Immune Globulin Preparations Research Articles

Immune globulin therapy and kidney disease: Overview and screening, monitoring, and management recommendations.

PurposeThis report calls attention to the potential risks of diminished kidney function when administering immune globulin (IG). The goal is to increase awareness of chronic kidney disease (CKD) and kidney function impairment in patients receiving IG and provide recommendations for screening, monitoring, and management to promote risk prevention and mitigation.SummaryHuman IG preparations for intravenous (IVIG) or subcutaneous (SCIG) administration are the mainstay of treatment in patients with primary immunodeficiency diseases. Increasingly, IVIG at high doses (1,000 to 2,400 mg/kg) is also used as a treatment for a variety of autoimmune and inflammatory conditions. Although some autoinflammatory disorders respond to a single course of IVIG therapy, the majority of patients require long-term, regular infusions, thereby increasing the overall risks. Often, both patients and physicians treating adults with IG are unaware of underlying CKD or kidney function impairment. This lack of awareness constitutes a major risk factor for potential worsening, particularly when using high doses of IVIG. Therefore, screening of all patients for CKD and kidney function impairment before the use of IG is essential. Identification of the cause of kidney impairment is strongly encouraged, as IG therapy may need to be modified.ConclusionAs detailed here, there are potential risks to patients with impaired kidney function with administration of IG, particularly at high doses. Product selection, volume, route of administration, and rate of infusion may impact those with compromised kidney function. Therefore, screening of all patients for CKD and kidney function impairment before the use of IVIG and SCIG, as well as ongoing monitoring and management, is critical. As with all potential adverse drug reactions, the best approach is to prevent them.

SARS-CoV-2 Antibody Profile of Immune Globulin Preparations

Intravenous immune globulin (IVIG) preparations, used for the treatment of antibody deficiencies, are generated from a pool of thousands of plasma donors. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, and a vaccine for the prevention of COVID-19 was authorized for emergency use in December 2020. We conducted a longitudinal analysis of SARS-CoV-2 antibody levels in various IVIG preparations.

Effectiveness and Safety of an Intravenous Immune Globulin (IVIG) Preparation in Post-exposure Prophylaxis (PEP) Against Measles in Infants.

Background: Administration of measles virus (MV)-specific IgG as post-exposure prophylaxis (PEP) is known to effectively prevent measles. Since the introduction of active immunization against measles, the levels of MV-specific IgG antibodies in the population have dropped. Therefore, the concentration of MV-specific antibodies in immunoglobulin products derived from human plasma donors has declined as the proportion of vaccinated donors has increased. Literature on the effectiveness of PEP with current available immunoglobulins is limited. Here we examine the effectiveness of 400 mg/kg intravenous immunoglobulin (IVIG) (IgVena®, Kendrion) as PEP in infants during a measles outbreak in Austria, 2019.Methods: After exposure to a highly contagious measles patient, identified infants were evaluated for eligibility for IVIG PEP. Infants were tested for measles maternal antibodies, if the result was expected to be available within 72 h after exposure. IVIG was administered to eligible infants with negative maternal IgG antibody levels (n = 11), infants with protective levels but result beyond 72 h (n = 2) and infants not tested for maternal IgG antibodies (n = 52). Telephone enquiries were made asking for measles infection. Effectiveness was calculated using exact logistic regression. Samples of four out of seven used IVIG batches were tested for MV-neutralizing antibody capacity.Results: In 63 (96.9%) of 65 infants PEP with IVIG was administered. The parents of two infants declined IVIG PEP. None of the infants with IVIG PEP got measles or symptoms suggestive for measles, but both infants who did not receive PEP were infected. Effectiveness of IVIG PEP was calculated to be 99.3% (CI 95%: 88.7–100%). No serious adverse event of IVIG treatment was observed. The investigation on MV-neutralizing antibody capacity showed a geometric mean titer ranging from 10.0 to 12.7 IU/ml, resulting in a 1.57–2.26-fold higher concentration than postulated as minimum level for immunity.Conclusions: Our findings suggest that the used IVIG preparation provided an at least non-inferior protection rate compared to IVIG preparations derived from donors before the global introduction of standard active immunization against measles.

