Immunoglobulin G Antibody Concentrations Research Articles

Protective antibody concentrations in primary immunodeficiency following infusion with 5% or 10% intravenous immunoglobulin.

Background: Inadequate production of immunoglobulin G (IgG) antibodies renders patients with primary immunodeficiency susceptible to infection by numerous pathogens, some of which can lead to severe asthma exacerbation and possible death. These patients who are immunocompromised are often reliant on intravenous immunoglobulin (IVIG) therapies, which provide passive antibodies against various respiratory pathogens, including measles virus and encapsulated bacteria. Objective: We conducted a subanalysis of data from a multicenter, multinational, phase III, open-label bioequivalence study to compare protective concentrations of IgG antibodies provided by a 5% and a 10% IVIG product in patients with primary immunodeficiency. Methods: Patients on stable 21- or 28-day regimens of previous IVIG products were assigned to receive study treatment (adults: 5% IVIG and 10% IVIG; children: 10% IVIG) at doses of 300-800 mg/kg per infusion. Trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, and IgG against Haemophilus influenzae type b and Streptococcus pneumoniae serotypes were evaluated. Results: A total of 48 patients (33 adults ages 16-55 years; 15 children ages 2-15 years) were enrolled and received treatment. No statistically significant differences in trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, or IgG directed at encapsulated bacteria were observed between the 5% and 10% formulations in analyses by age (adult or pediatric) or infusion schedule (every 21 or 28 days). All evaluated patients had trough IgG concentrations above accepted thresholds for protection against disease. Conclusion: These findings support the conclusion that, at dose levels and infusion schedules prescribed in clinical practice, this 5% and 10% IVIG product provided consistent, predictable, and bioequivalent IgG concentrations for adult and pediatric patients with primary immunodeficiency disease. Both formulations delivered trough antibody concentrations of total IgG, measles-neutralizing antibodies, and antibodies against encapsulated bacteria that are above thresholds accepted as protective.Clinical trial NCT01963143, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.

Social stress induces autoimmune responses against the brain.

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.

Machine learning to optimize cerebrospinal fluid dilution for analysis of MRZH reaction.

To create a supervised machine learning algorithm aimed at predicting an optimal cerebrospinal fluid (CSF) dilution when determining virus specific antibody indices to reduce the need for repeated tests. The CatBoost model was trained, optimized, and tested on a dataset with five input variables: albumin quotient, immunoglobulin G (IgG) in CSF, IgG quotient (QIgG), intrathecal synthesis (ITS) and limes quotient (LIM IgG). Albumin and IgG concentrations in CSF and serum were performed by immunonephelometry on Atellica NEPH 630 (Siemens Healthineers, Erlangen, Germany) and ITS and LIM IgG were calculated according to Reiber. Concentrations of IgG antibodies to measles, rubella, varicella zoster and herpes simplex 1/2 viruses were analysed in CSF and serum by ELISA (Euroimmun, Lübeck, Germany). Optimal CSF dilution was defined for each virus and used as a classification variable while the standard operating procedure was set to start at 2×-dilution of CSF. The dataset included 571 samples with the imbalanced distribution of the optimal CSF dilutions: 2× dilution n=440, 3× dilution n=109, 4× dilution n=22. The optimized CatBoost model achieved an area under the curve (AUC) score of 0.971, and a test accuracy of 0.900. The model falsely classified 14 (9.9 %) samples of the testing set but reduced the need for repeated testing compared to the standard protocol by 42 %. The output of the CatBoost model is mostly dependant on the QIgG, ITS and CSF IgG variables. An accurate algorithm was achieved for predicting the optimal CSF dilution, which reduces the number of test repeats.

Determining the Optimal SARS-CoV-2 mRNA Vaccine Dosing Interval for Maximum Immunogenicity.

