as Thailand Clinical Trials No. TCTR20221112001.

Optimizing COVID-19 Vaccination Strategy in Pediatric Kidney Transplant Recipients: Humoral and Cellular Response to SARS-CoV-2 mRNA Vaccination.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

Estimation of baseline IgG antibody levels to 23 pneumococcal vaccine-type capsular polysaccharides in healthy vaccine naïve Indian adults

Since immunological responses to pneumococcal vaccines are assessed by a fold-increase in antibody levels relative to pre-immunization levels, it is therefore critical to determine baseline antibody levels to establish putative threshold as a measure of normal response. Herein, for the first time, we measured baseline IgG antibody levels in 108 healthy unvaccinated Indian adults using WHO-recommended ELISA. Median baseline IgG concentration ranged between 0.54 µg/mL to 12.35 µg/mL. Highest levels of baseline capsule polysaccharide (cPS)-specific IgG were found against types 14, 19A, and 33F. Whereas, lowest baseline IgG levels were observed against types 3, 4, and 5. Overall, ∼79% of study population had median baseline IgG levels ≥1.3 µg/mL against 74% of cPS’s. Substantial baseline antibody levels in unvaccinated adults were observed. The study would be critical in bridging gaps in baseline immunogenicity data and may offer a valuable foundation for evaluating immune response of Indian adults to pneumococcal vaccination.

Clinical outcome of SARS-CoV-2 infections occurring in multiple myeloma patients after vaccination and prophylaxis with tixagevimab/cilgavimab.

Patients with multiple myeloma (MM) frequently reported immune impairment with an increased risk for infection-related mortality. We aimed to evaluate the immune response in MM patients vaccinated for SARS-CoV-2 during active treatment. We enrolled 158 patients affected by active MM or smoldering MM (SMM) and 40 healthy subjects. All subjects received 2 or 3 doses of the BNT162b2 (Pfizer/BioNTech) vaccine, and the anti-spike IgG values were evaluated after every dose. We applied the Propensity Score Matching (PSM) as a consequence of the limited sample size and its heterogeneity to adjust for differences in baseline clinical variables between MM patients who achieved or not a vaccine response after 2 or 3 doses. At 30 days from the second dose, the median antibodies level in MM was 25.2 AU/mL, lower than in SMM and in the control group. The same results were confirmed after the third dose, with lower median anti-spike IgG levels in MM, compared to SMM and control group. Following PSM, lack of response to SARS-CoV-2 complete vaccination plus boost was associated with age more than 70 years old and use of high-dose of steroids. We failed to identify an association between specific treatment types and reduced vaccine response. The use of prophylaxis with tixagevimab/cilgavimab for 40 non-responder patients after 3 doses of vaccine has proven to be an effective and safe approach in reducing the risk of serious illness in the event of a breakthrough SARS-CoV-2 infection, faced with a mild symptomatic course, and in providing protection instead of long-term humoral immune vaccine responses. Following PSM, only the high-risk cytogenetic abnormalities were associated with an increased risk of developing a breakthrough SARS-CoV-2 infection. Monitoring the immune response is fundamental in MM patients that remain highly vulnerable to SARS-CoV-2 despite the vaccine. The use of prophylaxis with tixagevimab/cilgavimab can guarantee better protection from the severe form of the disease.

Dynamics of SARS-CoV-2 Spike-IgG throughout Three COVID-19 Vaccination Regimens: A 21-Month Longitudinal Study of 82 Norwegian Healthcare Workers

To facilitate interpretation of clinical SARS-CoV-2 anti-spike IgG analyses post-vaccination, 82 healthcare workers were followed through three vaccination-regimens: two regimens were comprised of two doses of BNT162b2 three or six weeks apart, followed by a dose of mRNA-vaccine, and in the other regimen, the first dose was replaced by ChAdOx1 nCov-19. After each dose, anti-spike IgG was compared between regimens. As many participants became infected, anti-spike IgG persistence was compared between infected and uninfected participants. Thirteen to twenty-one days after the first dose, seroconversion, and the median anti-spike IgG level in the ChAdOx1 group was significantly lower than in the BNT162b2 groups (23 versus 68 and 73 AU/mL). The second dose caused a significant increase in anti-spike IgG, but the median level was lower in the BNT162b2-short-interval group (280 AU/mL), compared to the BNT162b2-long-interval (1075 AU/mL) and ChAdOx1 (1160 AU/mL) group. After the third dose, all groups showed increases to similar anti-spike IgG levels (2075-2390 AU/mL). Over the next half year, anti-spike IgG levels declined significantly in all groups, but appeared to persist longer after post-vaccination infection. This is the first three-dose study with one dose of ChAdOx1. Despite initial differences, all vaccine regimens gave similarly high antibody levels and persistence after the third dose.