The viral safety of intravenous immune globulin

The viral safety of intravenous immune globulin (IVIG) preparations has been investigated since 1983 when it was discovered that non-A, non-B hepatitis (NANBH) could be transmitted by an experimental IVIG preparation. Recently, it has been demonstrated that the virus causing NANBH is the hepatitis C virus (HCV). A number of subsequent episodes of HCV transmission by IVIG have been reported, but not all the factors that have led to this transmission are clearly understood. However, based on two episodes of HCV transmission by anti-D immune globulin (formulated for intravenous administration), it appears that cold ethanol fractionation is important in ensuring viral safety because both of the implicated anti-D immune globulin preparations were manufactured without cold ethanol fractionation. Other HCV transmission episodes have been associated with chromatography (particularly DEAE-Sephadex chromatography) as a separation step carried out to further purify IgG, after cold ethanol fractionation, and it is possible that such a procedure has only a marginal partitioning capacity for infective HCV virions. The role of anti-HCV screening in improving the viral safety of IVIG preparations remains unclear, but a recent transmission episode by a previously safe IVIG preparation suggests that the absence of anti-HCV antibodies during plasma fractionation may affect the partitioning characteristics of HCV and may also cause a loss of neutralizing antibody against HCV. All of the IVIG preparations associated with HCV transmission have been formulated as freeze-dried preparations and this may have been important in stabilizing HCV during the period prior to administration to patients. No other viruses appear to have been transmitted by IVIG preparations, but prior to seroconversion, HCV-infected plasma donors may continue to contaminate plasma pools used for the manufacture of blood products, despite anti-HCV screening, and additional viral inactivation steps such as incubation at pH4 or solvent-detergent treatment should be incorporated into the production process of all IVIG preparations.

Mechanisms of action of intravenous immune globulin in immune-mediated diseases

Intravenous immune globulin (IVIG) exhibits a number of immunomodulatory properties that are mediated by the Fe portion of IgG and by the spectrum of variable (V) regions contained in the immune globulin preparations. Five predominant and non-exclusive mechanisms of action have been proposed to account for the immunomodulatory effects of IVIG in immune-mediated diseases: (i) functional blockade of Fc receptors on splenic macrophages; (ii) inhibition of complement-mediated damage, an effect that is dependent on the ability of IgG to bind C3b and C4b and thus reduce the number of activated complement fragments that may deposit on target surfaces of complement activation; (iii) modulation of the production of cytokines and cytokine antagonists; (iv) neutralization of circulating autoantibodies by complementary (e.g. anti-idiotypic) antibodies in IVIG, a mechanism that accounts for the rapid decrease in titre of circulating autoantibodies that is often observed within hours following the infusion of IVIG; (v) selection of immune repertoires, a complex set of effects that may be observed in individuals receiving IVIG far beyond the half-life of the infused immunoglobulin and that is directly relevant to the ability of IVIG to, for example, suppress autoantibody-producing clones in patients with antibody-mediated autoimmune disease and modulate graft versus host disease (GVHD). IVIG has been shown to downregulate or activate B-cell clones expressing surface IgG that is complementary (anti-idiotypic) to V regions of antibodies present in IVIG. IVIG has been shown also to interact with surface molecules of T cells that are essential to immune regulation, such as the alpha beta TCR, CD5, CD4, non-polymorphic determinants of MHC class I molecules and adhesion molecules of T and B cells. The complex interactions of IVIG with functional molecules of cells of the immune system are relevant to its therapeutic effects in T cell- as well as B cell-mediated diseases and indeed, to our understanding of the physiological role of normal IgG and antibody networks in controlling autoreactivity in healthy individuals.

Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG

The authors have recently shown that antibodies with anti-idiotype (Id) specificity to pathogenic Ids of lupus nephritis may occasionally occur in several intravenous immune globulin (IVIG) preparations because they are present in healthy donors and the healthy relatives of SLE patients. In the present study, the authors purified these anti-Ids and treated two SLE patients with nephritis in parallel with conventional high-dose IVIG management with a commercial preparation (IVIG 6) in three controls for two months. Because pathogenic Ids of anti-DNA molecules, such as both 8.12 and F4 Ids, show a cationic mobility in isoelectric focusing, a commercial preparation of IVIG (11) was absorbed on a Sepharose column coupled with DC-305-39 myeloma protein, namely an 8.12+ and F4+ cationic IgG. Infusion of the eluate (EL-11) induced a prompt resolution of proteinuria levels and an evident decrease of serum levels of anti-DNA antibodies in both patients, whereas in the three controls, proteinuria and anti-DNA antibodies were scarcely reduced. In addition, plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were also significantly influenced by both treatments. The mean values of both cytokines increased significantly after 1 h and then progressively declined over the next 48 h. It was of interest, however, that the increased TNF-alpha in the two EL-11-treated patients was significantly lower than in the three controls. The data suggest that reduction of active lupus nephritis by enriched specific anti-Id molecules is the result of two (or perhaps more) mechanisms: suppression of pathogenic idiotypes at the cellular level and improvement in the mesangium of the secretion of anti-inflammatory cytokines, such as IL-6, whose defective function is related to the autoimmune disorder.