Emerging evidence indicates that longer SARS-CoV-2 vaccine dosing intervals results in an enhanced immune response. However, the optimal vaccine dosing interval for achieving maximum immunogenicity is unclear. This study included samples from adult paramedics in Canada who received two doses of either BNT162b2 or mRNA-1273 vaccines and provided blood samples six months (170 to 190 days) after the first vaccine dose. The main exposure variable was vaccine dosing interval (days), categorized as "short" (first quartile), "moderate" (second quartile), "long" (third quartile), and "longest" interval (fourth quartile). The primary outcome was total spike antibody concentrations, measured using the Elecsys SARS-CoV-2 total antibody assay. Secondary outcomes included spike and receptor-binding domain (RBD) immunoglobulin G (IgG) antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to wild-type spike protein and several different Delta variant spike proteins. We fit a multiple log-linear regression model to investigate the association between vaccine dosing intervals and the antibody concentrations. A total of 564 adult paramedics (mean age 40 years, SD=10) were included. Compared to "short interval" (≤30 days), vaccine dosing intervals of the long (39-73 days) group (β= 0.31, 95% Confidence interval (CI): 0.10-0.52) and the longest (≥74 days) group (β = 0.82. 95% CI: 0.36-1.28) were associated with increased spike total antibody concentration. Compared to the short interval, the longest interval quartile was associated with higher spike IgG antibodies, while the long and longest intervals were associated with higher RBD IgG antibody concentrations. Similarly, the longest dosing intervals increased inhibition of ACE-2 binding to viral spike protein. Increased mRNA vaccine dosing intervals longer than 38 days result in higher levels of anti-spike antibodies and ACE-2 inhibition when assessed six months after the first COVID-19 vaccine.

Immunogenicity of BNT162b2 Vaccine Booster Dose in Patients With Inflammatory Bowel Disease Receiving Infliximab Combination Therapy: A Prospective Observational Study.

IntroductionFew data exist regarding the immunogenicity of the third dose of BNT162b2 relative to the second dose in patients with inflammatory bowel disease (IBD) on different immunosuppressive therapies. We investigated the immunogenicity of BNT162b2 vaccine booster dose in patients with IBD on infliximab combination therapy.MethodThis is a prospective single-center observational study conducted from January 1, 2022 to February 28, 2022. Patients were recruited at the time of attendance at the infusion center. Eligibility criteria included patients with a confirmed diagnosis of IBD who are receiving infliximab with azathioprine or 6-mercaptopurine. Patients who received two doses of BNT162b2 vaccine (second dose group) were compared to patients who had received three doses of BNT162b2 vaccine [third dose (booster) group]. Patients were excluded if they were infected or had symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) previously since the start of the pandemic or received other vaccines than the BNT162b2. Our primary outcome was the concentrations of SARS-CoV-2 antibodies Immunoglobulin G (IgG) and neutralizing antibodies 40–45 weeks from the first dose of BNT162b2 vaccine in patients with IBD receiving infliximab combination therapy. Medians with interquartile range (IQR) were calculated.ResultsIn total, 162 patients with IBD and receiving infliximab combination therapy were recruited, and the number of patients in both the second dose group and third dose (booster) group was 81. Mean age was 35 years old in both groups. Median (IQR) SARS-CoV-2 IgG levels were significantly lower after the second dose [125 BAU/ml (43, 192)] compared to patients who received the third booster dose [207 BAU/ml (181, 234)] (P = 0.003). Neutralizing antibody levels were also lower after the second dose [80% (21, 95)] compared to patients who received the third booster dose [96% (93, 99)] (P ≤ 0.001). The percentage of patients who achieved positive SARS-CoV-2 IgG levels in the third (booster) dose group was 96.3%, whereas it was 86.4% in the second dose group. The percentage of participants who received the third (booster) dose and achieved a positive SARS-CoV-2-neutralizing antibody level was 100%, whereas it was 88.9% in the participants who received the second dose only.ConclusionMost patients with IBD on infliximab combination therapy had positive SARS-CoV-2 IgG and neutralizing antibody concentrations 40–45 weeks post BNT162b2 vaccination. However, SARS-CoV-2 IgG and neutralizing antibody concentrations were lower in patients who received two doses only compared to patients who received a third dose. A longer follow-up study is needed to evaluate decay in antibodies over time.

Freeze-dried plasma: From damage control resuscitation to coronavirus disease 2019 therapy.

