Bacterial Infections
Group B Streptococcus
Disease burden
Infection with group B streptococcus (GBS), also known as Streptococcus agalactiae, is one of the most important infectious causes of neonatal morbidity and mortality, causing meningitis, pneumonia and septicemia in the newborns and their mothers. Women vaginally or rectally colonized with GBS during pregnancy are at increased risk of transmitting the bacteria to their newborn infant during labor and delivery. Vaginal GBS colonization has been reported to occur in about 12%-27% of women worldwide. In the newborn, early onset of the disease presents as pneumonia and bacteremia within the first 7 days of life, and shows a case fatality rate of 4% to 29%, whereas late onset disease primarily occurs in the form of meningitis between 7 and 90 days of age, and shows a case fatality rate of 2% to 6% only. However, late onset disease often is followed by up to 30% permanent sequellae including hearing loss, retardation, and cerebral palsy. During the 1990s, the increased use of intrapartum antibiotic prophylaxis led to an 80% reduction in the incidence rate of early-onset disease [176] [177] [178] but the rate of late onset disease was little affected. An estimated 1 300 cases of late-onset GBS occur annually in the USA, most often in infants born before 37 weeks of gestation [179] . Invasive GBS disease also has been frequently reported in adults with diabetes, neurological impairment, breast cancer and cirrhosis. Its manifestations include soft tissue infections, bone and joint infections and pneumonia, or, more rarely, endocarditis and meningitis. Adults over 65 years of age are at the highest risk of death from invasive GBS disease [180] [181] [182] WLWfP_InkvMmGL [183].
Bacteriology
GBS (Streptococcus agalactiae) are aerobic Gram-positive diplococcic that can be divided into 9 serotypes (Ia, Ib, II through VIII) based on the antigenicity of their capsular polysaccharide (CP) [184] . CP serotype distribution varies with geographic areas. Some serotypes, for example CP III, seem to be associated with more severe disease, particularly neonatal sepsis. This might have to do with with the sialic acid residues incorporated into the CP primary structure. Well characterized virulence factors are involved in attachment of GBS and tissue invasion, including the capsular polysaccharide, lipotechoic acid, beta hemolysins that lyse epithelial and endothelial cells leading to tissue damage and spread of infection through host tissues, and the C protein that allows epithelial cell adherence.
Vaccines
Active immunization of mothers during the third trimester of pregnancy to elicit an antibody response and passively immunize the newborns represents an attractive strategy to protect the neonates from GBS infection
[185]
. The capsular polysaccharides (CP) from all 9 currently identified GBS serotypes were found to elicit serotype-specific protective immunity in animal models, but showed low immunogenicity if not conjugated to a protein carrier
[186]
. Conjugate vaccines were developed using a variety of protein carriers including tetanus and diphtheria toxoids, as well as a recombinant cholera toxin B subunit (CTB). Most of the resulting formulations were tested in mice
[187]
[188]
[189]
. Those few which were tested in Phase I and II clinical trials in elderly human adults and nonpregnant women
[190]
were well-tolerated and elicited a dose-dependent antibody response that correlated with in vitro opsonophagocytosis
[181]
[190]
[191]
[192]
[193]
. A type III CP-TT conjugate vaccine administered to third trimester-pregnant women was well tolerated and induced CP-specific antibodies that were efficiently transported to the infant and could be detected through 2 months of life
[194]
[195]
. A standardized, high-throughput opsonophagocytosis assay that uses differentiated human HL-60 effector cells has recently been developed to measure the functional activity of antibodies induced by conjugate CP vaccines
[196]
.
A more recent approach at developing GBS vaccines stemmed from the observation that low levels of maternal and neonatal antibodies to GBS surface proteins were associated with invasive neonatal GBS disease
[197]
. The search for GBS surface proteins allowed the discovery of many surface proteins that induced protective antibodies in animals, including the alpha and beta C proteins
[198]
[199]
, the alpha-like protein 3 (Alp3), the Rib protein
[200]
[201]
, the surface immunogenic protein (Sip)
[202]
, and the C5a peptidase
[203]
[204]
. Encapsulated C5a peptidase administered by the intranasal route induced both IgG and IgA in the vaginal tract of mice that protected both mothers and pups against GBS challenge. Purified GBS surface proteins could be used as effective carriers for conjugate CP vaccines while simultaneously inducing protective immunity against GBS. An improved Beta C protein carrier was recently developed which significantly improved the protective efficacy of a CP conjugate vaccine in mouse pups
[205]
. Microscience (USA) and Intercell (Austria) are developing vaccines based on novel surface protein candidates.
By sequence analysis of the GBS genome
[206]
, several putative surface-exposed, highly conserved proteins have also been found, including the SAP protein with pullulanase activity which induces functional cross-reactive antibodies interfering with both GAS and GBS infections
[207]
Still another approach was recently explored by Novartis in Siena which described the presence of 3 pilus variants in all GBS strains tested
[208]
[209]
[210]
. A combination of the 3 pilus components provided protection in animal models against all GBS challenge strains that were tested, paving the way for the development of a pilus-based vaccine
[211].
A major difficulty in developing Group B streptococcal vaccines is the existence of a multiplicity of serotypes with different geographical distributions
[183]
. A vaccine suitable for Asian or European populations may not be suitable for African populations. Another difficulty, similar to that encountered with Group A streptococcal vaccines, is the implementation of efficacy trials. A Phase III evaluation of candidate vaccines in women before pregnancy will require large sample sizes and take a long time. Administration of the vaccine to pregnant women may be difficult because of fear of risks of birth defects and subsequent liability.