Bacterial Polysaccharide Immune Globulin Research Articles

Acute otitis media in the era of effective pneumococcal conjugate vaccine: will new pathogens emerge?

The immunogenicity of pneumococcal conjugate vaccine (PCV) in young infants and its serotype-specific efficacy in otitis media (OM) results in a modest reduction in total episodes of OM and a more substantial reduction in disease due to the most frequent pneumococcal serotypes. Since PCV will only prevent disease due to the most common serotypes, concerns about potential changes in the microbiology of OM have emerged. Insight into potential changes can be obtained from reviewing middle ear and nasopharyngeal isolates from studies of antimicrobial prophylaxis and bacterial polysaccharide immune globulin for prevention of OM and PCV for prevention of invasive pneumococcal disease, respectively. In children receiving PCV, a shift in serotypes of SP colonizing the nasopharynx has been observed. Since non-vaccine serotypes are already present in the community as the etiology of acute purulent OM, it is predictable that these non-vaccine serotypes will become more common especially in children less than two years of age.

Anticapsular polysaccharide antibodies and nasopharyngeal colonization with Streptococcus pneumoniae in infant rats.

To evaluate the effect of passive immunization with anticapsular antibodies on nasopharyngeal carriage, two models of Streptococcus pneumoniae colonization were developed in infant rats. In a direct inoculation model, 3- to 4-day-old infant rats were intranasally inoculated with 2 x 10(5) cfu of S. pneumoniae type 3 or 6 x 10(3) cfu of S. pneumoniae type 23F. In an intralitter transmission model, 2 infant rats were intranasally inoculated with 10(3) cfu of pneumococcus type 3 or type 19F and placed in a cage containing 10 infant rats. Pretreatment with bacterial polysaccharide immune globulin led to a significant reduction in colonization of contact animals with S. pneumoniae type 3 or 19F in the intralitter transmission model (P < .05). No effect of immune globulin could be demonstrated in the direct inoculation model. These results indicate that systemic anticapsular antibodies conferred significant protection against nasopharyngeal acquisition by intralitter spread of S. pneumoniae type 3 and 19F.

Vaccination against middle-ear bacterial and viral pathogens.

Considerable evidence suggests that otitis media (OM) can be prevented by systemic immunization. Building on the highly effective H. influenzae type b (Hib) conjugate vaccine technology, pneumococcal conjugate vaccines are being developed to circumvent T-independence of these antigens and provide durable immunity at a very young age. Several pneumococcal conjugate vaccines are currently in clinical testing. Potential vaccine antigens of nontypable H. influenzae (NTHi) include OMP, HMW, pili, and fimbriae. Several OMPs show extensive homology among strains, but surface, determinants of others are highly variable so that antibodies to surface epitopes of one strain will not bind to surface epitopes of another. Several M. catarrhalis OMP and HMW antigens have vaccine potential, but no functional correlates of protection have been identified, and there is no clear evidence that antibody to M. catarrhalis is associated with OM protection. Attenuated viral vaccines also hold promise of preventing childhood OM. Two clinical trials with killed influenza vaccines have shown a significant reduction in OM among vaccine recipients compared to control children during periods of high influenza disease activity in the community. Passive immunoprophylaxis also has potential for preventing OM. Human bacterial polysaccharide immune globulin was protective for pneumococcal OM in children and in the chinchilla OM model. High-dose respiratory syncytial virus-enriched immunoglobulin reduced the incidence and severity of RSV lower respiratory tract infection in high-risk children. Passive immunoprophylaxis may also be effective in children with specific immune deficiencies, such as IgG2 deficiency, and patients who fail to respond to vaccines.

