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Immunogenic Proteins of Group B Streptococcus
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This entry is adapted from the peer-reviewed paper 10.3390/pathogens11010043

Streptococcus agalactiae (Group B Streptococcus, GBS) is an opportunistic pathogen, which asymptomatically colonizes the gastrointestinal and genitourinary tract of up to one third of healthy adults. Nevertheless, GBS carriage in pregnant women may lead to several health issues in newborns causing life threatening infection, such as sepsis, pneumonia or meningitis. Recommended GBS screening in pregnant women significantly reduced morbidity and mortality in infants. Nevertheless, intrapartum antibiotic prophylaxis, recommended following the detection of carriage or in case of lack of a carriage test result for pregnant women who demonstrate certain risk factors, led to the expansion of the adverse phenomenon of bacterial resistance to antibiotics.

Streptococcus agalactiae Group B Streptococcus immunogenic proteins immunodiagnostics proteomics newborn infections GBS carriage biomarkers innovative immunoassays

1. Introduction

Streptococcus agalactiae (Group B Streptococcus, GBS) is a β-hemolytic, Gram-positive bacterium, which colonizes the gastrointestinal and genitourinary tract of up to 30% of healthy adults [1]. Each year, over 21 million pregnant women worldwide are colonized with GBS, which includes approximately 18% of pregnancies [2]. This opportunistic pathogen can cause a life-threatening infection in newborns, which most often takes the form of sepsis, pneumonia and meningitis, and the first two are more common for early onset GBS disease (EOD, EOGBSD). EOD appears in the first week of life, however, the vast majority of cases concerns the first 24 h and it is a consequence of an infection acquired during natural childbirth from a GBS-colonized mother [1]. In the early 1970s, mortality in this group was very high, and even reached 55% in newborns diagnosed with GBS infection [3].
In response to this threat, in the 1990s, the American College of Obstetricians and Gynecologists (ACOG) and Centers for Disease Control and Prevention (CDC) developed guidelines to minimize this dangerous phenomenon, which led to a reduction in morbidity in newborns of over 80%, and presently the incidence of the disease caused by GBS reaches 0.23/1000 live births [4][5][6]. It included screening recommendations for women between the 36th (36-0/7) and 37th (37-0/7) week of pregnancy, by taking swabs from the vaginal introitus and the anal sphincter, followed by microbial cultivation on the appropriate growth medium [4]. This method is not flawless due to its time-consuming nature, as the waiting time for the results is up to 7 days. The results themselves can also be ambiguous due to the often-difficult differentiation of GBS from other beta streptococci using phenotypic methods. It is a severe limitation especially in the case of advanced preterm labor, before the 36th week of pregnancy, i.e., prior to the recommended carrier screening test. Therefore, as an alternative for cultivation methods, in the latest CDC guidelines, mass spectrometry MALDI is also recommended for GBS detection. The main advantage of this method is a reduction in the waiting time for results as well as the possibility to distinguish Streptococcus agalactiae from other streptococci: S. halichoeri or S. pseudoporcinus, whose pathogenic role in newborn infection is not known [4]. When a positive result from a pregnant woman is obtained and GBS is detected in the studied specimen, introducing intrapartum antibiotic prophylaxis (IAP) is recommended. This procedure significantly reduced the morbidity in the case of early onset disease, however, IAP has not reduced the incidence of late onset disease, which may appear between the 7th and 90th day of life [7]. Additionally, the side effect of the comprehensive use of antibiotics is that is leads to the expansion of the adverse phenomenon of bacterial resistance to antibiotic therapy [4]. Moreover, this solution led to an increase in the rate of infections caused by Gram-negative bacteria [8]. As an answer to the limitations mentioned above and the unfavorable phenomena, scientists conduct extensive research to find alternative methods for GBS carriage detection in pregnant women. Novel diagnostic techniques should, among others, provide rapid and unambiguous results. An immunodiagnostic assay (i.e., ELISA) based on highly immunogenic and specific bacterial proteins (antigens) for detection of anti-GBS antibodies is being considered as a good candidate for innovative GBS carriage diagnostics.

