The incidence of late-onset group B streptococcal (GBS) disease in the United States in 2013 was 0.25 per 1000 live births, or approximately 1000 cases.1 Late-onset cases are not reduced under current prevention strategies and, when associated with meningitis, often result in death or permanent disability.2 Third trimester maternal immunization with a glycoconjugate vaccine composed of the 5 common GBS capsular types (Ia, Ib, II, III and V) could potentially prevent over 85% of GBS invasive infection in infancy.3 Maternal immunization to prevent late-onset disease will require that infants passively acquire maternally derived GBS-specific antibodies at a concentration sufficient to sustain protective levels through their age of susceptibility. Transplacental transport of maternal IgG begins at about 17 weeks gestation, but the bulk is actively transferred to the fetus after 33 weeks gestation.
Approximately one half of infants with late-onset GBS disease in the United States are born at less than 37 weeks of gestation. Limited data are available that stratify late-onset GBS disease according to both the infant’s gestational age and the day of life at onset of the infection. Our objective was to stratify late-onset GBS cases by gestational age at birth and age at onset of infection to inform estimates of potential effectiveness of a GBS glycoconjugate vaccine administered to pregnant women during the third trimester to prevent late-onset GBS disease.
Infants age 7–89 days admitted to Texas Children’s Hospital or Ben Taub General Hospital, Houston, from January, 1993 to December, 2012 with late onset GBS disease comprised the study population. Late-onset disease was defined as isolation of GBS from a blood or cerebrospinal fluid (CSF) culture. Data regarding maternal ethnicity, gestation at delivery, infant birth weight and age at onset of infection were collected from hospital records. Infants with more than 1 pathogen isolated from a blood culture were excluded from the analysis as were those for whom gestational age was not available. Infants were stratified by gestational age into 4 groups: those born at term (≥37 weeks), near term (35 0/7 to 36 6/7 weeks), preterm (33 0/7 to 34 6/7 weeks) and very preterm (<33 weeks). The study was approved by the Institutional Review Boards for Human Research at the Baylor College of Medicine and the Harris County Hospital District.
Isolates of group B Streptococcus were obtained from the hospital laboratory and serotyped using the Lancefield capillary precipitin method.4
Dichotomous outcomes were compared with the Student t test.
Among 289 infants with late-onset disease, 6 (2%) were excluded on the basis of polymicrobial bacteremia and 35 (12%) because gestation was not specified. The remaining 248 infants comprised the study cohort. The distribution of cases was even over the 20-year interval, which encompassed implementation of widespread use of maternal intrapartum antimicrobial prophylaxis to prevent early-onset disease: 25% (1993–1997), 23% (1998–2002), 27% (2003–2007) and 25% (2008–2012). Overall, 87.9% of the infants had bacteremia with or without meningitis or other focal manifestations of infection; 12.1% had isolation of group B Streptococcus from CSF alone. Ninety eight infants (39.5%) had meningitis. The maternal race and ethnicity included 24.2% white, 32.3% African–American, 39.1% Hispanic, 2.4% Asian and 2% other or unknown, reflecting the ethnic composition of the Houston area during the study period.
One hundred fifty seven infants (63.3%) were born at term (50.8%) or near term (12.5%) gestation. Among the remaining 91 infants, 7.7% were born at 33-34 weeks and 29% before 33 weeks gestation. The age at diagnosis of late-onset GBS disease for infants born at ≥35 weeks gestation (median 27 days) was significantly younger than that for infants born before 35 weeks gestation (median 45 days; P < 0.001).
Among infants born at 35 or more weeks gestation, 51% developed illness between age 7 and 29 days, 38.2% between age 30 and 59 days and 10.8% between age 60 and 89 days (Fig. 1). Infants born at or near term gestation presenting with meningitis showed a trend toward becoming ill within in the first month of life compared with those with bacteremia without a focus (57% vs. 46%; P = 0.07). Overall, 72% of infants born at or near term gestation developed infection within the first 6 weeks and 92% developed infection within the first 9 weeks of life. Among infants born at less than 35 weeks gestation, 29.7% developed illness between age 7 and 29 days, 42.8% between age 30 and 59 days and 27.5% between age 60 and 89 days.
