IgG2 subclass restriction of antibody to pneumococcal polysaccharides

Studies in experimental animals suggest that antibody responses to certain polysaccharide antigens may be restricted in IgG subclass distribution. To determine if human antibodies to pneumococcal polysaccharides are similarly restricted we measured the IgG subclass specific response to immunization with purified polyvalent pneumococcal polysaccharide vaccine. For the type 3 pneumococcal antigen, the geometric mean titre of IgG2 antibody was significantly greater than that of IgG1, IgG3 or IgG4, in both pre-immunization and post-immunization sera. A significant rise in mean titre, comparing pre- to post-immunization sera was observed only for IgG2 antibody. Similar predominance of IgG2 antibody was found for pneumococcal polysaccharides types 6, 18, 19 and 23. In contrast, antibody to the protein antigen tetanus toxoid was exclusively of the IgG1 subclass. Patients with IgA/IgG2 deficiency demonstrated a normal IgG response to tetanus, a normal IgM response to pneumococcal polysaccharides, but no IgG antibody to pneumococcal antigens. IgG2 subclass restriction of antibody to pneumococcal polysaccharides suggest that these antigens may elicit an immune response analogous to the murine type 2 T-cell independent immunogens which show IgG subclass restriction and the requirement of a mature B cell subset defined by the Lyb5+ alloantiserum. Our findings support the possibility of subclass-specific inducing or regulating mechanisms for human responses to carbohydrate or polysaccharide antigens.     

Enhanced IgG1 and IgG3 responses to pneumococcal polysaccharides in isolated IgA deficiency

Serum IgG subclass-specific antibody concentrations to pneumococcal polysaccharides (PnPs) 1 and 14 were measured in 13 adult patients with isolated IgA deficiency and nine healthy adults immediately before and 4 weeks following immunization with polyvalent pneumococcal vaccine. Samples were analysed by enzyme immunoassay using pooled human serum as a reference preparation. A significant rise in median post-immunization antibody concentrations to PnPs14 was seen for all IgG subclasses, for IgA-deficient patients and for controls. For PnPs1, post-immunization IgG2 and IgG4 antibody concentrations rose significantly in the patient group, and IgG4 antibody concentrations rose significantly in the controls. The median IgG1 and IgG3 antibody concentrations to PnPs1 were significantly higher pre- and post-immunization in IgA-deficient individuals in comparison with controls, as were post-immunization IgG3 antibody concentrations to PnPs14. This enhancement of IgG1 and IgG3 antibody responses to pneumococcal polysaccharide antigens in IgA-deficient patients suggests an alteration in regulation of the normal switching processes in the generation of subclass and isotype diversity or could possibly be due to alteration in the affinity of subclass specific antibody.     

Evolution of the subclass of IgG antibody to type 3 pneumococcal polysaccharide during childhood

Human antibodies to bacterial polysaccharides consist primarily of IgG and are largely restricted to the IgG2 subclass in adults. We examined the ontogeny of the IgG subclass response to pneumococcal polysaccharide type 3 to determine if the poor response of infants to immunization with polysaccharide antigens is due to a diminished capacity to form this subclass of antibodies. Sera from 33 patients aged 2 months to 25 years who had previously been shown to respond to polyvalent pneumococcal polysaccharide vaccine by producing IgG antibodies, were assayed for pneumococcal type 3 specific antibodies of the IgG1, IgG2, IgG3, or IgG4 subclass. IgG1 antibodies to pneumococcal polysaccharide type 3 were uniformly low in all age groups. In contrast, IgG2 antibody activity was lowest in children less than the age of 2 years (170 +/- 20 ng/ml), but rose progressively in the age group 2-5 years (210 +/- 40 ng/ml), 5-10 years (330 +/- 30 ng/ml), and over the age of 10 (390 +/- 30 ng/ml) (differences significant at P less than 0.0005 by ANOVA). Thus, even in infants, pneumococcal polysaccharide responses are confined largely to the IgG2 subclass. Our findings are consistent with the hypothesis that purified bacterial capsular polysaccharide antigens preferentially activate IgG2-committed B cell clones at all ages.     