2. Alpha-like Protein

The best-known group of GBS proteins is the Alpha-like protein family (Alp), which include the following members: αC, Alp 1 (epsilon), Alp 2, Alp 3, Alp 4, and Rib. Alp proteins are conservative, chimeric and form mosaic structures on the GBS surface [9]. These surface-anchored proteins play an important role in Streptococcus agalactiae virulence, by supporting bacterial cell adherence to infected cells of the host (Figure 1). For example, αC protein mediates GBS invasion of cervical epithelial cells by interaction with glycosaminoglycan [10].
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Figure 1. Scheme of the distribution of immunogenic proteins within the Streptococcus agalactiae (GBS) cell. Legend: αC, Rib, R28 (Alp3)—surface proteins belonging to Alp-like family, BibA—Group B streptococcus immunogenic bacterial adhesin, EF Tu—elongation factor thermo unstable, FsbA—fibrinogen-binding protein, IMPDH—inosine 5′-monophosphate dehydrogenase, Lmb—laminin binding protein, ScpB—streptococcal peptidase C5a, Siglec-14—sialic acid-binding immunoglobulin-like lectin, Sip—surface immunogenic protein. The diagram is not true to scale, the individual elements have a schematic dimension.
Alp proteins consist of a major signal peptide domain, a N-terminus region, comprising 170–180 amino acids, repeat area with numerous tandem repeats (8–10) of approximately 80 amino acids each, and a C-terminus region built from 40–50 amino acids. Their molecular masses may vary among particular GBS strains, for example α mass can range from 65 kDa to 165 kDa, and it can be explained by the differences in the number of repeats [11][12]. Amino acid sequences consisting of Alp family members are very likely, which may induce cross-reactivity among the individual proteins in the family.
Alp proteins are also described as immunogenic proteins [9]. In the context of immunogenicity, the best-known proteins are αC and Rib proteins. The immunogenicity of αC was described as the first immunogenic GBS protein. It was described for the first time in the 1980s on mouse model, when it was shown that purified αC protein isolated from S. agalactiae cell induced immunogenic response and protected mice against infection caused by these bacteria [13]. Afterward, this observation was confirmed in other studies [14][15][16][17]. This protein, together with β protein, form the so-called C antigen, which was detected in serum against the whole bacterial cell [18][19]. It participates in GBS pathogenesis, what was examined in the mouse model. It was demonstrated that the deletion of bca gene, which encodes αC protein, led to a reduction in bacterial virulence [16].
Another well-described immunogenic Alp-like protein is Rib, which demonstrates likeliness to αC, which was demonstrated by the analysis of the N-end amino acid sequence. Surprisingly, no cross-reactivity between these proteins was noticed, even though the nucleotide sequences are identical [20][21]. The Rib protein has been studied as a component of anti-GBS vaccine as the first Group B Streptococcus protein. The results received for a prototype recombinant Alpha-like protein subunit vaccine (GBS-NN), combined with α are promising. In a randomized placebo-controlled double-blind Phase 1 trial in healthy adult women, the safety and immunogenicity of GBS-NN vaccine was proved [22]. This also indicates potential usability of these proteins as biomarkers in immunodiagnostic detection of GBS carriage and infections caused by this pathogen.
The Alp3 protein, which can be also found under the name R28 in the literature, was first described for Streptococcus pyogenes (Group A Streptococcus) and its molecular likeliness to other Alp proteins was showed [23]. Analysis of the amino acid sequences of the R28 protein showed an identity of 98% between S. pyogenes and S. agalactiae species [24]. The Alp3 protein is considered to be a chimera of three S. agalactiae proteins: α, β and Rib [25].
As it was described above, immunoreactivity of the Alp-like proteins had been proved. Additionally, their conservation allows to consider them as good candidates for markers in GBS immunodetection. Nevertheless, the distribution of individual Alp proteins within the species could be a limiting factor as long as only one Alp protein is present in a single GBS strain [26]. Therefore, constructing an immunoassay based on a single Alp protein can be insufficient and use of all Alp proteins should be considered.