Freeze-dried plasma (FDP) is a promising blood component for prehospital resuscitation given its logistic advantages over fresh frozen plasma (FFP). COVID-19 convalescent (CC) plasma has been used to treat coronavirus disease 2019 (COVID-19) patients, and its corresponding FDP has potential use during future pandemics. Therefore, we conducted the study to determine if the hemostatic and immunological properties of plasma can be retained after lyophilization. Hemostatic tests were conducted with Rotational Thromboelastometry (ROTEM) and a Stago analyzer. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG (Immunoglobulin G) and neutralizing activity were analyzed using Meso Scale Diagnostics immunoassay kits. There were no differences in ROTEM parameters and Stago measurements for prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer concentrations, and antithrombin, factor V, VIII, and protein S activities between FFP and FDP for either pre-COVID-19 or CC samples. Differences were observed in INTEM clotting time and PT and PTT when comparing reconstituted FDP stored at 4°C for 24 h or room temperature for 4 h to healthy control. Both CC-FFP and CC-FDP showed two orders of magnitude higher concentrations of IgG antibodies against SARS-CoV-2 antigens than pre-COVID-19-FFP and pre-COVID-19-FDP and healthy control. Similarly, the CC samples showed approximately 4-fold higher %-inhibition of receptor binding than the pre-COVID-19 samples. There were no differences in either the antibody levels or neutralization activity between CC-FFP and CC-FDP. We demonstrated that FDP and CC-FDP retained the same hemostatic and antibody functional activities relative to their initial plasma sources, supporting clinical evaluation of their benefits in severe trauma and COVID-19 patients.

Immunogenicity of a recombinant hemagglutinin neuraminidase-Porcine rubulavirus produced by Escherichia coli of Porcine rubulavirus gives protective immunity of litter after challenge.

Porcine rubulavirus (PRV) is a contagious virus that affects the Mexican swine industry. This work aimed to evaluate the immunogenicity of an recombinant hemagglutinin neuraminidase-Porcine rubulavirus (rHN-PorPV) candidate vaccine on pregnant sows, and the protective efficacy afforded to their 7-day-old suckling piglets against PRV lethal challenge. Three sows were immunized with rHN-PorPV formulated with immune-stimulating complex (ISCOMs) and two sows with rHN-PorPV protein alone as well as a mock-immunized pregnant sow (negative control). Quantitative ELISA detected a high concentration of anti-rHN-PorPV Immunoglobulin G (IgG) antibodies in sow sera after the second dose of vaccine administered on day 14 until farrowing, showing viral-neutralizing and cross-neutralization activity against different variants of PRV. Sera samples from piglets of immunized sows (with or without adjuvant), showed high concentrations of IgG antibodies. As expected, piglets from the negative control sow (n=5), exhibited severe signs of disease and 100% of mortality after PRV challenge study. Conversely, 75% and 87.5% of the piglets born from the rHN-PorPV and the rHN-PorPV-ISCOMs-immunized sows (n=8), survived, respectively, showing milder PRV clinical signs. Our data indicate that rHN-PorPV candidate vaccine produced in Escherichia coli induces efficient humoral response in pregnant sows and that the maternally derived immunity provides high protection to suckling piglets against PRV lethal challenge.

A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15 years-old healthy hepatitis A vaccine-naïve children

The Biological E inactivated hepatitis A (HAPIBEV™) vaccine was developed by importing the Healive® vaccine bulk from China and fill-finish it in India. Healive® vaccine is approved in China for both children and adults. This study assessed the safety and immunogenicity of HAPIBEV™ vaccine as compared to the Havrix 720® vaccine of GlaxoSmithKline (GSK) pharmaceuticals when administered intramuscularly (IM) 6 months apart in 1–15 years old hepatitis A virus (HAV) vaccine naive children in India.This Phase 3, single blind, parallel, randomized, active-controlled, two-arm study was conducted at 8 centers in India in healthy HAV vaccine–naive children. Subjects were stratified into 2 age subsets (1–7 and 8–15 years) and randomly assigned to either BE-HAPIBEV™ or GSK’s Havrix® vaccine and administered 2 IM injections 6 months apart. The immunogenicity evaluations included: (1) proportion of subjects who achieved the following at Day 210 from baseline: (a) seroconversion (≥20 mIU/mL) with anti-HAV immunoglobulin G (IgG) antibodies, (b) ≥4-fold increase in anti-HAV IgG antibodies, and (c) ≥2-fold increase in anti-HAV IgG antibodies concentration who were already seroconverted at baseline and (2) geometric mean concentrations (GMC) of anti-HAV IgG antibodies at baseline and Day 210. Safety was evaluated throughout the study.A total of 467 (89.8%) subjects completed the study. The non-inferiority criterion was met by HAPIBEV™ vaccine as seroconversion rates in both vaccine groups were 100%. Overall, other immunogenicity evaluations were either similar in both vaccine groups or higher in the HAPIBEV™ group compared with the Havrix® group. The safety profile was also comparable between HAPIBEV™ and Havrix® groups. The most common adverse event (AE) was injection site pain, and the majority of AEs were mild in severity. The HAPIBEV™ vaccine demonstrated an immunological and safety profile on par with Havrix® in 1–15 years old healthy HAV vaccine-naive Indian children.This study is registered with clinical trial registry of India bearing no: CTRI/2019/04/018384 on 02 Apr 2019.