Infectious risk of plasma donations: relationship to safety of intravenous immune globulins

Although intravenous immune globulin (IVIG) preparations may be derived from tens of thousands of donations, the residual risk of viral contamination of recovered plasma appears remarkably low, at least for human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Consequently, most pools are unlikely to contain these viruses although the situation is not as well understood for US-derived source plasma. In addition, routine preparation methods are likely to eliminate infectivity from the relatively fragile HIV. Current plasma screening measures are generally designed to maintain reasonable titres of anti-HBs in pools, perhaps contributing to the absence of HBV infection. The situation with respect to hepatitis C virus (HCV) is not well understood and it appears that sensitive screening for anti-HCV may have had an impact on the safety of at least one IVIG preparation. The implementation of effective viral inactivation procedures is expected to eliminate any further risk of HCV infection from IVIG preparations.

Parvovirus infection and its treatment

B19 parvovirus is an important pathogen in man. Acute infection produces fifth disease (erythema infectiosum) in normal individuals, transient aplastic crisis in the patient with haemolysis, and pure red cell aplasia in the immunologically incompetent host. Fetal infection can lead to hydrops fetalis. The target cell of the virus is the marrow erythroid progenitor. The immune response to the virus is largely humoral and directed against limited numbers of epitopes. Persistent infection is due to failure to produce neutralizing antibodies. Because viral infection is prevalent in the population, therapeutic immune globulin preparations are a good source of anti-B19 antibodies. IgG administration can lead to cure of anaemia in the congenitally immunodeficient patient and to its amelioration in AIDS patients with persistent parvovirus infection.

Primary Human Cytomegalovirus (HCMV) Infection in Pregnancy.

In 0.5-4% of pregnancies, the prospective mother sustains a primary infection with human cytomegalovirus (HCMV). An HCMV infection of the fetus in the first or second trimester can cause complex post-encephalitic impairment of the infant brain, leading to motor and mental retardation, cerebral palsy, epilepsy, retinal defects, and progressive hearing loss. This review is based on pertinent publications from January 2000 to October 2016 that were retrieved by a selective search in PubMed employing the terms "cytomegalovirus and pregnancy" and "congenital cytomegalovirus." 85-90% of all neonates with HCMV infection are asymptomatic at birth. The main long-term sequela is hearing impairment, which develops in 8-15% of these affected children. Hygienic measures can lower the risk of primary HCMV infection in pregnancy by 50-85%. The first randomized and controlled trial (RCT) of passive immunization with an HCMV-specific hyper - immune globulin (HIG) preparation revealed a trend toward a lower risk of congenital transmission of the virus (30% versus 44% with placebo, p = 0.13). The effect of HIG was more marked in the initial non-randomized trial (15% versus 40%, p = 0.02). The RCT also showed HIG to be associated with a higher frequency of fetal growth retardation and premature birth (13% versus 2%, p = 0.06). Valaciclovir is a further, non-approved treatment option. In the absence of an active vaccine against HCMV, counseling about hygienic measures may currently be the single most effective way to prevent congenital HCMV infection. Moreover, HCMV serologic testing is recommended in the guideline of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Further randomized trials of treatment with HIG and with valaciclovir are urgently needed so that the options for the prevention and treatment of congenital HCMV infection can be assessed.

Commercially Available Immunoglobulins Contain Virus Neutralizing Antibodies Against All Major Genotypes of Polyomavirus BK

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed.

Use of Intravenous immune globulin in Critically Ill Patients

Intravenous immune globulin (IVIG) preparations have been suggested for many years for the treatment of various conditions. It is apparent, through in vitro and in vivo studies, that IVIG exerts potent anti-inflammatory and immunomodulatory effects. However, the mechanism of action remains mostly unknown. The following article reviews the current literature and summarizes what is known about the mechanism of action of IVIG and the use of IVIG to treat certain conditions. Specifically, the use of IVIG for treatment of critically ill patients is outlined.