Qualitative and quantitative analyses of the antibody response elicited by Haemophilus influenzae type b capsular polysaccharide–tetanus toxoid conjugates in adults with IgG subclass deficiencies and frequent infections

Twenty-one IgG subclass-deficient adult patients with repeated infections of the respiratory tract, were immunized with Haemophilus influenzae type b capsular polysaccharide (HibCP) covalently bound to tetanus toxoid (TT). Specific immunoglobulin and IgG subclasses to HibCP and TT were quantified; the biological activities of HibCP antibodies were also investigated. Most patients showed an antibody response similar to that observed in healthy adults, and the bactericidal activity related to the post-immunization levels of HibCP antibodies. No relation was found between immunoglobulin isotype deficiency, the clinical symptoms and the IgG subclass responsiveness, and no relation was observed between HibCP and TT antibody responses. Our data indicate that some, but not all, patients with recurrent infections and IgG subclass deficiency have an abnormal serum antibody response to polysaccharide and protein epitopes of Hib-TT conjugate vaccine. Analysis of the antibody response after vaccination with HibCP-TT conjugate vaccine did not seem to predict the clinical course of such patients.     

Antibody response to pneumococcal vaccine in children receiving bone marrow transplantation

Fifty-three pediatric patients given an allogeneic or an autologous bone marrow transplantation (BMT) were immunized with a polyvalent pneumococcal capsular polysaccharide vaccine (Pneumovax II). Vaccine was administered six months or more after BMT and the pneumococcal IgM, total IgG, and IgG subclasses levels were evaluated before and three weeks after immunization. Immunization promoted a significant rise in antibody serum levels (P<0.000001), and all children vaccinated more than two years after transplantation responded to pneumococcal polysaccharides, whereas only 20–30% and 50% of patients given BMT between six months and one year and one and two years, respectively, mounted an eifective antibody production (P<0.0001). In univariate analysis, lapse of time from BMT to vaccination, chronic graft-versus-host disease occurrence, and female sex influenced the response rate. However, in multivariate analysis, only time between marrow transplant and immunization was a powerful predictor of response. Interestingly, four of 11 patients with IgG2 deficiency before immunization normalized serum levels of this IgG subclass after the pneumococcal antigenic challenge. Our study suggests that time after transplant is the major factor influencing the recovery of immune reactivity to polysaccharide antigens. This seems to confirm the hypothesis that ontogeny of the B-cell repertoire follows a predetermined sequential program in which polysaccharide antigens are some of the last to evoke an antibody response.     

Clinical and immunological evaluation of patients with mild IgG1 deficiency.

Serum IgG subclass concentrations were determined in patients visiting, the pulmonology out-patient clinic with chronic respiratory tract problems. A total of 24 patients with a serum IgG1 concentration < 4.9 g/l (i.e. below the reference range) and normal values for IgG2, IgM and IgA were included. Patients with a selective IgG1 deficiency were vaccinated with a 23-valent pneumococcal polysaccharide vaccine. There were nine patients with a poor antibody response to pneumococcal capsular polysaccharide antigens. Responsiveness to protein antigens was intact in all patients. Patients with pneumonia showed a significantly lower anti-polysaccharide response in the IgG2 subclass than patients without pneumonia. Patients with recurrent sinusitis showed a significantly lower response in the IgA isotype after vaccination with pneumococcal polysaccharide vaccine compared with non-sinusitis patients. It can be concluded that patients with recurrent sinopulmonary infections and a mild IgG1 subclass deficiency have an impaired IgG1 anti-polysaccharide response, which can extend to decreased IgG2 and IgA anti-polysaccharide responses.     

IgG Subclass Antibody Responses to Pneumococcal Polysaccharide Vaccine in Splenectomized, Otherwise Normal, Individuals

Subclasses of IgG antibodies to pneumococcal polysaccharide serotype antigens 4, 6A, and 23F were measured before and 4 weeks after vaccination with pneumococcal vaccine in young individuals splenectomized because of trauma and in a control group. An ELISA technique was applied. IgG2 anti-pneumococcal antibodies predominated before vaccination, especially against serotypes 4 and 6A. The youngest individuals in the splenectomy group tended to have lower IgG2 anti-pneumococcal antibody levels than the older ones. Vaccination induced antibodies of the IgG1 and IgG2 subclasses, and in some individuals also of the IgG4 subclass. Splenectomy does not seem to influence the IgG subclass pattern of antipneumococcal antibodies.     