Persistence of Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 in Relation to Symptoms in a Nationwide Prospective Study.

BackgroundAssessing the duration of immunity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a first priority to gauge the degree of protection following infection. Such knowledge is lacking, especially in the general population. Here, we studied changes in immunoglobulin isotype seropositivity and immunoglobulin G (IgG) binding strength of SARS-CoV-2–specific serum antibodies up to 7 months following onset of symptoms in a nationwide sample.MethodsParticipants from a prospective representative serological study in the Netherlands were included based on IgG seroconversion to the spike S1 protein of SARS-CoV-2 (N = 353), with up to 3 consecutive serum samples per seroconverted participant (N = 738). Immunoglobulin M (IgM), immunoglobulin A (IgA), and IgG antibody concentrations to S1, and increase in IgG avidity in relation to time since onset of disease symptoms, were determined.ResultsWhile SARS-CoV-2–specific IgM and IgA antibodies declined rapidly after the first month after disease onset, specific IgG was still present in 92% (95% confidence interval [CI], 89%–95%) of the participants after 7 months. The estimated 2-fold decrease of IgG antibodies was 158 days (95% CI, 136–189 days). Concentrations were sustained better in persons reporting significant symptoms compared to asymptomatic persons or those with mild upper respiratory complaints only. Similarly, avidity of IgG antibodies for symptomatic persons showed a steeper increase over time compared with persons with mild or no symptoms (P = .022).ConclusionsSARS-CoV-2–specific IgG antibodies persist and show increasing avidity over time, indicative of underlying immune maturation. These data support development of immune memory against SARS-CoV-2, providing insight into protection of the general unvaccinated part of the population.Clinical Trials RegistrationNL8473 (the Dutch trial registry).

A measles outbreak in Kansai International Airport, Japan, 2016: Analysis of the quantitative difference and infectivity of measles virus between patients who are immunologically naive versus those with secondary vaccine failure.

Since the elimination of the measles virus, patients with vaccination records for the measles-containing vaccine have increased in Japan. According to several studies, the transmission risk from previously immunized patients, especially those with secondary vaccine failure (SVF), is lower than that from those with primary measles infections. Immunological features of SVF were identified per specific immunoglobulin G (IgG) induction with high avidity and high plaque reduction neutralization antibody concentration. However, the virological features of SVF have not been well investigated. To examine not only immunological but also virological differences between SVF and immunologically naive patients, throat swabs and blood and urine specimens of 25 patients with confirmed measles infection after an outbreak at the Kansai International Airport in 2016 were analyzed. Patients were categorized as naive (n = 3) or with SVF (n = 22) based on measles-specific IgG antibody concentrations and their avidity. Virus isolation and quantitative real-time polymerase chain reaction were performed to quantify the viral load in clinical specimens and estimate the infectivity in each specimen. The number of viral genome copies in the blood specimens of those with SVF was significantly different and approximately 1 out of 100 of that in immunologically naive patients. However, genome copy numbers in throat swabs and urine specimens were not significantly different between the groups. The virus was isolated only from those in the naive group. Our study indicated low transmission risk of the virus in patients with SVF.

Preliminary study of serum 2019-nCoV IgM and IgG antibodies in the diagnosis of COVID-19