High levels of antibodies 6 months after COVID-19 vaccination in children with severe chronic diseases: A prospective longitudinal case series.

High levels of antibodies 6 months after COVID-19 vaccination in children with severe chronic diseases: A prospective longitudinal case series.

Antibody Response (IgM and IgG) After Two Doses of Immunization Against SARS-CoV-2 and Comparison of Two Different Third Dose Administrations

Türkiye's first SARS-CoV-2 vaccination campaign started with an inactivated vaccine (Sinovac Life Sciences Co., Ltd., Beijing, China) mid-January 2021 for healthcare workers. The second dose was administered at an interval of 21 days-one month. As of July 2021 (4-4.5 months after the second dose), the Republic of Türkiye Ministry of Health suggested the third vaccination dose for healthcare workers and people over 50. The individuals could select between the choice of CoronaVac or an mRNA vaccine BNT162b2 (Pfizer‐BioNTech, Inc) for the third dose vaccination. Thus, a heterogeneous immunization emerged in society. This study is aimed to investigate the humoral response (IgG and IgM) after two doses of the SARS-CoV-2 vaccine and the possible effects of factors for this response, as well as to compare the third dose of homogeneous and heterogeneous vaccine administration. The study included 512 volunteers who are 21-65 years old that have been immunized against SARS-CoV-2 in at least two doses, working at Bursa Uludag University Faculty of Medicine Health Application and Research Center. The demographic characteristics of the participants (such as age, gender, and place of duty), background (presence of chronic disease, risky contact for SARS-CoV-2 transmission, and history of COVID-19 infection), and immunization characteristics were obtained with a questionnaire. Participants were divided into five main groups regarding the time elapsed months after the second dose and the type of vaccine administered (CoronaVac or BNT162b2). Group 1b (n=11); (blood samples were taken) one month after the second dose of BNT162b2 vaccine, group1c (n=12); one month after the second dose of CoronaVac, group 2 (n=9); two months after the second dose of CoronaVac vaccine, group 3 (n=27); three months after of CoronaVac vaccine, group 4 (n=418); four months after the second dose of CoronaVac vaccine and group 5 (n=35); five months after the second dose of CoronaVac vaccine. One month later, blood samples were taken from 52 participants in group 4 who received the third dose of the vaccine. In these participants, IgG levels were compared after two different third-dose vaccines [BNT162b2; group 4b (n=30) and CoronaVac; group 4c (n=22)]. SARS-CoV-2 IgM and IgG responses were evaluated by SARS-CoV-2 IgM (Abbott, USA) and IgG Quant II (Abbott, USA) kits on Architect i2000SR (Abbott, USA) autoanalyzer with a chemiluminescent based method at Bursa Uludag University Faculty of Medicine Medical Microbiology Laboratory. In this study, a high rate (>80%) of anti-S IgG seroconversion was observed in all groups given two doses of the SARS-CoV-2 vaccine. The median IgG levels in groups 1b, 1c, 2, 3, 4, and 5 were 4315.3 AU/mL (24-10337), 721.5 AU/mL (154-1430), 842.5 AU/mL (365-4447), 183.0 AU/mL (14-1635), 165.0 AU/mL (4-31796) and 110.0 AU/mL (28-8757), respectively. After CoronaVac vaccination with two doses, groups 3, 4, and 5 had low levels of anti-SARS-CoV-2 IgG compared to group 1c (p values: 0.034, 0.006, and 0.001, respectively). IgM positivity was between 12.5-33.5% in the participants whose blood samples were obtained at one, two, and three months after the vaccination and 3.2-4.3% in the participants after four and five months (p=0.001). The heterogeneous immunization [two doses of CoronaVac and one dose of BNT162b2: median 11084.5 AU/mL (2948-40000)] has provided higher SARS-CoV-2 IgG levels compared to homogeneous immunization [three doses of CoronaVac: median 1707.0 AU/mL (304-8322)] (p<0.001). When the factors that affect the vaccine response were examined four months after two doses of the CoronaVac vaccine, IgM and IgG responses were higher in participants who also had past COVID-19 infection history (p=0.001). Advanced age (>60) was the most critical negative factor in IgG levels (p=0.001). Unlike previous research, it was found that the presence of comorbidity and gender did not affect the vaccine response after four months. Having a high-risk contact history and working in high-risk areas (pandemic ward) did not affect the antibody response. Among the factors evaluated, the only factor affecting IgM positivity was the combination of vaccine and natural immunity. Decreased levels of anti-S IgG antibody three months after the CoronaVac vaccine may affect the protection, especially in advanced age groups. Although this situation creates a guide for the planning of booster doses, the neutralizing antibody and T-cell response are important for protection.