3. β Protein

β protein (approx. 130 kDa), also called Bac, had been previously described as a component, together with αC, of antigen C, belonging to the Alp-like family. Although both proteins are encoded by genes located nearby on the chromosomes, they do not demonstrate a close relationship [12][14][27]. However, β indicates homology to the Alp3 protein, and it consists of 1159 residues [25][28]. The distinguishing feature of this protein, compared to most of the surface proteins representative of Gram-positive cocci, is lack of long repetitive tandem sequences [29]. Although the virulent nature of this protein has not been fully described yet, it is hypothesized that, due to its ability to bind to elements of the human immune system (Figure 1, Table 1), it may also be associated with virulence [30]. In addition, the β protein has an affinity for two components of the human immune system: the Fc fragment of IgA antibodies and the H factor, which regulate the alternative pathway of complement activation, so that its action is directed against the infecting pathogen, not human cells or tissues. This fact may suggest an important role of this protein in induction of immunity [12]. It was also showed that β protein binds to sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5), which is an inhibitory receptor for phagocytosis, and therefore attenuates innate immune responses in the infected organism, and promotes bacterial survival [31]. Moreover, GBS β protein binds to Siglec-14 on neutrophils, and this engagement counteracts the host immune suppression induced by pathogen by activation of p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways. It is also worth to underline that Siglec-5 and Siglec-14 expression has been present in amniotic epithelium, which is the place of the initial contact of S. agalactiae with the fetus [32].
Table 1. Summary of chosen GBS immunoreactive proteins—potential biomarkers in immunodiagnostic assays for detection of GBS carriage/infection and components of a vaccine against Streptococcus agalactiae infections.
Table
Proteins’ Name Molecular Mass Function/Characteristic Immunoreactivity Localization in Cell
Alpha-like proteins:
-αC,
-Alp 1 (epsilon)
-Alp 2
-Alp 3 (R28),
-Alp 4,
-Rib		 65 kDa–165 kDa
  • Facilitation of GBS adherence to epithelial cell by interaction with glycosaminoglycan
  • Participation in pathogenesis
  • First described immunogenic GBS protein—in mouse model (αC) in 1980
  • Component of the so-called C antigen (αC)
  • Component of prototype of anti-GBS vaccine (GBS-NN) – 1 phase of clinical trials (αC, Rib)
 Surface anchored
β-protein (Bac) 130 kDa
  • Ability to bind to elements of the human immune system, may indicate its virulence
  • Attenuates innate immune responses, and thus promotes bacterial survival by binding to sialic acid-binding immuno-globulin-like lectin 5 (Siglec-5)
  • Counteracts the host immune suppression by binding to Siglec-14 on neutrophils
  • Component of the so-called C antigen
  • Immunization of pregnant mouse with β-protein protected infants from GBS infection
  • Proven ability of IgG anti-β to pass through the placenta
  • Proven growth of IgG and IgM in pregnant women after exposure to GBS β protein
 Cell surface
Laminin binding protein (Lmb, LmbP) 43 kDa
  • Involved in colonization of the host and invasion through damaged epithelial cells
  • Immunogenicity of Lmb was shown for GAS, thus its immunoreactivity for GBS is hypothesized
 Cell surface
Surface immunogenic protein (Sip) 53 kDa
  • Unknown
  • Identified following immunological screening of a genomic library
  • Proved mouse protection against GBS infection representing 6 serotypes
  • Proved tilapia protection against GBS by oral vaccination
  • Proved mouse protection against GBS by oral vaccination
  • 75.6% sensitivity of indirect ELISA for bovine mastitis diagnostic
  • Component of fusion protein in the indirect ELISA assay for detection of bovine mastitis
  • Studied in the context of monoclonal antibody generation to develop immunochromatographic test kit for GBS detection in pregnant women
  • Promising biomarker in a rapid immunochromatographic test for GBS detection in pregnant women
 Cell surface
Group B Streptococcus immunogenic bacterial adhesin (BibA) 80 kDa
  • Demonstrates antiphagocytic properties
  • Mediates GBS adherence to both human cervical and lung epithelial cell
  • Multifactorial GBS virulence factor
  • Binds to C-4 binding protein in humans
  • Mice immunization with a recombinant BibA protein (GBS-V BibA) protected from vaginal colonization with GBS
  • Promising biomarker in indirect ELISA for GBS carriers/infection diagnosis
  • Promising biomarker in Luminex multiplex immunoassay for GBS detection
 Cell surface
Fibrinogen-binding protein (FsbA) ap. 26 kDa
  • Promotes GBS attachment to fibrinogen
  • Activates the innate immune responses in the host and relevant antibody responses
  • Proved protection of mice infants against GBS by pregnant mother immunization
  • Proved protection by bacterial opsonophagocytosis or neutralization of FbsA-mediated Fng binding by administration of serum with anti-FsbA antibodies
  • Proved tilapia protection after immunization
 Cell surface
Streptococcal peptidase C5a (ScpB) 126 kDa
  • Responsible for inactivation of one of the components of the human complement
  • Responsible for disrupting neutrophil recruitment
  • Demonstrates the ability to bind fibrinogen, thus promotes bacterial adhesion to epithelial and endothelial cells
  • Nasal immunization of mice with purified ScpB protein demonstrated higher bacterial clearance from the lungs
  • Proved opsonizing activity with mouse macrophages and human whole blood in experiments on hyperimmune rabbit serum
  • It has been hypothesized that antibodies directed against ScpB antigen may protect from infection by disrupting fibrinogen binding
  • Proved usability of ScpB in ELISA
 Cell surface
Enolase 47 kDa
  • Catalyzes the penultimate stage of glycolysis, which is the de-hydration reaction of 2-phosphoglycerate to phosphoenolpyruvate
  • Plays an important role in the pathogenesis by binding plasminogen on the surface of the host cell
  • Anti-enolase antibodies can be detected in certain autoimmune diseases
  • Enolase epitopes considered as potential biomarkers in immunodiagnostic assay
 Cell wall
Elongation factor thermo unstable (EF Tu) 44 kDa
  • Plays an important role in the pathogenesis by promoting adhesion, invasion, and modulation of the host immune system through stimulation of humoral immune response
  • Involved in the elongation phase of protein synthesis as well as in the translation process in prokaryotic cells
  • Ensures a catalysis reaction
  • Plays an important role in shuttling aminoacylated tRNAs to the ribosome during protein translation
  • Interacts with several molecules, such as CD21, factor H, fibrinogen, fibronectin, laminin, nucleolin, tachykinin, plasminogen and several complement factors
  • Anti-EF Tu antibodies are being detected after infection caused by several pathogen species
  • Vaccine against GBS based on EF Tu is being studied for tilapia
  • Mouse vaccination with rEF Tu of S. pneumoniae led to increased numbers of cytokine, IgG1 and IgG2a, and CD4+ T-cell
  • Epitopes of GBS EF Tu are being investigated as potential biomarkers in ELISA assay for carrier/infection diagnosis
 Part of membrane cytoskeleton, cell surface
Inosine 5′-monophosphate dehydrogenase (IMPDH) 53 kDa
  • By participation in catalysis of the key stage of de novo synthesis of the guanine and adenine nucleotide considered as crucial precursor for DNA and RNA synthesis
  • Catalyzes conversion of IMP to XMP
  • Involved in glycoprotein synthesis, energy transfer, signal transduction in cells, and NAD-dependent catalysis
  • Potential target in antiviral, antibacterial and anticancer therapies
  • Considered as a part of autoimmunological disease treatment
  • Proved immunoreactivity of IMPDH epitopes in the presence of human umbilical cord blood
 Intracellular
GroEL 57 kDa
  • Structurally and functionally closely related to the human heat shock protein (Hsp60)
  • Plays a key role in folding de novo emerging proteins (recognizing, binding, and releasing other proteins)
  • Participates in folding of a wide range of proteins, with special emphasis on these, which are typically large (>20 kDa), slow folding, and prone to aggregation
  • Known as a virulence factor and it participates in pathogenesis, however mechanism is unknown
  • GroEL may promote infection by replication and persistence followed by adhesion, invasion, evasion of host immune responses, and modification of host cell responses
  • GroEL can be considered as potential plant protection products
  • Promising results of vaccination of pregnant mice against several bacterial species
  • Promising results of anti-GBS vaccines administrated to tilapia
  • Proved immunoreactivity of GroEL epitopes in the presence of human umbilical cord blood and vascular blood
 Cytosol, cell surface, secretome
In the experiment based on active immunization with β protein of pregnant mice, it was shown that offspring did not develop infection after contact with GBS strains containing the β protein [33]. In addition, it has been shown that IgG anti-β antibodies can cross the placenta, which may indicate the possibility of mother-to-child transmission of immunity, and thus offer protection against GBS infection [34]. Immunogenicity in the presence of IgM and IgG class antibodies was studied by natural exposure of pregnant women to β protein. Geometric mean concentration of anti-β C protein IgM and IgG antibodies was measured in an enzyme-linked immunosorbent assay (ELISA). The research was carried out on 16 pregnant women colonized with GBS, and 48 uncolonized match-age pregnant women, who constituted the control group. In the study group, 3 out of 16 women demonstrated a significant growth in IgM and IgG antibodies; therefore, it had been concluded that GBS invasion, but not colonization, induces an increase in antibody titer [35]. In summary, with no doubt, immunogenicity of β protein had been shown, however, due to insignificant growth of the antibody concentration in carriers, usability of this protein as a marker in immunoassay could be limited to detection of GBS infection but not carriage.

4. Lmb Protein

Laminin binding protein (Lmb, LmbP) belongs to lipoproteins by its molecular weight of 43 kDa and it is exposed on the cell surface of most Streptococcus agalactiae strains (Figure 1, Table 1). The Lmb protein, consisting of 306 amino acids, shows homology to the members of the Lra1 protein family, which are known for their role in adhesion and metal transportation in Gram-positive bacteria. Lmb is involved in colonization of the host and invasion through damaged epithelial cells [36][37]. Even though the Lmb name was limited to Streptococcus agalactiae species, an almost identical protein of Streptococcus pyogenes has been referred to as Lsp or Lbp [38][39]. For both species, the gene encoding this protein is located above the C5a-peptidase encoding gene and nucleotide sequence identity between these two species is >98% in this region. Nevertheless, contiguous sequences in the two genomes show no homology, which may indicate that the region was horizontally transferred [38][40]. The immunogenic character of Lmb had been studied for Streptococcus pyogenes (GAS), which causes various diseases ranging from pharyngitis to severe infections such as a toxic shock-like syndrome and necrotizing fasciitis, and at some points, is phylogenetically similar to Streptococcus agalactiae [41][42]. A recombinant Lmb GAS protein (rGAS-Lmb) had been studied in the presence of serum from patients with rheumatic fever and individuals with uncomplicated streptococcal infections. Antibody response for the study and control groups was examined by ELISA assay, and the differences observed in reactivity were significant, whereas no difference between infection types was noticed [43]. No data for Lmb immunoreactivity for the studied group of pregnant women colonized by Streptococcus agalactiae is available, however it can be assumed that, according to its confirmed immunoreactivity for Streptococcus pyogenes, it may also be considered as a potential candidate for GBS detection.

5. Sip Protein

Sip protein (surface immunogenic protein) with weight of 53 kDa was, in opposition to other previously described surface proteins, identified following immunological screening of a genomic library. Sip is present in all GBS strains, regardless of the serotype represented (Figure 1, Table 1). Analysis of the nucleotide sequences for the studied strains confirmed their 98% identity of the sip gene, which encodes the Sip protein. It indicates the conservation of this 434 amino acid protein. Moreover, Sip is also described as an immunogenic protein. Immunization in mice with the recombinant Sip protein demonstrated efficient protection against severe consequences of GBS infection caused by strains representing six serotypes (Ia, Ib, II, III, V, and VI) [44]. Immunogenicity of the Sip protein was also studied in the context of the oral vaccine administrated to tilapia, a fish species in which infection caused by Streptococcus agalactiae is common and leads to huge financial losses in fishery. The immunizing protein against Streptococcus agalactiae was expressed in Bacillus subtilis spores. It was shown that immunization indicated an effective immune response and provided protection against GBS infection [45][46]. Another promising result was obtained for the investigation of a decrease in the S. agalactiae colonization in a mouse model following oral administration of the vaccine based on Sip protein [47]. This may suggest that Sip protein induces cross-protective immunity against GBS infections, therefore, it can be considered as a potential vaccine candidate; on the other hand, its conservation qualifies the Sip protein as a potential candidate for immunodiagnostic assay. Research on an immunodiagnostic assay based on Sip protein as a detection antigen has already been carried out. Nevertheless, selectivity examined in an indirect ELISA assay for bovine mastitis detection reached 75.6% (for 45 studied serum antibodies isolated from cows, 35 were positive, whereas control examination performed by PCR gave 100% positive results) [48]. Immunoreactivity of the Sip protein was also studied as an element of fusion protein combined with two other membrane surface-associated GBS proteins, which were fibronectin (FbsA) and phosphoglycerate kinase (Pgk) in the indirect ELISA assay for detection of bovine mastitis. The obtained results indicated relatively higher sensitivity in comparison with mono-antigen fusion protein Sip [49]. Immunogenicity of the Sip protein, according to its conservation, was also investigated in the context of usage for monoclonal antibody generation to develop immunochromatographic test kit for GBS detection in pregnant women [50]. Another study was focused on examination of Sip protein as a biomarker in a rapid immunochromatographic test for detection of Group B streptococcus colonization in vaginal and/or rectal tracts in pregnant women during the 35th–37th weeks of pregnancy. The obtained results were very promising, and the developed test was characterized by high specificity, with selectivity reaching respectively 93.1% and 100% [51]. Therefore, we conclude that the Sip protein can be doubtlessly considered as a GBS detection antigen.