Objective To analyze the clinical value of serum 2019 New Coronavirus (2019-nCoV) immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in the diagnosis of novel coronavirus pneumonia (NCP). Methods A total of 116 patients diagnosed with NCP in the First Affiliated Hospital of Hunan University of Chinese Medicine and the First Affiliated Hospital of Xiamen University were enrolled from January to February 2020 as the disease group. A total of 134 cases, including 84 non-NCP inpatients and 50 healthy individuals served as the control group. Serum samples from all subjects were collected. A fully-automated chemiluminescence immunoassay analyzer was used to detect the concentration of 2019-nCoV IgM and IgG antibodies in serum. The sensitivity and specificity of the 2019-nCoV IgM and IgG antibody single test and combined detection were compared using the χ2 test. χ2 test and Wilcoxon’s rank sum test were used to compare the positive rates and concentrations of IgM and IgG antibodies in NCP patients before and after their 2019-nCoV nucleic acid tests turning negative, respectively. The change trend of 2019-nCoV antibody concentration in the process of NCP patients was analyzed by Wilcoxon’s rank sum test. Results The sensitivity of 2019-nCoV IgG (90.5%, 105/116) was higher than that of 2019-nCoV IgM (75.9%, 88/116), the difference was statistically significant (χ2=8.91, P<0.05); The specificity of 2019-nCoV IgG (99.3%, 133/134) was higher than that of 2019-nCoV IgM (94.0%, 126/134), the difference was statistically significant (χ2=5.63, P<0.05). The sensitivity (89.7%, 87/97) of 2019-nCoV IgM combined with IgG was higher than that of 2019-nCoV IgM, the difference was statistically significant ( χ2=6.89, P<0.05). The specificity (100%, 125/125) of 2019-nCoV IgM combined with IgG was higher than that of 2019-nCoV IgM, the difference was statistically significant ( χ2=7.70, P<0.05). After 2019-nCoV nucleic acid test converted to negative, the positive rate (52.9%, 9/17) and concentration [13.0 (4.9, 24.7) AU/ml] of serum 2019-nCoV IgM antibody were significantly lower than those when the nucleic acid test was positive, positive rate (88.2%, 15/17) and concentration [29.5 (14.0, 61.3) AU/ml] , respectively (χ2=5.10, Z=-3.195, both P<0.05). In the course of NCP, patients' serum samples were collected from the first day of diagnosis to every three days, three times in total. The first 2019-nCoV IgM and IgG antibody concentrations [19.4 (12.4, 63.7) AU/ml, 105.8 (74.8, 126.1) AU/ml, respectively] were significantly higher than the second concentrations [15.8 (7.1, 40.3)AU/ml, 80.5 (66.7, 105.9) AU/ml], Z were -2.897, -3.179, both P<0.05. Conclusions 2019-nCoV IgG antibody has a good application value in the diagnosis of NCP; The concentration of 2019-nCoV IgM antibody has a certain correlation with the detection of 2019-nCoV nucleic acid; The combination of 2019-nCoV IgM and IgG antibodies with 2019-nCoV nucleic acid test may be the best laboratory index for the diagnosis of NCP at present. Key words: Coronavirus; Pneumonia, viral; Immunoglobulin M; Immunoglobulin G; Nucleic acids; Sensitivity and specificity; Real-time polymerase chain reaction

Blind Analysis of Food-Related IgG Identifies Five Possible Nutritional Clusters for the Italian Population: Future Implications for Pregnancy and Lactation.

Background: The influence of diet in pregnant women on the immune tolerance process is intricate. Food-specific immunoglobulin G (IgG) was associated with exposure to particular food antigens. The IgG antibodies can cross the placental barrier and enter into the colostrum, and maternal IgG is amply present in breast milk. This justifies studying the immunological connection between food-specific IgG antibodies and the mother–fetus relationship. This study was designed to analyze food-specific IgG concentrations and possible food-specific IgG concentration clusters in a large cohort of subjects with a common food culture. Methods: Food-specific IgG antibody concentrations were detected in 18,012 Caucasian or Southern European subjects over 18 years of age. We used an unsupervised hierarchical clustering algorithm to explore varying degrees of similarity among food-specific IgG antibodies. Results: We identified five food groups by the evaluation of food-specific IgG values: one includes foods with a high nickel content, the second cluster is associated with gluten, the third cluster includes dairy products, the fourth one is connected to fermented foods, and the last group is correlated with cooked oils. Discussion: The knowledge derived from studying a large sample allows us to determine food-specific IgG values from a single pregnant woman, compare it to an epidemic standard, and establish modifications required in her lifestyle to modulate her nutritional habits.

Pharmacokinetics of a novel human intravenous immunoglobulin 10% in patients with primary immunodeficiency diseases: Analysis of a phase III, multicentre, prospective, open-label study

Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2–75 years with common variable immunodeficiency (n = 43) or X-linked agammaglobulinaemia (n = 8). Patients were treated with IVIG 10% every 3 (n = 21) or 4 weeks (n = 30) at a dose of 200–800 mg/kg for 12 months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15 min post-infusion. The maximum concentration of total IgG (mean ± SD) was 21.82 ± 5.83 g/L in patients treated 3-weekly and 17.42 ± 3.34 g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2 g/L for patients on the 3-week schedule and between 8.10 and 8.65 g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5–65.9) days, with generally similar values for the IgG subclasses (26.7–38.0 days). Median half-lives for specific antibodies ranged between 21.3 and 51.2 days for anti-cytomegalovirus, anti-Haemophilus influenzae, anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti-Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections.

