A vaccine against Group B Streptococcus: recent advances
Group B streptococcus (GBS) causes a high burden of neonatal and infant disease globally. Obtaining a vaccine for pregnant women is the most promising strategy to prevent neonatal and infant GBS disease, endorsed by the World Health Organisation. GBS conjugate vaccines are at advanced stages of development but a large number of participants would be required to undertake phase III clinical efficacy trials. Therefore, efforts are currently focused on establishing serocorrelates of protection in natural immunity studies as an alternative pathway to get licensure of a GBS vaccine, followed by a phase IV study to evaluate its effectiveness. Protein vaccines are in earlier stages of development, but are highly promising as they would confer protection irrespective of serotype. Further epidemiological, immunological and economic studies are also required for vaccine development to reach the target population as soon as possible.
Group B streptococcus (GBS) is a leading cause of neonatal and infant sepsis and meningitis globally. GBS can also cause disease in pregnant women, immunocompromised adults and the elderly but the highest incidence of disease is in the first group.
A systematic review and meta-analysis conducted in 2017 estimated a global incidence of invasive infant GBS disease of 0.49 (95%Cl 0.43-0.56) per 1000 live births (1). In 2015, GBS was estimated to have caused 319,000 cases of invasive neonatal GBS disease globally, resulting in 90,000 deaths (2). However, the fulminating evolution of most cases during the first hours of life and the technical difficulties in getting the etiological diagnosis in many low- and middle-income settings might lead to a significant underestimation of the true burden of GBS disease. Epidemiological data, especially from many African and Asian countries, where most infant deaths occur, is required to inform about regional variation and possible preventive strategies (3).
Intrapartum Antibiotic Prophylaxis (IAP) have reduced the incidence of early onset disease (EOD, ocurring from day 0 to 6) in many countries using these strategies, especially those that screen all pregnant women for GBS rectovaginal colonisation. However, IAP has no impact on late onset disease (LOD, occurring from day 7 to 90) as well as a limited impact on pregnant women (4) (5). IAP strategies might also be an issue considering the international efforts to control antimicrobial resistance. Furthermore, the use of antibiotics and their effect on the infant gut flora has been associated to increased rates of allergy, asthma and obesity (6).
Novel features of a maternal vaccine for GBS
A suitable vaccine against GBS given to pregnant women could provide an effective solution to this problem, as a vaccine would be more easily accessible than GBS culture and IAP to all settings and would avoid the need for antimicrobial administration.
Maternal immunisation is already a successful tool to prevent tetanus (7), influenza (8) and pertussis (9) in neonates and infants. The transplacental transfer of maternal antibodies from mother to child reduces the window of vulnerability that infants suffer during the first months of life for developing infections (10). Therefore, the same rationale has been used to investigate new vaccines against common neonatal infections, such as respiratory syncytial virus (RSV) and GBS. The particularity of these new vaccines is that they are specifically designed for pregnant women, unlike the first vaccines used for the same purpose described above.
Vaccine development: overview of current efforts
In April 2016, the World Health Organisation (WHO) Initiative for Vaccine Research identified the development of GBS vaccines for maternal immunisation as a priority, based on an unmet global health need to help reduce neonatal and infant mortality worldwide (11). Recent estimates suggest that an effective GBS maternal vaccine (>80% efficacy), with high (90%) global coverage, could prevent 231,000 infant and maternal GBS cases, 41,000 stillbirths and 66,000 infant deaths annually (2).
Evidence suggests that maternal immunisation with protein-conjugated GBS capsular polysaccharides may reduce the disease risk in neonates and young infants in a serotype-specific manner. Protein-based vaccine candidates aiming to provide protection across the serotype spectrum are also under evaluation (12).
Capsular polysaccharide conjugate vaccines
A number of virulence factors that are expressed by GBS, are usually involved in its colonisation, adherence, invasion and immune evasion (13–15) and these could be used as potential vaccine candidates. One of the most well-studied virulence factors of GBS is its unique sialic acid-rich capsular polysaccharide (CPS) which inhibits complement deposition and protects the bacteria from opsonophagocytosis by immune cells, thus contributing to the evasion of host immune defense mechanisms (16–18). The latter also enhances biofilm formation, inhibits the binding of antimicrobial peptides and neutrophil extracellular traps (NET) as well as disturbs bacterial adherence to the epithelium and mucus, thus increasing GBS invasiveness (19–21).