Evidence of immune response to BNT162b2 COVID-19 vaccine in systemic lupus erythematosus patients treated with Belimumab.

To evaluate humoral and cell-mediated response after three doses of BNT162b2 SARS-CoV-2 vaccine in patients with systemic lupus erythematosus (SLE) treated with Belimumab (BLM). SLE patients were vaccinated with three doses of BNT162b2-mRNA vaccine (two-dose primary vaccination, third booster dose after 6months). The humoral immune response was assessed one and 6months after the second dose (T1, T2), and 6months after the booster dose (T3). Serological assay was performed (The Liaison® SARS-CoV-2 TrimericS IgG chemiluminescent). Spike-specific T-cell response was monitored 6months after the second vaccine dose and the percentage of cytokines producing T cells was assessed by flow cytometry. Twelve patients [12F; median age 46years (IQR 8.25); median disease duration 156months (IQR 188)] were enrolled. At T1, all patients showed seroconversion (median anti-Spike IgG levels 1610 BAU/mL, IQR 1390). At T2--day of the third dose--a significant reduction of median anti-Spike IgG antibodies levels was observed [214 BAU/mL (IQR 94); p = 0.0009]. Anti-Spike IgG were significantly increased at T3, reaching a median value of 1440 BAU/mL (IQR 1316; p = 0.005). Despite declining humoral immunity, almost 60% of patients mounted a virus-specific CD4 + T-cell response 6months after primary vaccination. BLM does not impair humoral response to primary BNT162b2 SARS-CoV-2 vaccination. During the follow-up, a decline in antibody levels is evident and the third dose is crucial to increase the specific immune response. Finally, we observed a recall T-cell response to the Spike antigen 6months after the first vaccination cycle.

Assessment of donor specific IgG Anti-HLA subclasses before and after kidney transplantation in Upper Egypt: A Single Center Study

Donor specific antibodies (DSAs) are known as the leading cause of antibody mediated rejection (AMR), graft loss in kidney transplant (KT) recipients. DSAs characteristics, as immunoglobulin (Ig) classes, subclasses, and strength, are important to assess the immunological risk, early prediction of AMR, and therefor proper management. This longitudinal, case control study included 32 KT recipients at Assiut University Urology Hospital and 10 age and sex matched normal subjects as the control group. Total IgG, its subclasses and anti-human leukocyte antigen (anti-HLA) panel reactive antibody (PRA) were detected pre-transplantation (pre-TX), at 6-12- and 24-36-months post-TX. Rejection occurred in 4 recipients, 3 of them had high total IgG, IgG1 and/or IgG3. IgG2 and IgG4 were normal in all recipients. There were preformed anti-DSAs antibodies in 3/32 recipients (9.4%). Of these, two recipients became negative with no rejection occurred. The third recipient had high post-TX mean fluorescence intensity (MFI) and AMR occurred. The pre-TX PRA was negative in 29/32 recipients (90.6%). The PRA was negative in 8/29 recipients (27.6%) and the remaining 21/29 recipients (72.4%) developed de novo DSAs post-TX (MFI < 3000->10000). Rejection occurred with both low and high MFI. In 11 recipients, anti-HLA class I and II were not different between pre-TX, 3-6- and 24-36 months post-TX with no rejection occurred. The frequency and median levels of total IgG, IgG1 and IgG3 were increased in all recipients 24-36 months post-TX when compared with their levels pre-TX and 6-12 months post-TX in the 11 recipients and with the control group. The graft survival time significantly decreased in recipients with positive post-TX class I PRA. In conclusion, preformed DSAs may persist post-TX or turn negative. De novo DSAs developed post-TX even in non-sensitized recipients. Serum total IgG, IgG1 and IgG3 frequency increase 2-3 years post-TX.