Similar Antibody Levels in 3-Year-Old Children Vaccinated Against Measles, Mumps, and Rubella at the Age of 12 Months or 18 Months.

Measles-mumps-rubella (MMR) vaccinations have been offered to Finnish children at 14-18 months and 6 years of age. In May 2011, the recommended age for the first vaccine dose was lowered to 12 months because of the European measles epidemic. Fingertip capillary blood samples were collected from 3-year-old Finnish children vaccinated once with MMR vaccine at 11-19 months of age. The immunoglobulin G (IgG) antibodies to all 3 MMR antigens were measured with enzyme-linked immunosorbent assay. Neutralizing antibodies and the avidity of antibodies were measured for measles virus. From April through October 2013, 187 children were enrolled. Equally high proportions of the samples were seropositive for measles virus, mumps virus, or rubella virus antibodies, and there were no significant differences in the IgG antibody concentrations in children vaccinated at 11-13 months of age, compared with those vaccinated at 17-19 months of age. However, among children vaccinated at 11-13 months of age, boys had lower antibody concentrations than girls. Neutralizing measles virus antibody titers were above the threshold for protective immunity in all 78 samples analyzed. The measles virus antibody avidity indexes were high for all children. MMR induces similar antibody responses in 12-month-old children as compared to 18-month-old children, but in boys increasing age appears to improve the antibody responses.

A detailed examination of the antibody prevalence and characteristics of anti-ESA antibodies

The antibody characteristics in erythropoiesis-stimulating agent (ESA)-treated patients who develop antibody-mediated pure red cell aplasia (PRCA; amPRCA) can be described as high-affinity, neutralizing anti-ESA antibodies with a mixed immunoglobulin G (IgG) subclass. The characteristics of an early-onset anti-ESA antibody response are not well documented, especially in the months prior to the development of amPRCA. Therefore, a detailed characterization of anti-ESA antibodies was performed in patients in both clinical studies and in a post-market setting. Both baseline and post-dose samples were tested and antibody-positive samples were characterized. Antibody characteristics such as concentration, isotype and specificity were evaluated in subjects with non-neutralizing anti-ESA antibodies and subjects that developed neutralizing anti-ESA antibodies associated with amPRCA. Serum samples were analyzed for the presence of anti-ESA antibodies, using a validated surface plasmon resonance (SPR)-based immunoassay or SPRIA. Among the clinical studies, pre-existing non-neutralizing anti-ESA antibodies were found in 6% of the subjects from clinical studies in nephrology, oncology and congestive heart failure (CHF). After ESA treatment, 2.3% of the subjects developed binding, non-neutralizing antibodies with 0.1% confirmed as having an IgG isotype and were specific to the ESA protein. IgM antibodies were detected at baseline and post-ESA treatment and reported to be specific to the glycosylation of the ESA. No clinical study subjects progressed to amPRCA. In contrast, anti-ESA antibody-positive subjects from the post-market setting with a confirmed IgG subclass were specific to the ESA protein. Subjects that had progressed to amPRCA were noted to have high antibody concentrations with neutralizing activity and a diverse IgG subtype. A low prevalence of non-neutralizing anti-ESA IgM specific to glycosylation on the ESA and IgG1 antibodies specific to the ESA protein was detected across all clinical patient populations. Patients with amPRCA were noted to have high IgG antibody concentrations, neutralizing antibodies and the presence of anti-ESA IgG4 antibodies.

Respiratory syncytial virus infection in children hospitalized for wheezing: Virus‐specific studies from infancy to preschool years

To evaluate whether the presence of immunoglobulin G (IgG) antibodies against respiratory syncytial virus (RSV) in early childhood is associated with later asthma, and to evaluate a new diagnostic test for RSV, reverse-transcription polymerase chain reaction (RT-PCR), comparing it to the antigen and antibody assays initially used in RSV diagnostics in the present cohort. At the start of the study in 1992-1993, RSV was studied by antigen detection (using time-resolved fluoroimmunoassay) and complement-fixing antibody assay. Advances in methodology allowed us to supplement RSV studies by RT-PCR in frozen nasopharyngeal aspirates obtained on admission, and by specific IgG antibodies (using enzyme immunoassay) in frozen serum samples obtained during the follow-up. On admission, 29 of the 100 children hospitalized for wheezing at <2 y of age were RSV positive. When compared with conventional methods, the sensitivity of RT-PCR was 83% (100% w.r.t. antigen detection) and its specificity was 92% in diagnosing RSV infection. RSV-specific IgG antibody concentrations rose with age, but were not predictive of asthma at any age. In the present cohort, wheezing without RSV was particularly associated with increased risk for later childhood asthma. Hospitalization for wheezing in infancy is associated with increased risk for later childhood asthma, particularly in children without RSV infection on admission, although children with RSV have also slightly increased risk for later asthma. However, mere serological evidence of RSV infection is not associated with the development of asthma. In addition to RSV, more attention should be paid to less virulent agents in order to find those wheezing infants who are at particular risk of later childhood asthma.

