Preventing the broad spectrum of perinatal morbidity and mortality through group B streptococcal vaccination

doi:10.1016/j.vaccine.2012.11.046

Vaccine

Volume 31, Supplement 4, 28 August 2013, Pages D66-D71

https://doi.org/10.1016/j.vaccine.2012.11.046 Get rights and content

Abstract

The development of a group B streptococcal (GBS) glycoconjugate vaccine and its upcoming evaluation in a phase 3 trial in pregnant women highlight the importance of defining the anticipated impact of GBS vaccination upon the broad spectrum of GBS-related perinatal morbidity and mortality. We present the specific pregnancy-associated and neonatal conditions attributable, at least in part, to GBS in high and lower income countries. We offer a rationale to support our contention that implementation of GBS glycoconjugate immunization during pregnancy will reduce the global burden of GBS-related morbidity and mortality in pregnant women and their infants.

Highlights

► GBS contributes substantially to maternal pregnancy-associated morbidity. ► GBS contributes substantially to neonatal morbidity and mortality. ► GBS immunization during pregnancy will reduce peripartum morbidity and rates of prematurity and stillbirth. ► GBS immunization during pregnancy will reduce deaths and improve long-term outcomes in neonates and young infants.

Introduction

Infections caused by group B Streptococcus (GBS) contribute substantially to morbidity and mortality among pregnant women and their infants [1]. The U.S. Centers for Disease Control and Prevention's (CDC) Active Bacterial Core Surveillance report estimated the total disease burden from invasive GBS disease as 24,700 people in 2010 with an estimated incidence of 8.0 cases per 100,000 population [2]. Approximately 20% of cases and 6% of the estimated GBS 1650 annual deaths occurred among adults of childbearing age. Infants accounted for approximately 2070 annual cases.

Prevention of GBS infections in pregnant women and their infants through maternal immunization has been a vision for decades and now is an attainable goal. Susceptibility to invasive GBS neonatal infection correlates with low concentrations of GBS capsular polysaccharide (CPS)-specific antibodies in serum [3], [4]. Investigational GBS CPS–protein conjugate vaccines have been well-tolerated and immunogenic in healthy adults, including pregnant women [5], [6], [7], [8], [9], [10]. Recently, a manufacturer's interest in GBS glycoconjugate vaccine development has increased and candidate vaccines capable of inducing in women strong, durable protective immunity against GBS are in clinical testing [11]. A phase 1 study enrolled 320 healthy, non-pregnant Belgian women in a placebo-controlled, dose-ranging trial of a trivalent GBS vaccine containing GBS types Ia, Ib and III conjugated to CRM₁₉₇ and found the vaccine well-tolerated and immunogenic [12]. A phase 3 efficacy trial in pregnant women is in the planning stages. Maternal immunization offers the potential to prevent GBS infection in the maternal–neonatal dyad by active protection in mothers and passively, through placental transfer of antibodies, in their infants. In addition, GBS vaccines can be administered to prevent disease in resource-limited settings where prenatal screening and intrapartum antibiotic prophylaxis is generally not feasible.

Our two-fold objective is to summarize the pregnancy-related and infant-associated conditions caused by or potentially attributable to GBS and to project the potential impact of GBS glycoconjugate immunization during pregnancy upon the broad spectrum of perinatal GBS disease morbidity and mortality. We propose that widespread implementation of immunization during pregnancy with a multivalent GBS vaccine will reduce substantially the global burden of maternal and neonatal GBS-related morbidity and mortality and will also result in a reduction in prematurity and stillbirths.

Section snippets

Incidence and scope of maternal infection

The incidence of invasive GBS disease in pregnant women and girls, as determined by the U.S. CDC Active Bacterial Core surveillance network in 1993, before implementation of consensus guidelines for the prevention of perinatal GBS disease, was 0.29 per 1000 live births [13]. The case definition employed required isolation of GBS from a normally sterile site, such as blood or cerebrospinal fluid, and did not include cases identified by isolation of GBS from amniotic fluid, placenta or urine

Incidence of invasive GBS in infancy

In an attempt to estimate the global burden of GBS disease in infants younger than three months of age, a systematic review and meta-analysis by region was conducted for the years 2000–2011 [38]. The mean incidence of invasive GBS disease in infants 0–89 days of age was 0.53 per 1000 live births (95% CI, 0.44–0.62) and the mean case fatality rate was 9.6% (95% CI, 7.5–11.8). The incidence of early-onset disease (0.43 per 1000 live births, 95% CI 0.37–0.49) and case fatality (12.1%, CI 6.2–18.3)