GBS expresses at least 10 types of CPS (Ia, Ib, II-IX) that are structurally and antigenically different (22). Various arranged monosaccharides and a sialic acid residue on the branching terminus of the repeating unit make up the CPS. According to recent systemic meta-analyses, 97% of invasive isolates in all geographical regions are due to five of the most common serotypes of GBS (Ia, Ib, II, III and V) (1). Furthermore, serotype IV is emerging and increasing the burden of invasive disease, especially in non-pregnant adults, with the potential to become an important cause of neonatal disease, as some cases have already been reported in this group in different countries (23) (24) (25) (26).
As polysaccharides are T-cell independent antigens, the antigenic polysaccharide is conjugated to a protein carrier in order to trigger a protective memory response. The earlier vaccines were conjugated to a tetanus toxin, that nowadays might be useful in low- and middle-income countries (LMIC), where neonatal tetanus is still a concern. However, the main carrier protein currently used is CRM197, a nontoxic mutant of diphtheria toxin. Studies using both carrier proteins demonstrated better immunogenicity with high levels of protective antibodies with CPS-conjugates compared to unconjugated vaccines (27) (28).
The first clinical trials were conducted with monovalent vaccines (Ia, Ib, II, III and V) (28) (29) (27) (30) (31). However, single serotypes do not produce cross-reactive immunity against other serotypes, thus multivalent vaccines began to develop. Phase I/II clinical trials (NCT01193920) of a trivalent (Ia, Ib and III) CRM197 conjugate vaccine in infants born to women who had received the vaccine portrayed higher levels of CPS-specific antibodies in the infants at birth demonstrating a good immunogenicity as well as safety (32). A clinical trial (NCT03170609) of a GBS polysaccharide conjugate vaccine targeting serotypes Ia, Ib, II, III and V commenced in 2017 and has now reached I/II phases with promising results. More recently, in view of the increase of disease caused by serotype IV, this was added in an hexavalent vaccine (Ia, Ib, II, III, IV, and V) with the aim to cover at least 98% of GBS isolates causing neonatal invasive disease (33). In order to verify the clinical safety and immunogenicity of this hexavalent vaccine, further clinical trials will be required.
It has been shown that opsonophagocytosis is the main mechanism for the host to clear GBS infection (34). A recent phase II study (NCT01446289) demonstrated that maternal antibodies of pregnant women vaccinated with a trivalent vaccine composed of CPS Ia, Ib and III have an effect on opsono-phagocytic killing (OPK) titers against each GBS serotype. Cord sera, which was also tested and analysed, also revealed a strong positive correlation between IgG concentrations and OPK titers, which is predictive of functional activity against GBS infection (35).
The role of anti-capsular antibodies in preventing GBS maternal colonisation, as well as ascending infection and neonatal transmission was recently evaluated in an animal model study (36). Results show that systemic immunisation with a type III glycoconjugate vaccine produces high levels of IgG that can reduce vaginal acquisition of serotype III during pregnancy. Further studies will be needed to confirm the same results in pregnant women.
Few studies have evaluated the number of doses that will be required per pregnancy and for full coverage. No increase on antibody levels was shown after a second dose of a trivalent GBS vaccine administered in a month time (37)(38). A recent study published in 2019 (NCT02690181), has evaluated safety and immunogenicity of a second dose of a trivalent (Ia, Ib and III) CRM197 conjugate vaccine in non-pregnant women over a long period of time (4 to 6 years) after the administration of the first dose. Antibody levels from previously GBS-vaccinated women increased ≥200-fold after a second dose. Women presenting with undetectable antibody levels also experienced an increase of anti-GBS concentrations after a second dose (39). These results suggest that further doses might be required in subsequent pregnancies.
Serocorrelates of protection
Although several vaccine candidates are undergoing clinical and preclinical trials, in order to develop an effective vaccine for GBS, phase III clinical trials must be not only achieved but they must also be very large in order to demonstrate efficacy in countries able to conduct such trials (40). As there is a good correlation between immune response and clinical protection, it has been suggested that approval of GBS vaccine could be based on antibody correlated with protection from infection using an immunogenicity assay (41–43). A systematic review undertaken in 2019 synthetised the scientific evidence to define a serocorrelate of protection against GBS disease supported by studies based on natural infection (44). This review suggested that licensure of a GBS vaccine would be significantly accelerated if a serocorrelate of protection was established. Licensure in such scenario would require a phase IV study in order to establish effectiveness post-licensure. This is the same approach used for licensure of meningococcal C and meningococcal B vaccines in the United Kingdom (45). Such an assay would be required to measure the quantity and quality of CPS-specific antibodies respectively (22,46–48). Such assay standardisation is currently underway through the GASTON consortium, a global initiative that has been recently set up with this aim.
