Effects of alum adjuvant or a booster dose on immunogenicity during clinical trials of group B streptococcal type III conjugate vaccines.

Phase 1 and 2 clinical trials of group B streptococcal (GBS) capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i) whether adsorption of conjugate vaccine to aluminum hydroxide would improve immunogenicity and (ii) whether the CPS-specific immunoglobulin G (IgG) response could be boosted by administration of a second dose. Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate vaccine to alum did not improve the immune response to a 12.5-microg dose in healthy adult recipients. Four weeks after vaccination, the geometric mean antibody concentrations (GMCs) for the 15 recipients of III-TT with or without alum were 3.3 and 3.6 microg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-microg dose 21 months later. At 4 weeks after the second dose, the GMCs of type III CPS-specific IgG were similar to those measured 4 weeks after the primary vaccination, suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 microg/ml) before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III CPS-specific IgG than after the initial immunization. These results suggest that prior natural exposure to type III GBS or a related antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.

Failure of rifampin to eradicate group B streptococcal colonization in infants.

BACKGROUND: Mucous membrane colonization with group B streptococci (GBS) frequently persists in infants after treatment of invasive infection and may be associated with recurrent disease. OBJECTIVE: To determine the frequency with which GBS colonization persists at mucous membrane sites after treatment of invasive early or late onset infection and to determine the efficacy of oral rifampin in eradicating colonization in these infants and their mothers. METHODS: Cultures for isolation of GBS were obtained from infants and their mothers after completion of the infant's parenteral therapy, 1 week later when rifampin therapy was initiated and at approximately 1 and 4 weeks after completion of rifampin therapy. Rifampin was administered (10-mg/kg dose; maximum, 600 mg) twice daily for 4 days. RESULTS: Ten of 21 infants (48%) and 13 (65%) of their 20 mothers were colonized with GBS at throat or rectal (infant) or vaginal, rectal or breast milk (mother) sites before rifampin was initiated. One week or less after rifampin treatment, 7 (70%) infants and 4 (31%) mothers remained colonized with GBS. At study completion 6 infants and 7 mothers had GBS colonization. Persistent colonization was not related to GBS serotype, to initial rifampin minimal inhibitory concentration or to the development of rifampin resistant strains. CONCLUSIONS: Rifampin treatment for four days utilized as a single agent after completion of parenteral therapy failed to reliably eradicate GBS colonization in infants.

Use of capsular polysaccharide-tetanus toxoid conjugate vaccine for type II group B Streptococcus in healthy women.

An estimated 15% of invasive group B streptococcal (GBS) disease is caused by type II capsular polysaccharide (II CPS). In developing a pentavalent vaccine for the prevention of GBS infections, individual GBS CPSs have been coupled to tetanus toxoid (TT) to prepare vaccines with enhanced immunogenicity. Type II GBS (GBS II) vaccine was created by direct, covalent coupling of II CPS to TT by reductive amination. In 2 clinical trials, 75 healthy nonpregnant women 18-45 years old were randomized to receive II CPS-TT (II-TT) conjugate (dose range, 3.6-57 microg of CPS component) or uncoupled II CPS vaccine. Both vaccines were well tolerated. II CPS-specific IgG serum concentrations (as well as IgM and IgA) peaked 2 weeks after immunization, being significantly higher in recipients of conjugated vaccine than in recipients of uncoupled CPS. Immunological responses to conjugate were dose dependent and correlated with opsonophagocytosis in vitro. These results support inclusion of II-TT conjugate when preparing a multivalent GBS vaccine.

Invasive disease due to group B Streptococcus in pregnant women and neonates from diverse population groups.

From 1993 through 1996, surveillance for invasive disease due to group B Streptococcus (GBS) in neonates aged <7 days and in peripartum pregnant women was performed in a racially and ethnically diverse cohort in 4 cities in the United States. In a birth population of 157,184, 130 neonatal cases (0.8 per 1000) and 54 maternal cases (0.3 per 1000) were identified. Significant correlates with neonatal disease were black or Hispanic race and a birth weight <2500 g. The attack rate for peripartum maternal infection varied widely by city and may have been influenced by the frequency of administration of intrapartum antibiotics or of evaluating febrile women by performance of blood cultures. Pregnancy loss or GBS disease in the infant occurred in 28% of these maternal cases. Among neonatal and maternal GBS isolates, serotypes Ia (34%-37%) and III (25%-26%) predominated, and type V was frequent (14%-23%). These results provide a description of invasive GBS perinatal infection during the period in which guidelines for prevention were actively disseminated.

A 5-year review of recurrent group B streptococcal disease: lessons from twin infants.