GBS glycoconjugate vaccines

Candidate glycoconjugate vaccines incorporating each of the five major capsular polysaccharides of GBS have been evaluated in phase 1 and 2 trials and found to be safe and immunogenic [5], [6], [7], [8], [9], [10], [12]. When vaccine was administered during the third trimester of pregnancy, placental transfer of antibodies to type III capsular polysaccharide in concentrations sufficient to protect neonates and young infants from invasive GBS infection was demonstrated [7]. Adults responding to

Conclusion

In conclusion, a glycoconjugate vaccine incorporating GBS types Ia, Ib, II, III and V can potentially prevent at least 85% of invasive GBS disease in neonates and young infants globally. A GBS vaccination program to immunize women during pregnancy has the potential to reduce the incidence of maternal invasive GBS infection by up to 88% and to prevent 1–2% of premature births and 5–10% of stillbirths related to infection.

Acknowledgments

We gratefully acknowledge Carol J. Baker, M.D. for reviewing the manuscript and for her helpful comments and Robin D. Schroeder for assistance in preparation of the manuscript.

Conflict of interest statement: Dr. Edwards is a consultant to and receives research funding from Novartis Vaccines & Diagnostics. Dr. Gonik is a consultant to Novartis Vaccines & Diagnostics.

References (72)

C.J. Baker et al.
Immunization of pregnant women with group B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine
Vaccine
(2003)
C.J. Baker et al.
Dose-response to type V group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine in healthy adults
Vaccine
(2007)
K.A. Boggess et al.
Bacteremia shortly after placental separation during cesarean delivery
Obstet Gynecol
(1996)
E.G. Wood et al.
A prospective study of group B streptococcal bacteriuria in pregnancy
Am J Obstet Gynecol
(1981)
V. Kubin et al.
Group B streptococci in the milk of lactating mothers
Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene
(1987)
S.L. Hillier et al.
Microbiologic causes and neonatal outcomes associated with chorioamnion infection
Am J Obstet Gynecol
(1991)
P.G.R. Seaward et al.
International multicenter term PROM study: evaluation of predictors of neonatal infection in infants born to patients with premature rupture of membranes at birth
Am J Obstet Gynecol
(1998)
G.J. Locksmith et al.
Maternal and neonatal infection rates with three different protocols for prevention of group B streptococcal disease
Am J Obstet Gynecol
(1999)
K.M. Edmond et al.
Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis
Lancet
(2012)
M.S. Edwards et al.
Long-term sequelae of group B streptococcal meningitis in infants
J Pediatr
(1985)

K.C. Chin et al.

Sequelae of early-onset group B hemolytic streptococcal neonatal meningitis

J Pediatr

(1985)

E. Georget-Bouquinet et al.

Group B streptococcal meningitis’ clinical, biological and evolutive features in children

Arch Pediatr

(2008)

M.S. Edwards et al.

Persistence of functional antibodies to group B streptococcal capsular polysaccharides following immunization with glycoconjugate vaccines

Vaccine

(2012)

H. Blencowe et al.

National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications

Lancet

(2012)

L. Liu et al.

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000

Lancet

(2012)

B. Mercer

Antibiotics in the management of PROM and premature labor

Obstet Gynecol Clin N Am

(2012)

M. Hood et al.

Beta hemolytic streptococcus group B associated with problems of the perinatal period

Am J Obstet Gynecol

(1961)

R.L. Goldenberg et al.

The infectious origins of stillbirth

Am J Obstet Gynecol

(2003)

C.R. Phares et al.

Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005

JAMA

(2008)

Centers for Disease Control and Prevention. Active bacterial core surveillance (ABCs) report, emerging infections...

C.J. Baker et al.

Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection

N Engl J Med

(1976)

C.J. Baker et al.

Quantitative determination of antibody to capsular polysaccharide in infection with type III strains of group B Streptococcus

J Clin Invest

(1977)

C.J. Baker et al.

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

J Infect Dis

(1999)

C.J. Baker et al.

Safety and immunogenicity of a bivalent group B streptococcal conjugate vaccine for serotypes II and III

J Infect Dis

(2003)

C.J. Baker et al.

Immune response of healthy women to 2 different group B streptococcal type V capsular polysaccharide–protein conjugate vaccines

J Infect Dis

(2004)

S. Hillier et al.

Women receiving group B Streptococcus serotype III tetanus toxoid (GBS III-TT) vaccine have reduced vaginal and rectal acquisition of GBS type III

DEVANI. Vaccine against neonatal infections: design of a vaccine to immunize neonates against GBS infections through a...