Recommended Timing of Routine Measles Immunization for Children Who Have Recently Received Immune Globulin Preparations

Passively acquired antibody can block replication of live viral vaccines and subsequent active immune responses.1-3 The persistence of transplacentally acquired maternal measles antibodies can interfere with the response to measles vaccine in some infants up to 12 months of age.4,5 Simultaneous or prior administration of immune globulin administered through the intramuscular or intravenous route has a similar blunting or blocking effect on the host response to certain live virus vaccines.1,6,7 The American Academy of Pediatrics previously recommended a 3-month interval after administration of immune globulin before parenteral administration of live viral vaccines, including measles, mumps, and rubella vaccines (MMR). This recommendation was based on the half-life of passively administered immune globulin and data from individuals who received low doses of immune globulin.2 However, immune globulin is now used in larger doses for treatment or prevention of several diseases, 8 necessitating a lengthening in the interval between use of immune globulin and the administration of certain live virus vaccines. INTERFERENCE WITH MEASLES IMMUNIZATION In a recent study high doses of immune globulin interfered with the response to measles immunization for more than 3 months.1 Children who received bacterial polysaccharide immune globulin (BPIG), a product under clinical evaluation, in a dose of 0.5 mL/kg (80 mg of IgG per kilogram) intramuscularly had reduced measles antibody response when measles vaccine was given as long as 5 months after administration of BPIG (Figure). The measles antibody concentrations (pen gram of protein) in BPIG were similar to concentrations found in preparations of immune globulin (IG) for intramuscular administration, specific immune globulin preparations (eg, VZIG, HBIG, and TIG), and immune globulin for intravenous administration (IGIV).

Bacterial polysaccharide immune globulin for prophylaxis of acute otitis media in high-risk children

We evaluated the prevention of recurrences of acute otitis media (AOM) by bacterial polysaccharide immune globulin (BPIG), a hyperimmune human immune globulin prepared by immunizing donors with bacterial polysaccharide vaccines. We used a randomized, stratified, double-blind, placebo-controlled design. Children < or = 24 months of age with 1 to 3 prior episodes of AOM received BPIG, 0.5 ml/kg, or saline placebo intramuscularly at entry and 30 days later. During the 120-day follow-up period, AOM was diagnosed by using clinical criteria and was confirmed with tympanocentesis and culture of the middle ear exudates. Eighty-eight episodes of AOM were observed in 76 patients who completed the study. The incidence of AOM during the entire 120-day study period was similar in BPIG and placebo recipients. Pneumococcal AOM was significantly less frequent in BPIG recipients (0.21 episode per patient) than in placebo recipients (0.45 episode per patient; p = 0.05). Time spent free of AOM was significantly prolonged in recipients of BPIG, in comparison with placebo recipients (51 vs 35 days; p = 0.034). This study demonstrated that circulating antibody, even without stimulation of specific local immunity, may prevent infection of the middle ear. The use of immune globulin preparations for longer periods or at a higher dosage might decrease the incidence of recurrent AOM in otitis-prone children, and deserves further evaluation.

Interference of immune globulin with measles and rubella immunization

Passively acquired antibody may interfere with the active antibody response to live viral vaccines such as measles and rubella. To evaluate the duration of this inhibitory effect, we measured the measles and rubella antibody responses of Apache children immunized with measles, mumps, and rubella vaccine at varying intervals after administration of an immune globulin termed bacterial polysaccharide immune globulin (BPIG). This specific immune globulin contained measles and rubella antibody titers similar to those in standard intramuscularly and intravenously administered immune globulins. Antibody responses to measles vaccine were inhibited for up to 5 months after a BPIG dose of 80 mg IgG per kilogram of body weight, but responses to rubella vaccine were inhibited for only 2 months. Most children who had a decreased measles antibody response to primary measles, mumps, and rubella immunization given 1 1/2 to 4 months after BPIG administration responded to a booster immunization given 6 months after their last BPIG dose. We conclude that high doses of immune globulin (> 10 mg/kg) may inhibit the antibody response to measles for more than 3 months. We propose that the interval between administration of immune globulin and measles and rubella immunization be adjusted on the basis of the dose of immune globulin.