Recurrent invasive disease due to group B Streptococcus (GBS) in twin infants has not been reported. We report 2 cases of recurrent GBS afflicting both siblings of a set of dichorionic twin infants. The maternal and infant colonizing and invasive strains were identical by serotyping and pulsed-field gel electrophoresis (PFGE). Despite attempts at eradication with different antibiotic regimens, the infants remained colonized after treatment of the second episode. A 5-year review of recurrent invasive GBS disease in infants in our affiliated hospitals was undertaken, and 6 further cases were identified. Serotyping and PFGE of isolates from initial and second episodes were genotypically identical for each case. Three infants each had GBS serotype Ia or V disease and 2 had GBS serotype III disease. The exact pathogenesis of recurrent GBS disease remains unclear, but our data support the hypothesis that persistent mucosal colonization with the original GBS strain rather than new acquisition is a pivotal factor in disease recurrence.

Changing epidemiology of group B streptococcal colonization.

OBJECTIVES: To define factors influencing vertical transmission of and neonatal colonization with group B streptococci (GBS) in neonates representing ethnically and economically diverse populations, and to determine the serotype distribution of isolates, especially new types IV-VIII. STUDY DESIGN: Prospective, cross-sectional study of neonates born to women evaluated for GBS colonization at admission for delivery to one of four hospitals between January 1994 and February 1995. Cultures of throat, umbilicus, and rectum were obtained from 24- to 48-hour-old infants for isolation of GBS. Isolates were classified by capsular polysaccharide (I-VIII) and C protein (alpha and beta) antigen components. RESULTS: Colonization was detected in 28% of 546 mothers, was higher in blacks than whites (40.6% vs 20.3%) and Hispanics (26. 9%), and was not influenced by socioeconomic status. Overall, ethnic origin did not seem to be related to GBS serotype, but whites were more likely to carry the new type V strain than blacks (6 out of 24 [25%] vs 1 out of 43 [2%]). Vertical transmission of GBS to neonates was significantly diminished when their mothers had intrapartum antibiotics (0% vs 52%), rupture of membranes <12 hours before delivery (38.4% vs 73.3%), or delivery by cesarean section (25.9% vs 45.2%). Colonization with GBS was found in 13.8% of 549 neonates, was acquired vertically in 97%, and was less frequent in neonates at the private hospitals (4% vs 20%) where intrapartum antibiotics were given more frequently (34.7% vs 17.3%). Among isolates from neonates, serotype Ia predominated (31.6%) followed by types II (25%), III (22.4%), and V (11.8%); approximately 40% of strains contained C protein antigen. CONCLUSIONS: Changes in the epidemiology of GBS colonization included diminished rates in some populations associated with use of maternal intrapartum antibiotics, and a shift in serotype prevalence, with Ia as predominant and V, in addition to II and III, as common.

Safety and immunogenicity of capsular polysaccharide-tetanus toxoid conjugate vaccines for group B streptococcal types Ia and Ib.

About 40% of invasive group B streptococcal (GBS) isolates are capsular polysaccharide (CPS) types Ia or Ib. Because infant and maternal GBS infections may be preventable by maternal vaccination, individual GBS CPS have been coupled to tetanus toxoid (TT) to prepare vaccines with enhanced immunogenicity. Immunogenicity in rabbits and protective capacity in mice of a series of type Ia- and Ib-TT conjugates increased with the degree of polysaccharide-to-protein cross-linking. In total, 190 healthy, nonpregnant women aged 18-40 years were randomized in four trials to receive Ia- or Ib-TT conjugate (dose range, 3.75-63 microg of CPS component), uncoupled Ia or Ib CPS, or saline. All vaccines were well-tolerated. CPS-specific IgG serum concentrations peaked 4-8 weeks after vaccination and were significantly higher in recipients of conjugated than of uncoupled CPS. Immune responses to the conjugates were dose-dependent and correlated in vitro with opsonophagocytosis. These results support inclusion of Ia- and Ib-TT conjugates when formulating a multivalent GBS vaccine.

Endotracheal colonization with Candida enhances risk of systemic candidiasis in very low birth weight neonates.

OBJECTIVE: To determine whether growth of Candida from an endotracheal aspirate identifies a population of very low birth weight (VLBW; < or = 1500 gm) neonates at increased risk of systemic candidiasis. DESIGN: Prospective evaluation with weekly cultures of endotracheal and rectal specimens to determine colonization status. SUBJECTS: One hundred sixteen VLBW neonates (mean birth weight, 975 +/- 23 gm, estimated gestational age, 27.6 +/- 0.2 weeks) with endotracheal tubes in place who were admitted to a level III nursery between Jan. 8 and Dec. 2, 1992. RESULTS: Of the 116 subjects, 39 infants were colonized with Candida (34%). Thirteen neonates had growth of Candida in one or more cultures of endotracheal specimens. Eleven of these could be examined, and in five systemic disease developed (disease in 5/11 vs 2/26; relative risk = 5.9; 95% confidence interval, 1.34 to 26). Eight infants were colonized with Candida in the first week of life. Seven of these could be examined, and in five systemic candidiasis developed (disease in 5/7 vs 2/30; RR = 9.3; 95% confidence interval, 2.3 to 38.0). CONCLUSIONS: Colonization with Candida occurs frequently in VLBW infants. Progression from colonization to systemic infection is more common in the smallest neonates. Detection of colonization in the first week of life or the growth of Candida from an endotracheal aspirate identifies a group of VLBW neonates with an endotracheal tube in place whose risk of systemic candidiasis is increased. A prospective trial of intervention in this high-risk population is warranted.