G. Leroux-Roels et al.

Development of a trivalent vaccine to prevent group B Streptococcus infection

S.J. Schrag et al.

Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis

N Engl J Med

(2000)

Prevention of perinatal group B streptococcal disease: revised guidelines from CDC

MMWR

(2002)

J.D. Blanco et al.

Bacteremia in obstetrics: clinical course

Obstet Gynecol

(1981)

D.J. Sexton et al.

Pregnancy-associated group B streptococcal endocarditis: a report of two fatal cases

Obstet Gynecol

(1985)

R.R. Wolfe et al.

Fatal maternal beta-hemolytic group B streptococcal meningitis: a case report

Am J Perinatol

(1998)

J.B. Hill et al.

Acute pyelonephritis in pregnancy

Obstet Gynecol

(2005)

Prevention of perinatal group B streptococcal disease revised guidelines from CDC, 2010

MMWR

(2010)

D.S. McKenna et al.

Maternal group B streptococcal (GBS) genital tract colonization at term in women who have asymptomatic GBS bacteriuria

Infect Dis Obstet Gynecol

(2003)

Cited by (34)

Safety and immunogenicity of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 1/2, randomised, placebo-controlled, observer-blinded, dose-escalation trial
2021, The Lancet Infectious Diseases
Group B streptococcus (GBS) is a major cause of invasive disease in young infants. Infants born to women with sufficient pre-existing anti-GBS capsular IgG antibodies are at reduced risk of GBS disease, making maternal immunisation a potential strategy for prevention. We aimed to assess the safety and immunogenicity of a novel hexavalent (serotypes Ia, Ib, II, III, IV, and V) GBS conjugate vaccine (GBS6).
This phase 1/2, placebo-controlled, observer-blinded, dose-escalation trial, was done at four clinical research centres in the USA (Kentucky, Georgia, and two sites in Utah). Healthy, non-pregnant adults aged 18–49 years were randomly assigned using an interactive, web-based response technology system. Within each dose group (low, medium, or high), participants in sentinel cohorts were randomly assigned 2:2:1 and expanded cohort participants were randomly assigned 4:4:1 to receive GBS6 with aluminium phosphate (AlPO₄), GBS6 without AlPO₄, or placebo (saline control). One 0·5 mL dose of either saline placebo or 5 μg capsular polysaccharide per serotype in the low-dose group, 10 μg capsular polysaccharide per serotype in the medium-dose group, or 20 μg capsular polysaccharide per serotype in the high-dose group was administered by intramuscular injection into the deltoid muscle on day 1. The primary outcome was safety up to 6 months after vaccination, including the proportion of sentinel cohort participants with clinical laboratory abnormalities at 1 week, the proportion of all participants reporting solicited local reactions, systemic events, or use of antipyretic or pain medication within 14 days, adverse events up to 1 month, and medically attended or serious adverse events up to 6 months. The secondary outcome was GBS immunogenicity (serotype-specific IgG geometric mean concentrations at 1 month). This study is registered with ClinicalTrials.gov, NCT03170609.
Between June 5, 2017, and June 25, 2018, 365 participants were randomly assigned and 364 (52 in each dose group) were vaccinated and included in the safety analysis. Unsolicited adverse events were reported by 15 (29%) participants in the 5 μg with AlPO₄ group, 13 (25%) in the 5 μg without AlPO₄ group, 22 (42%) in the 10 μg with AlPO₄ group, 12 (23%) in the 10 μg without AlPO₄ group, 25 (48%) in the 20 μg with AlPO₄ group, 21 (40%) in the 20 μg without AlPO₄ group, and 20 (38%) in the placebo group. The most common unsolicited adverse events were in the system organ class of infections and infestations in any dose or formulation of GBS6 (ranging from six [12%] in the 10 μg without AlPO₄ group to 15 [29%] in the 20 μg with AlPO₄ group and placebo group). Three participants reported at least one serious adverse event during the study, one each in the 5 μg GBS6 with AlPO₄ group (diabetic ketoacidosis, two events; resolved), 10 μg GBS6 with AlPO₄ group (died by suicide), and 20 μg GBS6 with AlPO₄ group (metrorrhagia; resolved). None of these serious adverse events were considered related to the vaccine. 11 of the 365 participants were excluded from the evaluable immunogenicity population, including one participant who did not receive the vaccine, and ten who at 1 month after vaccination were withdrawn for various reasons. GBS serotype-specific IgG geometric mean concentrations increased by 1 week after vaccination for all GBS6 groups, peaked at 2 weeks, stabilised by 1 month, and declined gradually but remained higher than placebo at 6 months.
GBS6 was well tolerated in healthy adults and elicited robust immune responses for all dose levels and formulations that persisted 6 months after vaccination. This study supports further evaluation of GBS6 in pregnant women.
Pfizer.
Natural acquired humoral immunity against serotype-specific group B Streptococcus rectovaginal colonization acquisition in pregnant women
2015, Clinical Microbiology and Infection
Citation Excerpt :
Vertical transmission of GBS occurs to approximately 50% of newborns of GBS-colonized pregnant women, of whom 1% to 2% develop EOD in the absence of intrapartum antibiotic prophylaxis (IAP) [3,4]. Rectovaginal GBS colonization of pregnant women has also been associated with preterm birth and stillbirth [5]. Screening for GBS rectovaginal colonization in pregnant women at 35 to 37 weeks' gestation, coupled with IAP during labor, has reduced the incidence of EOD in high-income settings [6].