Prevention of Haemophilus influenzae type b disease

Haemophilus influenzae type b (Hib) is the leading cause of meningitis in children < 5 years of age. The majority of cases of Hib occur in infants < 2 years of age. Until recently the only vaccine available against this disease contained the pure polysaccharide (PRP) of Hib (Hib-PRP vaccine). The Hib-PRP vaccine was demonstrated to be efficacious in infants >18 months of age but not below that age. This product was licensed for routine use in the USA for children aged 24 months or more. Recently a hyperimmune globulin termed bacterial polysaccharide immune globulin (BPIg) was prepared by immunizing adult donors with Hib-PRP, meningococcal and pneumococcal vaccines, BPIg has been demonstrated to prevent Hib infections when it is administered to infants at 4-month intervals. However, BPIg has not been licensed for routine use in the USA. A number of new Hib conjugate vaccines have also been developed in the last few years by convalently linking the Hib-PRP to different carrier proteins. Four different Hib conjugate vaccines have undergone clinical trials in the USA. Two of these vaccines, HbOC (Hib capsular oligosaccharide linked to CRM197) and Hib-OMPC (Hib capsular polysaccharide linked to Neisseria meningitidis outer membrane protein complex) have been demonstrated to protect infants aged 2 months or more from Hib disease. Both HbOC and Hib-OMPC are currently licensed for routine use in the USA. The widespread use of these vaccines should have a substantial impact in reducing morbidity and mortality from Hib disease.

Passive Immunization for Infection With Haemophilus influenzae Type b

Haemophilus influenzae type b is the leading cause of meningitis in children younger than 5 years of age in the United States. The incidence of infection with H influenzae type b in certain populations, such as Apache and Navajo Indians and Alaskan Eskimos, is 10 to 20 times higher than in the general US population. Another important feature of H influenzae type b infections in these populations is that more than 80% of the cases occur during the first year of life, with 35% to 45% occurring during the first 6 months. One of the currently licensed vaccines that contains the capsular polysaccharide of the H influenzae type b organism is not reliably immunogenic in infants younger than 18 months of age. A number of new H influenzae type b vaccines prepared by covalently coupling the H influenzae type b capsular polysaccharide with a protein carrier antigen are undergoing clinical evaluation. One of these conjugate vaccines was shown to be efficacious in preventing disease caused by H influenzae type b in Finnish infants when they were immunized at 3, 4, and 6 months of age. Unfortunately, in a recently concluded trial, the same vaccine was not found to be efficacious in preventing such disease in infants younger than 1 year of age among the Alaskan Eskimo population. We have evaluated an alternative approach for protecting high-risk infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of pneumococcal otitis media in chinchillas with human bacterial polysaccharide immune globulin

Clinical and experimental observations suggest that immune globulin may prevent otitis media (OM) in children. We performed experiments in chinchillas to test the hypothesis that human bacterial polysaccharide immune globulin (BPIG) might prevent OM caused by Streptococcus pneumoniae. Animals were given BPIG or saline intraperitoneally on day 0. On day 3 the epitympanic bulla was inoculated with S. pneumoniae type 7F. All 12 saline-treated and none of 12 BPIG-treated animals developed pneumococcal OM by day 7 (P less than 0.0001). Bacteremia developed in 6 of 12 saline- and 0 of 12 BPIG-treated animals (P = 0.007). Death with pneumococcal OM occurred within 28 days in 5 of 12 saline- and 0 of 12 BPIG-injected animals (P = 0.02). A chinchilla-specific immunoassay was used to show that surviving saline-injected animals developed serum anticapsular antibody; BPIG-treated animals had no detectable response. At levels of anticapsular immunoglobulin G similar to those of human adults, BPIG given systemically prevented pneumococcal OM and disseminated infection in chinchillas. BPIG may be of value in preventing human bacterial infection and may also inhibit development of antibody if it affects local infection or colonization. Specific immunoglobulin G antibody may provide an important antibacterial defense of mucosal surfaces of the respiratory tract.

Prevention ofHaemophilus influenzaeType b Infections in High-Risk Infants Treated with Bacterial Polysaccharide Immune Globulin

Apache Indian infants have a high frequency of Haemophilus influenzae type b (Hib) and pneumococcal infections. Forty percent of Hib infections in these infants occur before the age of six months, when active immunization may not be protective. To evaluate the efficacy of passive immunization with a human hyperimmune globulin (bacterial polysaccharide immune globulin [BPIG]) prepared from the plasma of immunized adult donors, we randomly assigned 703 infants in a double-blind fashion to receive 0.5 ml of BPIG per kilogram of body weight (n = 353) or 0.5 ml of saline (n = 350) intramuscularly at 2, 6, and 10 months of age. Hib-antibody levels were significantly higher in BPIG recipients than in placebo recipients at 4, 6, and 10 months of age (P less than 0.001). During the first 90 days after BPIG or placebo injection, no Hib or pneumococcal infections were detected in the BPIG group, whereas seven Hib infections (six cases of bacteremia and one of meningitis) and four pneumococcal infections (bacteremia) were detected in the placebo group (P = 0.007 and 0.06, respectively). During the fourth month, one case of Hib meningitis and two cases of pneumococcal bacteremia developed in the BPIG group, whereas there were no Hib or pneumococcal infections in the placebo group. We conclude that BPIG given at four-month intervals provided significant protection against serious Hib disease for three months, and that in high-risk infants it might be used alone, perhaps at three-month intervals, or together with active immunization.