2300. Neonates born to mothers with SARS-CoV-2 infection in pregnancy: a follow-up and serological study

Abstract Background To evaluate the early and late clinical outcomes of neonates born to mothers with SARS-CoV-2 infection in pregnancy, the dynamics of maternal IgG trans placental transfer and its persistence during the first month of life. Methods Prospective study enrolling neonates born to mothers with SARS-CoV-2 infection in pregnancy at IRCCS Azienda Ospedaliero Universitaria di Bologna, Italy, between April 2020 and September 2021. Neonates born to women with infection onset before 2 weeks prior to delivery were enrolled in a 12-month follow-up, including clinical and laboratory evaluations, cranial ultrasound, fundoscopy evaluation. Quantitative IgG to S1/S2 subunits of spike protein were assessed in mother-neonate dyads within 48 hours post-delivery and during follow-up until negative. Transplacental IgG transfer ratio was assessed in relation to the type and trimester of maternal infection. Results One hundred and forty-five neonates were included. the rate of preterm delivery was similar between women with and without SARS-CoV-2 infection (6.2% versus 8.7%, P=0.53). No clinical, laboratory, cerebral and fundoscopy abnormalities were detected at birth or during follow-up, through 11 months (range 8–12). MedianIgG level at birth was not different between neonates born to asymptomatic or symptomatic mothers (18.5 AU/mL, IQR 12–49, versus 31.5 AU/mL, IQR 15–71, P=0.07) nor in relation to the trimester of maternal infection (Table 1), even though mothers with third trimester infections had higher IgG level at birth. Transplacental transfer ratio was higher following second trimester maternal infections and was the lowest following third trimester infections (Table 1). Maternally derived IgG were rapidly weaned, with most infants (115/140, 82%) seronegative by 4 months of age. Conclusion Early and later outcomes of infants born to SARS-CoV-2 infected mothers were favorable. IgG trans placental transfer was higher following second trimester maternal infections, which could be relevant to inform studies on appropriate vaccination strategies aimed at neonatal protection. Maternally derived IgG are rapidly weaned in the first months of life. Disclosures All Authors: No reported disclosures.

Neutralizing monoclonal antibody in patients with coronavirus disease 2019: an observational study

BackgroundClinical data on patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant are limited, especially on clinical status after the application of antibody therapy.MethodsWe evaluated clinical status in patients with the SARS-CoV-2 delta variant after BRII-196 and BRII-198 treatment in an infectious disease hospital in China. We collected data on clinical symptoms, laboratory tests, radiological characteristics, viral load, anti-SARS-CoV-2 antibodies, treatment, and outcome.ResultsIn mid-June 2021, 36 patients with delta variant infection were identified in Shenzhen. The most common symptoms at illness onset were cough (30.6%), fever (22.2%), myalgia (16.7%), and fatigue (16.7%). A small number of patients in this study had underlying diseases, including diabetes (5.6%) and hypertension (8.3%). The application of BRII-196 and BRII-198 can rapidly increase anti-SARS-CoV-2 IgG. The median peak IgG levels in the antibody treatment group were 32 times higher than those in the control group (P < 0.001). The time from admission to peak IgG levels in the antibody treatment group (mean: 10.2 days) was significantly shorter than that in the control group (mean: 17.7 days). Chest CT score dropped rapidly after antibody therapy, with a mean duration of 5.74 days from admission to peak levels.ConclusionThe results of this study suggest that the application of BRII-196 and BRII-198 antibody therapy improved clinical status in patients with SARS-CoV-2 delta variant infection.

Changes in Serum Immunoglobulin G Subclasses during the Treatment of Patients with Chronic Obstructive Pulmonary Disease with Infectious Exacerbations.