Characterization of the Impaired Antipneumococcal Polysaccharide Antibody Production in Immunosuppressed Pediatric Patients Following Cardiac Transplantation

We previously have demonstrated impaired pneumococcal polysaccharide IgG antibody responses in children immunosuppressed following cardiac transplantation in early childhood. We have further characterized the antibody defect. To further investigate the production of antibody, antipneumococcal polysaccharide (PPS) specific IgM, IgG, IgG subclasses, and IgA were measured in postvaccination sera by enzyme-linked immunosorbent assay. Two groups were studied: posttransplant children who made pneumococcal antibody in vivo following natural exposure or PPS immunization (R) and those with an impaired response (NR). There was no difference in IgM or IgA levels between R and NR. IgG and IgG2 levels were higher in R than NR (P = 0.002), even after adsorption of nonspecific common cell wall antigen antibody. Differences in anti-pneumococcal antibody levels suggest that immunoglobulin isotype switching from IgM to IgG and particularly IgG2 is impaired in patients immunosuppressed at a young age. These findings confirm data regarding the effect of immunosuppressive agents derived from animal models in humans.     

Impaired antibody response to Haemophilus influenzae type b polysaccharide and low IgG2 and IgG4 concentrations in Apache children

BACKGROUND AND METHODS. Because Native American children are at much higher risk for invasive Haemophilus influenzae type b infection than white children, we compared the antibody responses to H. influenzae type b polysaccharide vaccine in healthy Apache and white children. RESULTS. The concentrations of H. influenzae type b antibody after immunization with polysaccharide vaccine were approximately 10-fold lower in 24-month-old Apache children than in whites of a similar age (P less than 0.01). The decreased response involved H. influenzae type b antibodies of the IgG, IgM, and IgA classes. Concentrations of IgG antibody to tetanus toxoid did not differ significantly, and IgG antibodies to diphtheria toxoid were only twofold lower (P = 0.028). Although total IgG, IgM, and IgA levels were higher in two-year-old Apaches than in whites (all P less than 0.001), IgG2 and IgG4 subclasses were lower (both P less than 0.001). Among the Apaches, individual immunoglobulin levels and allotypes were not significantly correlated with their antibody responses to H. influenzae type b polysaccharide. CONCLUSIONS. Apache children have significant impairment of their antibody response to H. influenzae type b polysaccharide and little or no impairment of their antibody responses to protein toxoids. This immunodeficiency may explain the high incidence of H. influenzae type b infection in this population.     

Serotype-specific and age-dependent generation of pneumococcal polysaccharide-specific memory B-cell and antibody responses to immunization with a pneumococcal conjugate vaccine

Glycoconjugate vaccines have dramatically reduced the incidence of encapsulated bacterial diseases in toddlers under 2 years of age, but vaccine-induced antibody levels in this age group wane rapidly. We immunized adults and 12-month-old toddlers with heptavalent pneumococcal conjugate vaccine to determine differences in B-cell and antibody responses. The adults and 12-month-old toddlers received a pneumococcal conjugate vaccine. The toddlers received a second dose at 14 months of age. The frequencies of diphtheria toxoid and serotype 4, 14, and 23F polysaccharide-specific plasma cells and memory B cells were determined by enzyme-linked immunospot assay. The toddlers had no preexisting polysaccharide-specific memory B cells or serum immunoglobulin G (IgG) antibody but had good diphtheria toxoid-specific memory responses. The frequencies of plasma cells and memory B cells increased by day 7 (P < 0.0001) in the adults and the toddlers following a single dose of conjugate, but the polysaccharide responses were significantly lower in the toddlers than in the adults (P = 0.009 to <0.001). IgM dominated the toddler antibody responses, and class switching to the IgG was serotype dependent. A second dose of vaccine enhanced the antibody and memory B-cell responses in the toddlers but not the ex vivo plasma cell responses. Two doses of pneumococcal conjugate vaccine are required in toddlers to generate memory B-cell frequencies and antibody class switching for each pneumococcal polysaccharide equivalent to that seen in adults.     