Detection of opsonic antibodies against Enterococcus faecalis cell wall carbohydrates in immune globulin preparations.

Three different commercially available polyvalent immune globulins (IG) were investigated for the existence of antibodies against cell wall carbohydrates of four different E. faecalis serotypes (using a cell wall carbohydrate-enzyme-linked immunosorbent assay), and whether these antibodies mediated opsonic killing (using an opsonic-killing assay). All three IG preparations contained antibodies against all four serotypes (CPS-A to CPS-D). However, only one of the three IG preparations showed opsonic killing against all four serotypes. Average killing was higher against serotypes A and B (72 and 79 %, respectively) than against serotypes C and D (30 and 37 %, respectively). Such IG preparations could play a role as an adjuvant therapeutic option in life-threatening infections with E. faecalis, particularly when resistant strains are involved.

Maternal Immunization: An Update for Pediatricians

The immunization of women during pregnancy can protect both the mother and her infant against serious infectious diseases. The prevention of infection through maternal immunization reduces the risk of exposure to the baby, results in higher concentrations of transplacentally transferred pathogen-specific maternal antibodies to the newborn, and provides protection to the infant during a period of vulnerability. The benefits of vaccinating pregnant women outweigh any theoretic risk when there is a risk of exposure to an infectious disease that threatens the mother or the newborn's health. Toxoids and inactivated virus or bacterial vaccines are safe and cause no harm to the mother or fetus. Live vaccines, viral or bacterial, are contraindicated during pregnancy as a precaution because of the theoretic risk of infection of the fetus. However, there has been no evidence to date of direct fetal injury after the administration of live viral vaccines to pregnant women. The administration of immune globulin preparations to pregnant women results in no known risks to the fetus. In the United States, vaccines recommended in pregnancy include the seasonal influenza vaccine, tetanus toxoid, and the pertussis vaccine as a combined tetanus-diphtheria toxoid and acellular pertussis vaccine (Tdap). Pregnant women who travel or who have unavoidable exposures to vaccine-preventable diseases should be immunized. Breast-feeding is not a contraindication to the vaccination of mothers with inactivated and most live vaccines. Women who are not immune to rubella should be immunized after delivery. Similarly, the influenza and Tdap vaccinations may be administered postpartum in women who were not vaccinated during pregnancy.

Amino Acid Residue-Specific Neutralization and Nonneutralization of Hepatitis C Virus by Monoclonal Antibodies to the E2 Protein

Antibodies to epitopes in the E2 protein of hepatitis C virus (HCV) reduce the viral infectivity in vivo and in vitro. However, the virus can persist in patients in the presence of neutralizing antibodies. In this study, we generated a panel of monoclonal antibodies that bound specifically to the region between residues 427 and 446 of the E2 protein of HCV genotype 1a, and we examined their capacity to neutralize HCV in a cell culture system. Of the four monoclonal antibodies described here, two were able to neutralize the virus in a genotype 1a-specific manner. The other two failed to neutralize the virus. Moreover, one of the nonneutralizing antibodies could interfere with the neutralizing activity of a chimpanzee polyclonal antibody at E2 residues 412 to 426, as it did with an HCV-specific immune globulin preparation, which was derived from the pooled plasma of chronic hepatitis C patients. Mapping the epitope-paratope contact interfaces revealed that these functionally distinct antibodies shared binding specificity for key amino acid residues, including W(437), L(438), L(441), and F(442), within the same epitope of the E2 protein. These data suggest that the effectiveness of antibody-mediated neutralization of HCV could be deduced from the interplay between an antibody and a specific set of amino acid residues. Further understanding of the molecular mechanisms of antibody-mediated neutralization and nonneutralization should provide insights for designing a vaccine to control HCV infection in vivo.

Human Antibodies Can Cross Guinea Pig Placenta and Bind Its Neonatal Fc Receptor: Implications for Studying Immune Prophylaxis and Therapy during Pregnancy

Despite increased use of monoclonal and polyclonal antibody therapies, including during pregnancy, there is little data on appropriate animal models that could humanely be used to understand determinants of protection and to evaluate safety of these biologics in the mother and the developing fetus. Here, we demonstrate that pregnant guinea pigs can transport human IgG transplacentally at the end of pregnancy. We also observe that human IgG binds to an engineered soluble variant of the guinea pig neonatal Fc receptor in vitro in a manner similar to that demonstrated for the human variant, suggesting that this transplacental transport mirrors the receptor-based mechanism seen in humans. Using an intravenous antihepatitis B-specific immune globulin preparation as an example, we show that this transport results in neutralizing activity in the mother and the newborn that would potentially be prophylactic against hepatitis B viral infection. These preliminary data lay the groundwork for introducing pregnant guinea pigs as an appropriate model for the evaluation of antibody therapies and advancing the health of women and neonates.