Despite the theoretical importance of serum immunoglobulin (Ig) in the outcome of COPD exacerbations, the existing evidence for this has not been enough. This study was performed to evaluate changes in serum Ig levels and their relationship with outcomes of acute infectious exacerbations in patients with COPD. The prospective study was conducted at Military Hospital 103 from August 2017 to April 2019. Group D patients with COPD with infectious exacerbation were selected for participation in the study. The control group consisted of 30 healthy people. The patients were provided clinical examination and laboratory service; simultaneously, we measured their serum Ig levels (total IgG, IgG1, IgG2, IgG3, IgG4) at two time points: at admission (T1) and the final health outcome (T2). The median levels of total IgG in patients at times T1 and T2 were significantly lower compared with those in the healthy group (1119.3 mg/dL and 1150.6 mg/dL compared with 2032.2 mg/dL) (p &lt; 0.001). Regarding changes among IgG subclasses, the IgG1, IgG3, and IgG4 levels measured at T1 and T2 were reduced significantly compared with the control group (p &lt; 0.05); the IgG3 levels at T1 were significantly higher than those at T2. IgG3 levels in patients with life-threatening exacerbations were significantly lower than the remaining ones (24.6 (26.8-155.5) mg/dL and 25.6 (29.5-161.2) mg/dL, respectively, p = 0.023). In group D patients with COPD with infectious exacerbations, there was a decrease in the serum IgG, IgG1, IgG3, and IgG4 levels. IgG3 levels were associated with the severity of COPD exacerbation.

The Impact of B-Cell-Directed Therapy on Sars-Cov-2 Vaccine Efficacy in CLL: 1-Year Follow up

Background Decreased immune response to vaccinations has been a long-standing concern for patients with chronic lymphocytic leukemia (CLL), particularly those receiving B-cell directed therapy. We have previously demonstrated the negative impact of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors on COVID vaccine efficacy for those with CLL with an overall seroconversion rate of 41% (Ujjani et al, BJH 2022). Here we present the 1-year follow up data of from our cohort. Methods This prospective observational study was conducted at the University of Washington/Fred Hutchinson Cancer Center. Eligible patients had a diagnosis of CLL or SLL, were at least 18-years-old and had no known prior history of SARS-CoV-2 infection. Patients were enrolled into 3 cohorts: 1) currently receiving or recently completed venetoclax + anti-CD20 monoclonal antibody (Arm A), 2) currently receiving a BTK inhibitor (Arm B), and 3) previously untreated (Arm C). Patients underwent testing prior to vaccination (Visit 1), 1 (Visit 2), 3 (Visit 3), 6 (Visit 4), and 12 (Visit 5) months after first vaccine. Vaccine response was assessed via the Roche Elecsys Anti-SARS-CoV-2 S, a semiquantitative total antibody assay against the spike protein receptor binding domain (anti-S) and SARS-CoV-2 spike D614G pseudotyped lentivirus neutralization assays. We have previously demonstrated that these assays perform similarly with non-significant discordance, (p = 0.617). Reference interval for a negative result was <0.8 AU/ml on the Roche anti-S assay and ND50 < 20 for the neutralization assay. Results Of the original cohort of 37 evaluable patients, 14 remain on study at 1 year of follow up. The median age was 67 years (range 42-77) and 9 were male (64%). The median IgG level was 657 mg/dL (range 214-1016). Ten received BNT162b2 (72%), 3 mRNA-1273 (22%), and 1 Ad26.COV2.S (6%). Patient enrollment by arm was Arm A (n=3), Arm B (n=4), Arm C (n=7). All of the patients in Arm A had recently completed venetoclax therapy prior to first vaccination, whereas all of the patients in Arm B remained on a BTK inhibitor during the observation period of this study. None of the patients in any of the arms initiated a new line of therapy before Visit 5. Of the 6 patients who had received any prior anti-CD20 monoclonal antibody, all had received it more than 1 year prior to first vaccination (range 13-106 months). Anti-nucleocapsid antibody was non-reactive in all patients, indicating no evidence of prior SARS-CoV-2 infection. Median Anti-S levels at Visit 2 were 92.3 AU/mL (3.47-494) in Arm A, 8.7 AU/mL (0.95-12.8) in Arm B, and 20.1 AU/mL (1.14-1081) in Arm C. Anti-S levels from Visits 1-5 are depicted in Figure 1 by Arm. Variables that may have impacted serologic response, such as booster vaccinations, prophylactic tixagevimab with cilgavimab, COVID-19 infections, are depicted in Table 1. All 6 patients who received a booster after Visit 3 (3 months) were noted to have an increase in Anti-S by the Visit 4 (6 months) assessment. The increase was noted in 3 patients in Arm A, 1 patient in Arm B, and 1 patient in Arm C. Of the 9 patients who received a booster after Visit 4, 7 were noted to have increased Anti-S levels by the Visit 5 (12 months) assessment. There was no consistent trend for increased Anti-S levels after prophylactic tixagevimab with cilgavimab or COVID-19 infection. Roche Anti-S testing at Visit 5 showed similar results to neutralization antibody testing. The only discrepancy was noted in a patient with a minor, but technically positive, Anti-S level of 23.8 AU/mL and negative neutralization results. Two COVID-19 infections were noted (Table 1). Both were uncomplicated courses in previously untreated patients who had robust serologic responses to the vaccine. The infections occurred between Visits 4 and 5, during the Omicron variant phase but sequencing data was not available. Neither patient had received prophylactic tixagevimab with cilgavimab. One of these patients had received one dose of Ad26.COV2.S, whereas the other had received 3 doses of BNT162b2. Conclusion Here, we show that while CLL patients typically have inferior serologic responses to initial COVID vaccinations, these responses can be augmented with the administration of booster vaccinations. Benefit was primarily noted in patients who had completed venetoclax therapy and those who were previously untreated. Patients with CLL remain a vulnerable population as new variants arise. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors and Clinical Complications Associated with Antiphospholipid Antibodies in Sickle Cell Disease