Group B Streptococcus (GBS) rectovaginal colonization in pregnant women is associated with invasive GBS disease in newborns, preterm delivery and stillbirths. We studied the association of GBS serotype-specific capsular polysaccharide (CPS) antibody on new acquisition and clearance of rectovaginal GBS colonization in pregnant women from 20 weeks until 37 to 40 weeks' gestation. Serum serotype-specific CPS IgG antibody concentration was measured by multiplex enzyme-linked immunosorbent assay and opsonophagocytic activity (OPA) titres. Rectovaginal swabs were evaluated for GBS colonization, using standard culture methods and serotyping by latex agglutination, at five to six weekly intervals. Higher serotype III CPS antibody concentration was associated with lower risk of rectovaginal acquisition of serotype III during pregnancy (p 0.009). Furthermore, serotype-specific OPA titres to Ia and III were higher in women who remained free of GBS colonization throughout the study compared to those who acquired the homotypic serotype (p <0.001 for both serotypes). Serum CPS IgG values of ≥1 μg/mL for serotype V and ≥3 μg/mL for serotypes Ia and III were significantly associated with protection against rectovaginal acquisition of the homotypic serotype. A GBS vaccine that induces sufficient capsular antibody in pregnant women, including high OPA titres, could protect against rectovaginal colonization during the latter half of pregnancy.
Use of the Serum Bacterial Antigen Test for the Detection of Group B Streptococcal Neonatal Sepsis
2015, Newborn and Infant Nursing Reviews
Citation Excerpt :
As various strategies in the developed world have developed to provide more regimented evaluation, the incidence of GBS sepsis has dropped precipitously.34,45,46 However, GBS sepsis remains the leading cause of neonatal morbidity secondary to sepsis.46–48 Prophylaxis with Penicillin, Ampicillin, or other antibiotics capable of reducing GBS colonization in mom is an important consideration in this process.
The Revised Guidelines from the Centers for Disease Control for the Prevention of Perinatal Group B Streptococcal Disease were presented in the Morbidity and Mortality Weekly Report. An algorithm for evaluation of Group B Streptococcal sepsis (GBS) included CBC and differential, blood culture, possible chest x-ray, and lumbar puncture when signs of sepsis were present. The serum bacterial antigen was not mentioned in the recommendations although its clinical use for GBS evaluation has continued. We sought to determine if routine use of Group B Streptococcal Serum Antigen screening was indicated. According to hospital practice, serum bacterial antigens were drawn along with blood cultures in evaluation of sepsis for patients up to 2 months of age. Use of serum bacterial antigen testing using the BD Directigen Combo test was analyzed retrospectively over a five year period. Predictive value, sensitivity, and specificity of the analysis were studied relative to presence of a positive blood culture result. Over a five year period (2001–2005), 3336 serum bacterial antigens were performed. During that time, there were 23 positives (0.69%) for GBS. There were 3313 negatives (99%). There were 11 cases where the bacterial antigen predicted the Group B neonatal sepsis. There were 12 cases where the bacterial antigen test was positive for GBS; however, the blood cultures had no growth. In two cases, the antigen test was positive for GBS with a positive blood culture for a different bacterium: one blood culture grew Bacillus species; and the other, coagulase negative Staphylococcus. During 2005, the NICU had no positive blood cultures for GBS, and there were only two other cases hospital-wide where the bacterial antigen test predicted a positive blood culture for GBS. Although sensitivity, specificity, and negative predictive value were 99%–100%, the positive predictive value was 48% with a disease prevalence of 0.33%. Continued evaluation of Group B Streptococcal Antigen would not result in an identifiable risk reduction and is not justifiable for routine screening.
Protectome analysis: A new selective bioinformatics tool for bacterial vaccine candidate discovery
2015, Molecular and Cellular Proteomics
Citation Excerpt :
In the case of pathogens whose pathogenicity is mediated by secreted toxins, single inactivated toxins have been shown to be sufficient to prevent disease. Likewise, one antigen abundantly expressed on the bacterial surface can be sufficient to induce excellent bactericidal/opsonophagocytic antibodies; typical examples are polysaccharides constituting glycoconjugate vaccines, and fHbp of MenB (4, 30, 31). For other pathogens with a much more complex mechanism of pathogenesis, such as GAS and S. aureus, effective vaccines are expected to require cocktails of several antigens in order to neutralize different bacterial virulence factors.
New generation vaccines are in demand to include only the key antigens sufficient to confer protective immunity among the plethora of pathogen molecules. In the last decade, large-scale genomics-based technologies have emerged. Among them, the Reverse Vaccinology approach was successfully applied to the development of an innovative vaccine against Neisseria meningitidis serogroup B, now available on the market with the commercial name BEXSERO® (Novartis Vaccines). The limiting step of such approaches is the number of antigens to be tested in in vivo models. Several laboratories have been trying to refine the original approach in order to get to the identification of the relevant antigens straight from the genome. Here we report a new bioinformatics tool that moves a first step in this direction. The tool has been developed by identifying structural/functional features recurring in known bacterial protective antigens, the so called “Protectome space,” and using such “protective signatures” for protective antigen discovery. In particular, we applied this new approach to Staphylococcus aureus and Group B Streptococcus and we show that not only already known protective antigens were re-discovered, but also two new protective antigens were identified.
Serotype distribution, antimicrobial resistance, and molecular characterization of group B Streptococcus isolates from Chinese pregnant woman
2024, Journal of Maternal-Fetal and Neonatal Medicine
Prevalence and determinants of early onset neonatal sepsis at two selected public referral hospitals in the Northwest Ethiopia: a cross-sectional study
2023, BMC Pediatrics