Immune responses to novel pneumococcal proteins pneumolysin, PspA, PsaA, and CbpA in adenoidal B cells from children.

Studies of mice suggest that pneumococcal proteins, including PspA, pneumolysin, PsaA, and CbpA, are promising vaccine candidates. To determine whether these proteins are good mucosal immunogens in humans, adenoidal lymphocytes from 20 children who had adenoidectomies were isolated and tested by ELISpot for antigen-specific antibody-secreting cells (ASCs). Cells were also cultured for 7 days in the presence of a concentrated culture supernatant (CCS) from a type 14 strain of pneumococcus which contained secreted pneumococcal proteins, including PspA, pneumolysin, PsaA, and CbpA, and then tested by ELISpot. ELISpot assays done on freshly isolated cells detected ASCs to all four antigens in most children studied. However, there were differences both between antigens and between isotypes. The densities of immunoglobulin G (IgG) ASCs against both PsaA and CbpA were significantly higher than those of ASCs for PspA and PdB (pneumolysin toxoid B) (P < 0.001). For all antigens, the numbers of IgA ASCs tended to be lower than those of both IgG and IgM ASCs. The numbers of anti-CbpA and -PsaA IgA ASCs were higher than those of anti-PdB IgA ASCs (P < 0.01). Concentrations of IgA antibodies to PspA and PsaA in saliva correlated with the numbers of IgA ASCs to PspA and PsaA in freshly isolated adenoidal cells, but no such correlation was found between salivary IgG antibody concentrations and IgG ASCs to the four antigens in adenoidal cells. In cultured cells, anti-PspA, -PsaA, and -CbpA IgG ASCs proliferated significantly, but only two of eight samples showed >2-fold increases in anti-CbpA and -PspA IgA ASCs after CCS stimulation. The results suggest that CbpA, PsaA, and PspA may be good upper respiratory mucosal antigens in children. Adenoids may be important inductive sites for memory IgG responses and important sources of salivary IgA. Some protein antigens may also prime for mucosal IgA memory. These data support the effort to explore mucosal immunization against pneumococcal infection.

Titres of specific antibodies to poliovirus type 3 and tetanus toxoid in saliva and serum of children with recurrent upper respiratory tract infections.

A study of antibody levels (in saliva and blood) against common vaccine antigens was performed in a population of 32 children suffering from recurrent upper respiratory tract infections (URTI). None of the patients had primary or secondary immunodeficiency syndromes or other known predisposing factors for respiratory diseases. Titres of the isotype-specific antibodies immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) against two vaccine antigens--poliovirus type 3 (P3) and tetanus toxoid (TT), a viral antigen and a bacterial antigen, respectively--were measured in unstimulated saliva and serum, both in patients and in 24 healthy children (controls), by using a standard enzyme-linked immunosorbent assay (ELISA). In addition, levels of total IgA and avidity of IgA antibodies to both P3 and TT in saliva were evaluated. No difference was found between patients and controls as to levels of total IgA, or specific IgA and IgM antibodies against both P3 and TT in saliva. Furthermore, the avidity of salivary IgA antibodies against the two antigens did not differ between the two populations. However, the average concentrations of saliva-specific IgG antibodies to both the viral and the bacterial antigen were significantly lower (p <0.01 for P3 and p <0.05 for TT, respectively) in saliva of children with recurrent URTI, whereas no difference was found in serum for any immunoglobulin isotype determined compared with healthy individuals. The results of the present study provide suggestive evidence for the existence of subtle IgG-restricted defects in antibody responses at the mucosal level, but not at the serum level, in some children with undue susceptibility to URTI.

Transplacental transmission of serotype-specific pneumococcal antibodies in a Brazilian population.