Introduction. The antiphospholipid syndrome is characterized by the presence of anti-phospholipid autoantibodies (aPL) leading to a hypercoagulable state as well as an arterial, venous, and microcirculatory vasculopathy. Under several physiological and pathological situations, including the sickling of red blood cells (RBC), negatively charged phospholipids translocate from the inner to the outer surface of cell membranes leading to the potential generation of the antigenic target of aPL. We tested the following two-part hypothesis: 1) repeated exposure of the immune system of patients with sickle cell disease (SCD) to the antigenic target of aPL leads to an increased formation of aPL; and 2) the presence of aPL is associated with pregnancy and SCD-related complications. Methods. We conducted a cross-sectional study in 63 adults with SCD who had aPL testing performed during a hospital admission between August 1999 & June 2017. We compared individual aPL levels with categorical and linear variables using the Kruskal-Wallis test and linear regression analysis, respectively. The anticardiolipin (aCL) IgG and lupus anticoagulant (LA) levels were log-transformed for these analyses. An abnormal aPL was defined as any of the following: IgM or IgG anti-b2GPI >20 IU/mL, IgM or IgG aCL > 20 IU/mL, LA > 10 seconds. Clinical complications were compared by abnormal aPL status using the chi-square test. Results. The median age of the SCD cohort was 32 years (IQR, 21 - 39 years), 49 (78%) were female, 62 (98%) were African American, 5 (8%) had a diagnosis of systemic lupus erythematosus (SLE), 43 (68%) were Hgb SS genotype, 17 (27%) were on hydroxyurea, and 16 (25%) were on chronic anticoagulation therapy. SCD patients with SLE had higher median aCL IgM (6 vs. 1 IU/mL, respectively; P=0.02) and anti-b2GPI IgG (3.5 vs. 0 IU/mL, respectively; P=0.008) levels compared to those without SLE, while lower hemoglobin concentrations were associated with higher aCL IgG levels (β -0.12; P=0.07) and longer LA times (β -0.18; P=0.02). Fifteen of 63 (24%) patients with SCD had an abnormal aPL. Patients with an abnormal aPL had a lower hemoglobin concentration (Figure 1A), a higher white blood cell (WBC; 13.5 vs. 11.8 x109/L, respectively; P=0.06) count, and a lower platelet (268 vs. 340 x109/L, respectively; P=0.05) count at the time of hospitalization compared to those with a normal aPL. A lower hemoglobin concentration (odds ratio [OR], 1.9; P=0.008), a higher WBC count (OR 1.2; P=0.03), and a lower platelet count (10 platelets/µL increment: OR 1.05, P=0.06) were independently associated with the presence of an abnormal aPL by logistic regression analysis, adjusting for age, sex, and prior SLE diagnosis. Consistent with the second part of our hypothesis, several adverse outcomes trended higher in SCD patients with an abnormal aPL. An abnormal aPL was more prevalent among women with ≥ 3 miscarriages, preterm deliveries, or pre-eclampsia as well as during a hospitalization complicated by acute chest syndrome or multiorgan failure (Figure 1B). Conclusions. These data support the hypothesis that patients with SCD have a high predilection to form aPL, and that the presence of an abnormal aPL is associated with pregnancy complications and the severity of acute SCD-related complications during hospitalization. Our study is limited by its small number of patients. Further larger studies are needed to assess the mechanisms of aPL generation as well as to determine the prevalence and associated risk of abnormal aPL status in patients with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Host Immune Changes Following Treatment with Venetoclax Plus Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia

Background: Immune dysregulation is a hallmark of chronic lymphocytic leukemia (CLL) and often leads to hypogammaglobulinemia and frequent infections. Treatment with anti-CD20 antibodies (Abs) such as rituximab (R) is a known risk factor for hypogammaglobulinemia. Despite the widespread use of anti-CD20 Abs in combination with venetoclax (Ven), a B cell lymphoma 2 inhibitor, little has been reported on the long-term impact of this therapy on B cell recovery. We report long-term immune changes post treatment in patients (pts) with relapsed/refractory CLL in the MURANO phase 3 trial (NCT02005471) who completed the full VenR course without progressive disease (PD). Methods: Overall, 389 pts were randomized to either VenR (2 years of Ven with R for the first 6 months) or 6 months of bendamustine-R. Minimal residual disease (MRD) status has been previously reported (Kater et al. J Clin Oncol 2020). In the VenR arm, immunoglobulin (Ig) G, A and M, and T, B, and natural killer (NK) cells were measured centrally at baseline (BL), cycle 4 day 1 (C4D1), end of combination treatment (EOCT), end of treatment (EOT), and every 3 months for up to 3 years, then every 6 months until PD. This is a post hoc analysis among evaluable pts; statistics are descriptive only. Results: In total, 130 pts completed 2 years of VenR without PD (27 pts were excluded from this analysis as they received Ig therapy during the study). BL characteristics amongst those included were consistent with the whole population. Median change from BL by visit (EOT, 12 months, and 24 months post EOT) was calculated among pts with paired evaluable BL and visit samples (Table 1). IgG was significantly decreased at EOT vs BL (n=91; median change from BL, -5.9%). At 12 months (n=77; median change from BL, -4.8%) and 24 months (n=58; median change from BL, 1.1%) post treatment, IgG was not significantly different to BL levels. While there was no reduction in IgA from BL at EOT, at 12 and 24 months post treatment, IgA levels were significantly increased (median change from BL, 12.5% and 35.1%, respectively). IgM levels were significantly reduced at EOT vs BL (median change from BL, -32.3%), but returned to BL levels at 12 months post treatment (median change from BL, 11.1%). At 24 months post treatment, IgM had significantly increased by 49.5% compared with BL levels. There was no significant difference in median IgG, IgA and IgM levels at any time point amongst pts who achieved undetectable (u)MRD at EOT vs pts with MRD at EOT. In pts who received VenR the overall infection rate was low; however, there was a non-statistically significant, but numerically higher rate of grade ≥3 infections occurring on treatment in those with uMRD at EOT compared with those who had MRD at EOT (15.2% [10/66] vs 7.1% [2/28]; p=0.5). T, B and NK cell data were available for all 130 pts. A depletion in CD19+ B cells was observed on treatment, which was more pronounced in pts with uMRD at EOT. After EOCT, B cell recovery started ~1 year later, and stabilized ~30 months after EOCT, regardless of EOT MRD status (Figure 1). Given the differences in disease burden at EOT, comparable CD19+ B cell recovery in pts with uMRD and MRD is likely to be representative of a larger relative proportion of normal B cells vs CLL cells. Additional analyses to test this are underway. At BL, total CD3+ T cells were increased (median [range], 1,991 [135-17,334]; reference values as previously reported, 700-2,100/µL [de Weerdt et al. Blood Adv 2019]). Though a reduction of CD3+ T cells was observed during combination treatment (C4D1), the number of CD3+ T cells were maintained within the reference range post treatment. A similar pattern was observed for NK cells. The median (range) CD4/CD8 ratio at BL was 1.10 (0.33-5.77) and was maintained throughout the study. Conclusions: Overall, pts demonstrated immune recovery following fixed-duration treatment with VenR in this post hoc exploratory analysis. This is the first time that post-treatment serial Ig levels have been reported following VenR therapy. Recovery of IgG, IgA and IgM levels post treatment was observed regardless of EOT MRD status. While the overall incidence of grade ≥3 infections was low, the rate was numerically higher in pts with uMRD at EOT compared with pts with MRD. Additional analyses are underway to assess the correlation between infection and MRD state. A normalization of CD3+ T cells during and after VenR is consistent with previous reports. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal