Progress toward a group B streptococcal vaccine

Abstract

Streptococcus agalactiae (group B Streptococcus, GBS) is a leading cause of severe invasive disease in neonate, elderly, and immunocompromised patients worldwide. Despite recent advances in the diagnosis and intrapartum antibiotic prophylaxis (IAP) of GBS infections, it remains one of the most common causes of neonatal morbidity and mortality, causing serious infections. Furthermore, recent studies reported an increasing number of GBS infections in pregnant women and elderly. Although IAP is effective, it has several limitations, including increasing antimicrobial resistance and late GBS infection after negative antenatal screening. Maternal immunization is the most promising and effective countermeasure against GBS infection in neonates. However, no vaccine is available to date, but two types of vaccines, protein subunit and capsular polysaccharide conjugate vaccines, were investigated in clinical trials. Here, we provide an overview of the GBS vaccine development status and recent advances in the development of immunoassays to evaluate the GBS vaccine clinical efficacy.

Keywords: Streptococcus agalactiae; group B Streptococcus; maternal immunization; vaccine.

Figure 1.

Genetic organization of the cps locus in Streptococcus agalactiae. (A) Comparative cps gene organization in nine serotypes: Ia (AB028896.2), Ib (AAJS01000021.1), II (ALQD01000015.1), III (AF163833.1), IV (AF355776.1), V (AF349539.1), VI (AF337958.1), VII (LT671990.1), VIII (ALST01000010.1), and IX (LT671992.1). Gene designations are indicated on each arrow. Similarity between the genes is indicated by the same or similar colors. Gene names are the same as those used in a previous study,⁴⁵ except for cpsP, cpsS, and cpsQ. (B) Predicted CPS functions based on the results of previous studies and sequence comparisons.

Figure 2.

Biochemical capsular polysaccharide (CPS) structure of Streptococcus agalactiae. Association of the encoded sugar transferases and polymerases (cpsH) with each corresponding CPS structure. Links between two sugars are represented as black lines (β1→4), red lines (β1→4), blue lines (β1→6), and green lines (α2→3).

Figure 3.

Representative Wzx/Wzy-dependent capsular polysaccharide (CPS) biosynthesis pathway in the group B streptococcal serotype III. (A) Serotype III cps gene organization and putative functions of the gene products.³⁷ (B) Biochemical steps during the CPS synthesis. Galactose-1-phosphate is initially transferred to an undecaprenyl-phosphate by CpsE and the repeat unit is rapidly assembled by glycosyltransferases. Individual repeat units are translocated across the cytoplasmic membrane by flippase (cpsL) and linked to form lipid-linked CPS by polymerase (cpsH).

Figure 4.

Schematic representation of the group B streptococcal surface proteins. (A) Alp protein family. Signal peptide (S), conserved domain (CD), repeating domain (R), LPxTG cell-wall anchoring domain (green). (B) BetaC protein, containing IgA binding domain (blue) and factor H binding domain (brown). (C) Serine-rich repeat protein family. Ig-like domain (N1, N2, and N3), serine-rich repeat glycosylation domain (SRR1 and SRR2). (D) C5a peptidase. Protease activity domain (Protease), protease-associated domain (PA), fibronectin type III domain (Fn1, Fn2, Fn3). (E) Pilin proteins. Ig-like domain (D1-D3), pilin sorting motif (IPNTG, FPKTG, IPKTG), and a membrane-spanning hydrophobic domain (M).