The highest incidence of severe pneumococcal infections in children occurs in the first 6 months of life; however, immunization of infants with the existing polysaccharide vaccines is ineffective. We wished to determine the prevalence of immunoglobulin G (IgG) pneumococcal antibodies in unimmunized Brazilian mothers and their transplacental transmission to term and preterm infants. Total IgG, IgG1 and -2 subclass levels, and IgG antibodies against Streptococcus pneumoniae serotypes 1, 3, 6B, 9V, and 14 were determined in 15 pairs of mothers and term newborns (gestational age, >/=37 weeks) and in 18 pairs of mothers and preterm newborns (gestational age, 32 to 36 weeks). Serotype-specific anti-pneumococcal antibodies were detected by a recently standardized enzyme-linked immunosorbent assay calibrated with the 89-SF reference serum. Varying percentages of the mothers had antibody concentrations below arbitrarily defined protective levels: 33% for serotype 1, 67% for serotype 3, 30% for serotype 6B, 52% for serotype 9V, and 22% for serotype 14. In term newborns, IgG1 concentrations were slightly higher than maternal concentrations; in preterm newborns, the concentrations were much lower. Concentrations of IgG2 in term and preterm infants were significantly lower than in the mothers. Transplacental transmission of antibodies to serotypes 3 and 14 was clearly different from that of antibodies to serotypes 1, 6B, and 9V. Concentrations of IgG antibodies against serotypes 3 and 14 were similar to or higher than those of the mothers; against serotypes 1, 6B, and 9V they ranged from 77 to 83% of maternal concentrations in term newborns and also in preterm infants, although transplacental transmission of antibodies was proportionally lower for each specific serotype in preterm than in term infants. These data are relevant for developing strategies to protect infants against pneumococcal infections in the first months of life. Our findings and a review of existing information stress the importance of understanding the relationships among pneumococcal immunization, IgG subclass antibodies to individual serotypes, transplacental transport, half-life, and antibody function and their protective values against infection.

862 Transplacental transmission of serotype-specific pneumococcal antibodies in a Brazilian population

The highest incidence of severe pneumococcal infections in children occurs in the first 6 months of life; however, immunization of infants with the existing polysaccharide vaccines is ineffective. We wished to determine the prevalence of immunoglobulin G (IgG) pneumococcal antibodies in unimmunized Brazilian mothers and their transplacental transmission to term and preterm infants. Total IgG, IgG1 and -2 subclass levels, and IgG antibodies against Streptococcus pneumoniae serotypes 1, 3, 6B, 9V, and 14 were determined in 15 pairs of mothers and term newborns (gestational age, >37 weeks) and in 18 pairs of mothers and preterm newborns (gestational age, 32 to 36 weeks). Serotype-specific anti-pneumococcal antibodies were detected by a recently standardized enzyme-linked immunosorbent assay calibrated with the 89-SF reference serum. Varying percentages of the mothers had antibody concentrations below arbitrarily defined protective levels: 33% for serotype 1, 67% for serotype 3, 30% for serotype 6B, 52% for serotype 9V, and 22% for serotype 14. In term newborns, IgG1 concentrations were slightly higher than maternal concentrations; in preterm newborns, the concentrations were much lower. Concentrations of IgG2 in term and preterm infants were significantly lower than in the mothers. Transplacental transmission of antibodies to serotypes 3 and 14 was clearly different from that of antibodies to serotypes 1, 6B, and 9V. Concentrations of IgG antibodies against serotypes 3 and 14 were similar to or higher than those of the mothers; against serotypes 1, 6B, and 9V they ranged from 77 to 83% of maternal concentrations in term newborns and also in preterm infants, although transplacental transmission of antibodies was proportionally lower for each specific serotype in preterm than in term infants. These data are relevant for developing strategies to protect infants against pneumococcal infections in the first months of life. Our findings and a review of existing information stress the importance of understanding the relationships among pneumococcal immunization, IgG subclass antibodies to individual serotypes, transplacental transport, half-life, and antibody function and their protective values against infection. Pneumococcal infections cause high morbidity and mortality in children during the first 2 years of life, with the highest incidence of severe, systemic pneumococcal infections occurring in the first year of life (15, 18). Immunization of infants with the existing polysaccharide vaccines, however, becomes effective only after 2 years of age. Conjugate pneumococcal vaccines containing five or seven polysaccharides have been found to be immunogenic in the first year of life in several studies (1, 3, 31). However, these vaccines are still experimental and the small number of serotype polysaccharides included in the vaccines may limit the coverage they offer. A 10-year study of 308 cases of meningitis