Pneumococcal antibody responses in elite swimmers

The ability of elite swimmers to mount an antibody response to the pneumococcal vaccine, Pneumovax 23, was assessed at the end of an intensive 12-week training programme. Antibody titres to six pneumococcal polysaccharide types were measured in 20 elite swimmers (10 male, 10 female) aged 17–23 years and 19 sedentary age- and sex-matched students (eight male, 11 female) aged 18–23 years. Blood samples were tested 14 days apart to assess the magnitude of the antibody response and changes in serum immunoglobulin isotypes and IgG subclasses. There were no significant differences in any of the pneumococcal antibody responses to the Pneumovax between swimmers and controls, and no gender effect, either before or after vaccination. The clinically adequate response to the vaccine was greatest for the pneumococcal serotype 4, which was 97% for the total study population. There were no significant correlations between the magnitude of any of the pneumococcal antibody responses and (i) changes in the scores for the swimmers’ international performance; (ii) infection rates in either swimmers or controls; (iii) any psychological variables, assessed by the Profile of Mood States (POMS) questionnaire for either swimmers or controls. Swimmers had significantly lower concentrations of serum IgG2 (P = 0·04) and IgG3 (P = 0·002) before pneumococcal vaccination. The swimmers had an increase in all immunoglobulin isotypes and IgG subclasses post-vaccination, suggesting a polyclonal response to the vaccine that was not observed in control subjects. The magnitude of the subclass responses after vaccination was significantly greater in swimmers compared with controls for IgG1 (P = 0·04), IgG3 (P = 0·04) and IgG4 (P = 0·01). The data indicated that elite swimmers undertaking an intensive training programme were capable of mounting an antibody response to pneumococcal antigens equivalent to that of age- and sex-matched sedentary control subjects, despite the swimmers having lower prevaccination levels of serum immunoglobulins.     

Antibody Response to a Seven-Valent Pneumococcal Conjugated Vaccine in Patients with Ataxia-Telangiectasia

Immunodeficiency is a characteristic feature of ataxia-telangiectasia (A-T). Humoral immunodeficiency generally consists of hypogammaglobulinemia and impaired antibody response to bacterial and viral antigens. We previously observed defective antibody response to 23-valent pneumococcal polysaccharide vaccine (PPV) in 96% of 29 patients with A-T. In this study, we investigated the antibody response to a seven-valent pneumococcal conjugate vaccine, PCV7, in 14 patients with A-T. IgG antibody levels to four pneumococcal serotypes, 6B, 14, 19F, 23F, which were included in PCV7, were measured by ELISA in pre- and postimmunization serum samples. Antibody titers against each individual Streptococcus pneumoniae serotype was considered to be positive when serotype specific pneumococcal antibody titer was higher than 10% (>10 U/mL) of the reference plasma pool level. However, when the fold increase (FI) in postimmunization antibody titer was less than two, the subject was determined to be unresponsive to the given serotype. The values were compared with the results obtained in age- and ethnic-matched children after one dose of PPV. Only two patients produced antibodies to one serotype each; one to serotype 19 with a fold increase of <2, and the other to serotype 23F with a fold increase of 5.7 based on the above criteria, although the differences between pre- and postvaccine antibody titers for serotypes 14, 19, and 23 appeared to be statistically significant. In conclusion, A-T patients failed to respond to one dose of PCV7 vaccine. Two or more doses of conjugated vaccine may be required to recruit the help of T lymphocytes in A-T patients.     

Plasma anti-pneumococcal antibody activity of the IgG class and subclasses in otitis prone children

Plasma anti-pneumococcal polysaccharide antibody activity (serotypes 3, 6a and 23) was determined in samples from 15 otitis prone children, at 30 months of age, and compared with age matched control children and adults. A recently developed enzyme immunoassay, using IgG subclass specific monoclonal antibodies for analysis of pneumococcal antibody activity of different IgG subclasses was employed. Adult sera always contained the highest antibody concentrations, almost exclusively of the IgG2 subclass. Children, on the other hand, had higher amounts of IgG1, significantly exceeding those of the adults, healthy children having higher IgG1, as well as IgG2 values than otitis prone children. The most significant differences were seen with type 6a, less so with type 23 antibodies. No differences in IgG1 anti-type 3 pneumococcal activity were observed between the children and the adults. These findings support the concept that pneumococcal antibody activity is confined to IgG2 and, in addition, it was found that sera from children contain antibodies of both IgG1 and IgG2 subclasses.     

Class- and subclass-specific pneumococcal antibody levels and response to immunization after bone marrow transplantation.

Immunoglobulin class- and subclass-specific antibodies to a polyvalent pneumococcal capsular polysaccharide vaccine (Pneumovax II) were measured before and after immunization in children, 1 year or more after bone marrow transplantation for a variety of genetic disorders. The median titres of specific IgG, IgG1 and IgG2 pneumococcal antibodies fell significantly (P less than 0.05) from pre-transplantation levels. The levels of pneumococcal antibodies in the patients before immunization were markedly lower than those in control children of comparable age, for antibodies of IgM, IgG, IgG1 and IgG2 classes (P = less than 0.001 in each case). Apart from IgG2 antibodies, the median response to immunization with Pneumovax II was not significantly different from the controls (P greater than 0.05). However, because of the lower pre-immunization levels, the patients did not achieve a high post-immunization-specific antibody titre in any immunoglobulin class or subclass, when compared with normal children. Neither the pre-immunization specific antibody levels nor the response to immunization were affected by splenectomy or the presence of chronic graft-versus-host disease. Immunization of the donor before bone marrow harvest did not influence the level of specific antibody 1 year or more after transplantation. No significant correlation was found between the total serum IgG2, the patients' age at the time of assessment, or time after transplantation, and the IgG2-specific antibody response. The lack of specific antibodies and the poor IgG2 response to pneumococcal antigens may contribute towards the occurrence of infection with Streptococcus pneumoniae in the late post-transplantation period.     

Hemophilus influenzae type B disease in children vaccinated with type B polysaccharide vaccine

We studied 55 cases of invasive Hemophilus influenzae type b disease occurring in children at least three weeks after vaccination with type b polysaccharide vaccine. Their mean age at the time of immunization was 27.8 months (range, 18 to 47). Meningitis developed in 39 patients, of whom 3 died and 6 had neurologic sequelae. We investigated certain host factors that may have contributed to the failure of the vaccine. The geometric mean concentration of antibody to type b polysaccharide in convalescent-phase serum from 31 of the vaccinated patients who had hemophilus disease was significantly lower than that in serum from 25 patients of similar age with the disease who had never been vaccinated (0.59 vs. 3.46 micrograms per milliliter, P less than 0.001). However, only 3 of 46 patients in whom the vaccine failed and who were tested for hypogammaglobulinemia had this finding, and none of 33 children tested for IgG2 had low serum concentrations of this immunoglobulin subclass, which is thought to be important in the immune response to polysaccharide antigens. In addition, all but 1 of the 46 patients in whom the vaccine failed and who were tested for IgG antibody to tetanus toxoid protein, a thymic-dependent antigen, had normal values, and 19 of 20 tested for hemolytic complement activity had normal levels. In white children, the presence of the Gm immunoglobulin phenotype (1,2,3, 17; ;5,13,21) was associated with a sevenfold increase in the relative risk of vaccine failure (P less than 0.003). We conclude that vaccine failure may be related in part to genetic factors, and that most vaccinated children in whom Hemophilus influenzae disease develops have deficient antibody responses to the type b polysaccharide despite normal serum concentrations of immunoglobulin and normal antibody responses to tetanus toxoid.     

The syndrome of chronic mucocutaneous candidiasis with selective antibody deficiency.

BACKGROUND: Most patients with chronic mucocutaneous candidiasis (CMC) have a selective defect of cell-mediated immunity against Candida albicans (as demonstrated by cutaneous anergy and decreased lymphoproliferative responses to Candida antigen) and intact antibody responses. Many CMC patients also develop infections with other organisms, suggesting a more extensive immunologic defect. OBJECTIVES: The aim of this study was to describe a patient with CMC and selective antibody deficiency and identify eight similar previously reported patients. DATA SOURCES: Relevant articles in the English language derived from searching the MEDLINE database were used. RESULTS: We describe an 18-year-old male patient who was identified with CMC as an infant and later developed immunoglobulin (Ig)G2, IgG4, and IgA deficiency at age 12 associated with poor antibody responses to vaccine antigens. We have identified eight other previously reported CMC patients with selective antibody deficiencies and bacterial infections. IgG2 deficiency was present in all nine patients, and was associated with IgG4 deficiency in 8 patients and IgA deficiency in 3 patients. Six patients had poor or absent antibody responses to pneumococcal polysaccharide vaccine, and all nine patients developed severe recurrent lung infections. CONCLUSIONS: We suggest that these cases represent a distinct phenotype of CMC and should be studied for common histocompatibility leukocyte antigen types and molecular defects.     