Neonatal sepsis caused by a new group B streptococcal serotype.

Two infants with typical clinical presentations for invasive neonatal group B streptococcal disease caused by a new serotype, type V, are described. Organisms of this capsular type should be sought among isolates from sick neonates to evaluate their prevalence and associated patterns of disease.

Fibronectin levels in premature infants with late-onset sepsis.

Physical features do not reliably distinguish premature infants with bacterial infections from those with noninfectious conditions. We evaluated the association of depressed plasma fibronectin with sepsis among hospitalized very low birth weight infants (< 1500 gm). Reference values were determined by sequential plasma sampling from 60 healthy very low birth weight infants. Among 17 very low birth weight infants with proved late-onset sepsis (mean age, 20 days; range, 10 to 42 days), 9 had plasma fibronectin levels more than 1 SD below the age- and birth weight-associated mean. Overall, the sensitivity and specificity of the finding of depressed fibronectin levels were 53% and 94%, respectively. These data suggest that depression of plasma fibronectin occurs commonly in association with late-onset sepsis among hospitalized premature infants.

Role of intravenous immunoglobulin in prevention of late-onset infection in low-birth-weight neonates. The Neonatal IVIG Study Group.

As a result of inadequate placental transport of maternal IgG, preterm neonates of less than 32 weeks' gestation, especially those with birth weights less than 1,500 g, are profoundly hypogammaglobulinemic at birth, a condition that worsens during the first several weeks of life. This hypogammaglobulinemia is believed to contribute to their high frequency of late-onset sepsis, with its accompanying morbidity and mortality. Animal studies suggest that human immunoglobulin prepared for intravenous use (IVIG) improves host defense against pathogens that cause neonatal infections, but studies of IVIG in human neonates have been inconclusive because of the small numbers of infants included, lack of suitable controls, use of clinical rather than strict microbiologic definition of sepsis, and performance only in a single hospital outside the United States. A double-blind, randomized, placebo-controlled multicenter trial in the United States is in progress to determine the efficacy of IVIG in the prevention of late-onset infections in infants with birth weights between 500 and 1,750 g. Infants are infused with 500 mg of IVIG/kg or albumin-saline placebo at 3-7 days of age, 7 days later, and every 14 days for five doses. Efficacy parameters include mortality, number of proved infectious episodes (bacterial, fungal, or viral), and infection-related morbidity. Definitive guidelines for the possible use of prophylactic IVIG in low-birth-weight neonates should result from this evaluation of 500 to 700 infants in the United States.

Patterns of immune response among survivors of group B streptococcal meningitis.

Serum samples from 10 infants surviving type III, group B streptococcal (GBS) meningitis were collected acutely and longitudinally for 6 months to determine patterns of antibody response to the capsular polysaccharide and their in vitro functional correlates. Five infants who failed to develop specific antibody at a mean of 3.8 weeks after diagnosis had an increase of greater than or equal to 1.0 microgram/ml after another 4-8 weeks. This IgM-predominant type-specific antibody declined to baseline 2-4 months later. Opsonophagocytosis of type III GBS increased from 0 to 88% in parallel with peak antibody response. Three infants developed increased antibody and opsonophagocytosis at 15-31 weeks after diagnosis, while two had no detectable response. Despite increasing complement levels, opsonophagocytosis of type III GBS was poor with low specific antibody levels These results suggest that survivors of GBS meningitis transiently develop specific antibody and associated efficient opsonophagocytosis, but functional competence does not persist despite maturation to adult levels of complement proteins.

Pharmacokinetics of intravenous immunoglobulin in very low birth weight neonates.

We studied the pharmacokinetics of single doses of intravenous immunoglobulin (IVIG) of 1000, 750 and 500 mg/kg administered to 21 neonates with birth weights from 750 to 1500 g. No adverse effects were detected. Mean pharmacokinetic values for the large, intermediate and small dose groups, respectively, were: elimination half-life, 19.6, 28.7 and 22.1 days; clearance, 5.2, 5.6 and 3.7 ml/kg/day; volume of distribution, 151, 255 and 130 ml/kg. Mean peak IgG concentrations in serum were 1826, 1476 and 1257 mg/dl for the large, intermediate and small dose groups, respectively. Mean IgG on post-infusion Days 1 to 28 were similar for the intermediate and small dose groups but were higher in the larger dose group. Both large and intermediate doses achieved larger increases in IgG over preinfusion values (delta IgG) than the small dose. The differences in delta IgG between the large and intermediate doses were less notable. The wide variability observed indicates that individualization of intravenous immunoglobulin dosage will be required in these patients.