View all citing articles on Scopus

View full text

ReviewPreventing the broad spectrum of perinatal morbidity and mortality through group B streptococcal vaccination

Abstract

Highlights

Introduction

Section snippets

Incidence and scope of maternal infection

Incidence of invasive GBS in infancy

GBS glycoconjugate vaccines

Conclusion

Acknowledgments

Vaccine

Vaccine

Obstet Gynecol

Am J Obstet Gynecol

Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Lancet

J Pediatr

J Pediatr

Arch Pediatr

Vaccine

Lancet

Lancet

Obstet Gynecol Clin N Am

Am J Obstet Gynecol

Am J Obstet Gynecol

Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005

JAMA

Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection

N Engl J Med

Quantitative determination of antibody to capsular polysaccharide in infection with type III strains of group B Streptococcus

J Clin Invest

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

J Infect Dis

Safety and immunogenicity of a bivalent group B streptococcal conjugate vaccine for serotypes II and III

J Infect Dis

Immune response of healthy women to 2 different group B streptococcal type V capsular polysaccharide–protein conjugate vaccines

J Infect Dis

Women receiving group B Streptococcus serotype III tetanus toxoid (GBS III-TT) vaccine have reduced vaginal and rectal acquisition of GBS type III

Development of a trivalent vaccine to prevent group B Streptococcus infection

Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis

N Engl J Med

Prevention of perinatal group B streptococcal disease: revised guidelines from CDC

MMWR

Bacteremia in obstetrics: clinical course

Obstet Gynecol

Pregnancy-associated group B streptococcal endocarditis: a report of two fatal cases

Obstet Gynecol

Fatal maternal beta-hemolytic group B streptococcal meningitis: a case report

Am J Perinatol

Acute pyelonephritis in pregnancy

Obstet Gynecol

Prevention of perinatal group B streptococcal disease revised guidelines from CDC, 2010

MMWR

Maternal group B streptococcal (GBS) genital tract colonization at term in women who have asymptomatic GBS bacteriuria

Infect Dis Obstet Gynecol

Review
Preventing the broad spectrum of perinatal morbidity and mortality through group B streptococcal vaccination