6. BibA Protein

BibA protein (Group B Streptococcus immunogenic bacterial adhesin) is an immunogenic bacterial adhesin, exhibiting molecular weight of approx. 80 kDa, which demonstrates antiphagocytic properties. BibA mediates GBS adherence to both human cervical and lung epithelial cells (Figure 1, Table 1). The protein consists of the N-end α-helix rich domain, proline-rich region, LPXTG cell-wall anchoring motif, and is composed of 594 amino acids. Due to its N-terminal helical domain, which consists of three antiparallel α-helical-bundle motifs, it is considered as unique, and thus is qualified to a new class of Gram-positive surface adhesins [52]. This protein is identified on the surface of S. agalactiae strains, but interestingly, it is also present in GBS culture supernatants [53][54]. Four allelic variants (I, II, III, IV) of this protein correlated with serotypes had been described, and what is worth underlining, variant IV, which demonstrated high likeliness to the bovine counterparts, was exclusively associated with the highly virulent ST-17 GBS strain. Therefore, BibA is considered as a multifactorial GBS virulence factor [7][55][56]. BibA expression is modulated by the CovS/CovR 2-component regulatory system, and it specifically binds to C-4 binding protein in humans, which is a regulator of the classical complement pathway. It has been demonstrated that deletion of bibA gene resulted in reduced capacity of GBS to survive in human blood as well as decreased ability to resist opsonophagocytic killing by human neutrophils. Additionally, BibA expression led to an increase in the GBS virulence in a mouse model [53][54]. While mice immunization with a recombinant BibA protein (GBS-V BibA) conferred immunity and protected them from vaginal colonization by S. agalactiae, and eventually led to decrease in mortality. Antibody response after immunization was examined in ELISA assay in which plates were coated with BibA protein. This indirect use indicates the usability of BibA protein as detection antigen in ELISA for GBS carriage and/or infection diagnosis [57]. A similar conclusion can be drawn from the research whose aim was to examine the association between antibodies against Streptococcus agalactiae surface proteins and recto-vaginal colonization during pregnancy, in which titers of IgG antibodies were measured in Luminex multiplex immunoassay [58].

2.6. FsbA Protein

Fibrinogen-binding protein (FsbA), approx. 26 kDa, is one of the virulence factors of Streptococcus agalactiae, and its role is the attachment to fibrinogen, which leads to fibrinogen-dependent aggregation of platelets (Figure 1, Table 1). It was demonstrated that GBS mutants lacking fsbA gene lost the aggregation ability. Furthermore, application of monoclonal anti-FsbA antibodies impeded bacterial binding to fibrinogen as well as platelet aggregation caused by Streptococcus agalactiae [59][60][61]. FsbA is composed of 16 amino acid repetitive units. It has been demonstrated that human fibrinogen was bound by the repetitive protein region, and even a single repeat had the ability attach to fibrinogen [60]. FsbA protein consists of C-terminus cell wall anchoring motif (LPKTG), which indicates that this protein is covalently attached to the cell wall. The second GBS fibrinogen binding protein is FsbA’s analogue—FsbB, even though these proteins do not reveal significant likeliness to each other. The feature distinguishing FsbA from other fibrinogen binding proteins, representative to other bacterial species, is the LPKTG motif [62]. As long as FsbA protein structure is well described, its function is barely known, except its immunogenic role. It was shown that maternal immunization of mice with 6pGST, a protein fragment which consists of five repeats, significantly protected the offspring against lethal infection caused by Streptococcus agalactiae. It was demonstrated that the protective role of the antibodies can be obtained by administration of anti-6pGST serum from adult animals. The introduction of serum with antibodies led to protection by bacterial opsonophagocytosis or resulted in neutralization of FbsA-mediated Fng binding. Two-track action had also been noticed [63]. Other studies showed RPS (relative percentage survival) value after tilapia vaccination consisting of GBS FsbA protein reached 40.63% [64]. It allows to define FsbA as a multifunctional immunogenic protein, including immunoprotection as well as activation of the innate immune responses in the host and relevant antibody responses [65].

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