Group B streptococcal breast abscess in a mother and mastitis in her infant.

Group B streptococcus is a common cause of postpartum infection, but breast abscess in a lactating woman has not been reported. Seven days postpartum, a woman developed mastitis resulting from type Ib/c group B streptococcus. She was treated with oral antibiotics for 1 week, with apparent resolution. Breast-feeding was continued, but at reduced frequency on the affected side. Two days later, local and systemic symptoms recurred, and a large breast abscess was surgically drained. Five days into the mother's initial episode of mastitis, her infant developed type Ib/c group B streptococcal mastitis, requiring hospitalization and parenteral antibiotic therapy. It is likely that the pathogenesis of infection in this mother-infant pair was circular, and that either early abscess formation during the mother's first clinical infection and/or milk stasis due to decreased frequency of breast-feeding resulted in transient group B streptococcal bacteremia, with seeding of breast tissue in the newborn.

Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus.

Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus is a promising strategy for the prevention of perinatal infections caused by group B streptococci. To explore the feasibility of this strategy, we vaccinated 40 pregnant women at a mean gestation of 31 weeks with a single 50-microgram dose of the Type III capsular polysaccharide of group B streptococcus. The only adverse effect detected was a mild local reaction in nine women (22 percent). Of the 35 women with low or unprotective antibody levels before immunization (less than 2 micrograms per milliliter), 20 (57 percent) responded to the vaccine. The geometric mean antibody level rose from 1.3 to 7.1 micrograms per milliliter four weeks after vaccination (P less than 0.02), and these levels persisted at delivery and three months post partum. Sixty-two percent of the vaccine-induced immunoglobulin in the mothers was IgG, which readily crosses the placenta. Infant antibody levels in cord serum correlated directly with maternal antibody levels at delivery (r = 0.913, P less than 0.001). Of the 25 infants born to women who responded to the vaccine, 80 percent continued to have protective levels of antibody at one month of age and 64 percent had protective levels at three months. Serum samples from infants with greater than or equal to 2 micrograms of antibody to Type III group B streptococcus per milliliter uniformly promoted efficient opsonization, phagocytosis, and bacterial killing in vitro of Type III strains. This effect could be mediated exclusively by the alternative complement pathway. Although this vaccine with an overall response rate of 63 percent is not optimally immunogenic, we conclude that maternal immunization is feasible and can provide passive immunity against systemic infection with Type III group B streptococcus in the majority of newborns. Larger trials with better vaccines will be required to evaluate the safety and clinical effectiveness of this strategy.

PIP: Of the 11,000 cases of neonatal infection with group B streptococcus that occur each year in the US, 2/3 are caused by Type III strains. Although only 63% of adults produce an immune response to the Type III capsular polysaccharide of group B streptococcus, the high infant morbidity from this strain makes the development even of a less than optimal maternal vaccine worthwhile if the antibodies can cross the placental barrier and confer immunity to the infant. 40 pregnant women, aged 21-39, in the 26th to the 36th week of pregnancy, were immunized subdermally with 50 mc of Type III capsular polysaccharide of group B streptococcus. 63% of the women responded to the vaccine, and 62% of the antibodies produced in response to the vaccine were IgG, which readily crosses the placental barrier. Serum samples from the 25 infants born to the responders contained more than 21.8 mc per milliliter of antibody to Type III group B streptococcus at birth. 64% of these infants' serum still showed protective antibody levels at 3 months of age. These antibody levels were sufficiently high to activate the alternative complement pathway required for the opsonization and phagocytosis of Type III strains. Thus, even though this vaccine is only 63% immunogenic, it can prevent a substantial number of group B streptococcus infections in infants.

Role of fibronectin in diagnosing bacterial infection in infancy.

Plasma fibronectin levels and complete blood cell counts were assessed prospectively among 100 infants less than 3 months of age with the provisional diagnosis of "possible sepsis". Seven of the ten infants with culture-proved bacteremia, meningitis, or urinary tract infection had low plasma fibronectin levels as did 12 (13%) of 90 infants with superficial or no documented bacterial infection. The positive predictive value of a low plasma fibronectin level in conjunction with leukocytosis and elevated band ratio for discriminating serious bacterial infection was 71%. Normal white blood cell counts or fibronectin level alone or in combination predicted the absence of serious bacterial infection with an accuracy of at least 94%. Plasma fibronectin determination provides a useful adjunct to the complete blood cell count for the rapid evaluation of extent of illness in young infants with possible sepsis.