Immunoglobulin G antibody responses to polyvalent pneumococcal vaccine in children in the highlands of Papua New Guinea.

The immunoglobulin G (IgG) antibody responses to a pneumococcal polysaccharide vaccine were examined for 480 children aged 3 months to 5 years and living in Tari, Southern Highlands Province, Papua New Guinea. Antipneumococcal IgG to the seven serotypes most frequently causing invasive disease (types 2, 5, 6B, 7F, 14, 19F, and 23F) was measured by an enzyme-linked immunosorbent assay in serum collected before vaccination and 1 and 6 months after vaccination. Prevaccination antibody levels fell rapidly after 3 months of age and remained low throughout the first 2 years of life. One month after vaccination, geometric mean titers of antipneumococcal IgG to serotypes 2, 7F, 23F, and 5 were at least twice those of antibodies in nonvaccinated children of the same age from the ages of 5, 6, 9, and 12 months onwards, respectively; postvaccination antibody responses to serotypes 6B, 14, and 19F rose gradually during the second year of life. Elevated antibody titers to serotypes 2 and 7F were maintained 6 months after vaccination. Thus, young Papua New Guinean children are capable of mounting a good immune response to some pneumococcal capsular polysaccharides from a young age, and the antibody responses to capsular polysaccharides are consistent with studies in developed countries. However, in Papua New Guinea, the serogroup distribution of invasive disease matches the immunogenic components of the pneumococcal polysaccharide vaccine more closely than in developed countries, a fact which helps to explain the results of controlled trials in Papua New Guinea, in which this vaccine prevented death and severe morbidity from pneumonia in young children.     

Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalized lymphadenopathy.

Pre- and post-immunization serum antibodies to pneumococcal polysaccharides (PPS) and tetanus toxoid (TT) were measured in 25 patients with persistent generalized lymphadenopathy and serum antibodies to the human immunodeficiency virus (HIV). The increase in post-immunization anti-PPS antibodies was lower than 40% in 16/25 patients. Isotype analysis indicated that the IgM, IgA, IgG2, but not the IgG1 antibody responses were lower in patients that in healthy controls, whereas pre-immunization values were similar. For TT, no difference was found between the patients and the healthy group in total and IgG1 antibody response whereas IgG4 response was lower in patients. No significant association was found between the defect in anti-PPS antibody response and associated thrush or constitutional symptoms or other immunological parameters. These findings suggest that defective response to a thymo-independent polysaccharide antigen is a distinctive consequence of HIV infection.     

Antipolysaccharide antibodies in 450 children with otitis media

We have measured antibodies to pneumococcal and Haemophilus polysaccharides in a prospective study of 450 children aged 2–16 years with otitis media requiring grommets (ear tubes). Pneumococcal antibody levels were significantly higher in the 2–6 year (P < 0.004) and 7–10 year (P < 0.04) study groups in comparison with age-matched controls. There was no difference in Haemophilus antibody levels between the study and control group children for the age groups 2–6 years and 11–16 years. Haemophilus antibody levels were significantly lower in the 7–10 year (P < 0.003) group in comparison with age-matched controls. Eighty-eight out of 450 (19.6%) children had pneumococcal antibody levels below the 25th percentile. Nineteen out of 88 (21.6%) children with pneumococcal antibody levels below the 25th centile were test immunized with 23 valent Pneumococcal polysaccharide and unconjugated Haemophilus type b capsular polysaccharide. Of these 19 children (aged 4–11 years), five mounted suboptimal responses to both polysaccharide antigens, whilst one child failed to respond to Haemophilus polysaccharide alone. There was no significant difference in the prevalence of IgG subclass deficiency between the normal responders and poor responders to immunization (P= 0.12). We found no evidence of specific polysaccharide antibody deficiency in the vast majority of the 450 children studied. However, the significance of poor antibody responses to test immunization in a small minority of children with otitis media is unclear. Long-term follow up of these children is required to determine whether poor immunization responses herald the development of frank antibody deficiency.