The most frequent GBS capsular type causing late-onset infection was III, accounting for almost two thirds [157 of 248 (63.3%)] of cases. The remaining isolates were types Ia (21.4%) and V (6.5%), followed by Ib (5.7%), II (1.2%), IV (1.2%) and VI (0.4%). One isolate was not available for typing. Among CSF isolates from infants with meningitis, 66% were type III and 18% were type Ia GBS.
Stratifying late-onset GBS cases by gestation at birth and age at onset of infection affords an opportunity to interrogate assumptions regarding the potential effectiveness of a GBS vaccine administered during the third trimester of pregnancy. We assumed that infants born at term or near term gestation would transplacentally acquire maternal GBS-specific antibodies in concentrations sufficient to prevent infection.5 Including only infants born at 35 weeks of gestation or more who become ill during the first 6 weeks of life, or approximately 2 half-lives of antibody decay, we found that third trimester maternal immunization theoretically could prevent 72% of infections in this group and approximately one half (46%) of all late-onset GBS infections. If the duration of potential protection was extended to 9 weeks of life or approximately 3 half-lives of antibody decay, 92% of infections in infants born at ≥35 weeks and 58% of all late-onset disease cases could be prevented because very few cases have their onset in more mature infants during the third month of life. The estimate of potential vaccine efficacy would be higher if some infants born at less than 35 weeks of gestation, among whom 29.7% of cases occur between 7 and 30 days of life, receive passively acquired antibody at a concentration sufficient to prevent late-onset infection.
Several variables modulate the potential for protection against late-onset GBS disease through maternal immunization. The first is the proportion of term and near term deliveries among late-onset cases. Among 455 infants with late-onset GBS disease between 2003 and 2005 in the United States,6 46% were born at term and another 13% at 34–36 weeks gestation. In Italy, 31% of 98 infants with late-onset disease from 2003 to 2010 were preterm but near term rates were not specified.7 This distinction is helpful in predicting vaccine efficacy because late-preterm infants (those born at 34 0/7 to 36 6/7 weeks gestational age) account for approximately 74% of all preterm births in the United States.8
Other variables modulating the effectiveness of passively acquired maternal antibody for prevention of late-onset GBS disease include the concentration of GBS-specific IgG required for protection and the rate of decay of antibody. A concentration of maternal delivery capsular polysaccharide-specific antibody of 1 μg/mL is sufficient to protect most neonates from early-onset GBS types Ia and III disease.5 Findings from a cohort of infants born to healthy women who received a type III glycoconjugate vaccine at 32-34 weeks of gestation suggest that potentially protective antibody concentrations are indeed sustained through the interval of late-onset disease susceptibility.9 Maternal immunization provided a geometric mean cord blood concentration of 7.5 μg/mL of IgG to the type III capsular polysaccharide for these term infants. At 2 months of age, the infants’ geometric mean antibody concentration was 2.2 μg/mL, substantially higher than that estimated to provide protection.5
Because the nonimmunospecific IgG plasma half-life is about 21 days, a decline after birth of maternally derived antibodies can be estimated. Our findings indicate that among term and near term infants with a gestational age of at least 35 weeks, almost three fourths (72%) develop late-onset GBS disease by 6 weeks of age, suggesting that within a 2 plasma half-life interval of decay, most cases will have occurred in the infant cohort most likely to benefit from maternal immunization. Of interest, the half-life of GBS specific IgG among infants in the maternal immunization trial was approximately 35 days, suggesting that specific antibodies elicited by immunization could provide a more sustained duration of passive protection.9
Preliminary data also suggest that a GBS vaccine undergoing clinical trials could prevent late-onset GBS disease. A trivalent vaccine to GBS types Ia, Ib and III elicited sufficiently robust geometric mean concentrations at 61 days after immunization to anticipate that, if administered during pregnancy, passively transferred antibodies could confer protection for the first months of life.10 According to the distribution of GBS types in our cohort, this GBS conjugate vaccine would target 91% of late-onset disease cases overall and would include most cases (84%) of late-onset meningitis.
The authors thank Robin Schroeder for her assistance in preparation of the manuscript.
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