SUSCEPTIBILITY TO INVASIVE H. INFLUENZAE (Hi) INFECTION IMMEDIATELY AFTER IMMUNIZATION WITH THE CAPSULAR VACCINE

To understand the immunologic mechanism underlying early (<7 day) “vaccine failure” after administration of the Hi capsular polysaccharide vaccine (HiPV), we used the infant rat model to evaluate whether HiPV might, for a short period, decrease the protection afforded by anticapsular antibody (ACA). 74 five day old infant rats were passively protected with bacterial polysaccharide immune globulin (BPIG) prepared from adults immunized with HiPV. One day later, the mean ACA concentration was 173 ± 85 ng/ml. The pups were immunized 24 hours after BPIG with either 75 or 7500 ng HiPV. The lower HiPV dose was extrapolated from that currently recommended for infants. Controls were given BPIG alone or HiPV alone. All animals were challenged ip with 5×103 cfu Hi type b one day after immunization. Detectable bacteremia and meningitis were more frequent in HiPV immunized BPIG recipients than in unimmunized BPIG recipients (100* vs 18%, p<.00001 for bacteremia and 100% vs 18%, p<.00001 for meningitis). Also, in bacteremic animals, the magnitude of bacteremia in the BPIG/HiPV recipients exceeded that in BPIG protected, non-HiPV recipients (104.6 vs 102.1, p=.0005). HiPV administration did not deplete complement. However, animals given BPIG followed by HiPV had lower mean ACA concentrations than animals receiving BPIG alone (29 vs 151 ng/ml, p < .01). Moreover, ACA was undetectable (< 25 ng/ml) in 18/20 BPIG/HiPV recipients. We conclude that immunization with HiPV may decrease the ACA concentration and produce a ‘window’ of susceptibility to Hi disease in the early post-vaccination period.

Preparation of human hyperimmune globulin to Haemophilus influenzae b, Streptococcus pneumoniae, and Neisseria meningitidis.

As a first step in exploring the feasibility of passive antibody prophylaxis and therapy of serious infections caused by common encapsulated bacteria, we have immunized healthy adults with Haemophilus influenzae type b vaccine, 14-valent pneumococcal vaccine, and meningococcal group A and C vaccine; collected plasma by repeated pheresis; and purified a hyperimmune globulin termed bacterial polysaccharide immune globulin by the cold-ethanol fractionation method of Cohn and Oncley. Specific antibacterial antibody concentrations were measured in individual donors before and after immunization. In addition, antibody concentrations were measured in plasma pools prepared from immunized donors and from unimmunized controls and in the immunoglobulin-containing Cohn-Oncley fractions II and III derived from the respective plasma pools. A comparison of Cohn-Oncley fractions II, which contain primarily immunoglobulin G and which are used therapeutically as immune globulin, revealed that antibody to H. influenzae type b was enriched 15.3-fold and that antibody to meningococcal serogroups and pneumococcal types was enriched a mean of 4.4-fold (range, 1.2- to 9.9-fold). Enrichment of antibacterial antibody in Cohn fraction III, which contains substantial amounts of immunoglobulin M and immunoglobulin A in addition to immunoglobulin G, closely paralleled that in fraction II. Only antibodies to pneumococcal types 1 and 7 were increased disproportionately in fraction III. Based on the clinical experience that conventional immune serum globulin at a dose of 100 mg/kg protects agammaglobulinemic patients for ca. 1 month, we estimate that bacterial polysaccharide immune globulin, in similar dosage, will provide protection from systemic H. influenzae type b infection for 4 to 6 months and from pneumococcal and meningococcal infections for 3 to 4 months.