Efficacy, Safety, and Pharmacokinetics of a 10% Liquid Immune Globulin Preparation (GAMMAGARD LIQUID, 10%) Administered Subcutaneously in Subjects with Primary Immunodeficiency Disease

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤ 30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease.

Anthrax vaccination induced anti-lethal factor IgG: Fine specificity and neutralizing capacity

The efficacy biomarker of the currently licensed anthrax vaccine (AVA) is based on quantity and neutralizing capacity of anti-protective antigen (anti-PA) antibodies. However, animal studies have demonstrated that antibodies to lethal factor (LF) can provide protection against in vivo bacterial spore challenges. Improved understanding of the fine specificities of humoral immune responses that provide optimum neutralization capacity may enhance the efficacy of future passive immune globulin preparations to treat and prevent inhalation anthrax morbidity and mortality. This study (n=1000) was designed to identify AVA vaccinated individuals who generate neutralizing antibodies and to determine what specificities correlate with protection. The number of vaccine doses, years post vaccination, and PA titer were associated with in vitro neutralization, reinforcing previous reports. In addition, African American individuals had lower serologic neutralizing activity than European Americans, suggesting a genetic role in the generation of these neutralizing antibodies. Of the vaccinated individuals, only 69 (6.9%) had moderate levels of anti-LF IgG compared to 244 (24.4%) with low and 687 (68.7%) with extremely low levels of IgG antibodies to LF. Using overlapping decapeptide analysis, we identified six common LF antigenic regions targeted by those individuals with moderate levels of antibodies to LF and high in vitro toxin neutralizing activity. Affinity purified antibodies directed against antigenic epitopes within the PA binding and ADP-ribotransferase-like domains of LF were able to protect mice against lethal toxin challenge. Findings from these studies have important implications for vaccine design and immunotherapeutic development.

Seroepidemiological study of human parvovirus B19 among human immunodeficiency virus-infected patients in a medium-sized city in Rio de Janeiro, Brazil

Parvovirus B19 (B-19) may cause chronic anaemia in immunosuppressed patients, including those infected with human immunodeficiency virus (HIV). We studied single serum samples from 261 consecutive HIV-infected patients using an enzyme immunoassay to detect IgG antibodies to B-19. The seroprevalence of B-19-IgG was 62.8%. The differences in seroprevalence across gender, age, educational categories, year of collection of the serum samples, clinical and antiretroviral therapy characteristics, CD4+ count, CD4+ and CD8+ percentage and CD4+/CD8+ ratios were neither substantial nor statistically significant. There was a non-significant, inverse association between B-19 seropositivity and plasma HIV load and haemoglobin level. Our results indicated that 37.1% of patients might be susceptible to B-19 infection and remained at risk for being infected, mainly during epidemic periods. As B-19 infection can be treated with immune globulin preparations, it may be included in the diagnostic approach toward chronic anaemia in HIV-infected patients.

Mechanisms of action of immune globulin

Mechanisms of action of immune globulin

Induction of an inhibitor antibody to factor XI in a patient with severe inherited factor XI deficiency by Rh immune globulin

AbstractIn this paper, we report an inhibitor antibody to factor XI (FXI) in a woman with severe inherited FXI deficiency, induced by FXI present in an Rh immune globulin preparation. The patient is homozygous for the Glu117Stop mutation, associated with a FXI level of less than 1 U/dL. Unlike all previously described patients with severe FXI deficiency and an inhibitor, the patient had never been exposed to blood products. Following 3 injections of Rh immune globulin during pregnancy, she developed an inhibitor to FXI (8 Bethesda units) that was shown to bind specifically to FXI and inhibit factor IX cleavage by purified FXIa. The administered Rh immune globulin and 2 other similar products were shown to contain FXI. Clinicians should be aware of the potential for immunization of severely FXI-deficient patients by FXI present in Rh immune globulin preparations.