Assays for Antibody Quantification and Evaluation
The concentration of antibodies against serotype-specific CPS antigens can be quantified using standard immunogenic assays (IA). However, there are several limitations of using current IA as the concentration measurement is very dependent on how well CPS is immobilised on an ELISA plate. There are other technical difficulties including inconsistent binding of immobilized CPS to the solid phase or a nonspecific serotype-independent binding, of the antibodies, with lower avidity (28). There has been much debate about the methods of binding and two current methods, that used is pneumococcal assays using ply-l-lycin or the novel biotin-streptavidin methods have been proposed to overcome these (44). The biotinylated method has the advantage of being able to use mass spectroscopy to determine the exact binding site of the biotin to the CPS, enabling the monitoring of any potential conformational changes to the CPS (49). Moreover, the immunogenicity of the CPS in different serotypes may be very different despite the fact that their repeat structure is highly similar.
The radio-antigen binding assay (RABA) had been used successfully to quantify levels of anti-GBS antibody as it measures antibody in its native state (50); however, as with most assays, there are several limitations, including low detection sensitivity, various difficulties in obtaining and using of radioisotopes and limited ability in quantifying IgG isotopes. Therefore, it is imperative for techniques quantifying capsular serotype-specific antibodies in serum to be sensitive as well as serotype-specific (51). Multiplex immunoassays (MIAs) based on the Luminex technology are very useful in simultaneously quantifying the concentration of IgG antibodies against the capsule of multiple GBS serotypes. A Luminex-based direct immunoassay (dLIA) was recently developed for pneumococcal CPS (52). The latter could generate up to 143 test results in a single 96-well plate and performs on the same principle as an ELISA assay for evaluating vaccine clinical trials. MIAs quantifying IgG antibodies against the five most frequent GBS capsular variants (Ia, Ib, II, III and V) would prove to be extremely useful in the standardisation of the assay used for GBS vaccine development.
The functionality of antibodies also has a significant role in protection against GBS infections. ELISAs are limited in this aspect as they cannot distinguish between antibodies with low avidity and those with high avidity. Therefore, the opsonisation killing assay (OPkA) enables the measurement of antibody functionality by opsonising GBS for phagocytosis (48). For the validation of the pneumococcal vaccine, the granulocytic cell line (HL60) was used, making the assay more specific and reproducible (53). The assay was also a multiplexed OPkA, which proved to be advantageous as it was less time-consuming and the amount of serum needed for the assay was reduced (54,55). Although a multiplexed OPkA for GBS (GBS-MOPA) has been developed for use in newborns, it only targets serotypes IA, III and V (56). Therefore, a GBS-OPA targeting all possible vaccine serotypes is necessary for future GBS vaccine development and evaluation.
Although CPS vaccines have been demonstrated to induce good immunogenicity, there are still several limitations including potential immune interference with other types of conjugate vaccines such as Haemophilus influenzae type b, meningococcal and pneumococcal conjugate vaccines. There is also the possibility of serotype replacement and switching post vaccination, as well as an increase in unencapsulated GBS strains (57–59). Alternative vaccine candidates include structurally conserved protein antigens, which can induce a strong immune response against most of GBS strains. In order to develop a vaccine that can confer broad protection against GBS, several studies have identified proteins common to all GBS strains. Members of the Alp family, including AlphaC, BetaC, Alp1, Alp2, Alp3 (R28), Alp4 and Rib, are the most well-known and abundant surface proteins. Although there have been preclinical vaccine investigations using AlphaC, Alp3 and Rib proteins, the heterogeneity of the Alp sequence restricts the use of Alp proteins as potential vaccine candidates (60,61). Nonetheless, a protein vaccine based on the highly immunogenic N-terminal domains of AlphaC and Rib (GBS-NN) reached Phase I clinical trial (NCT02459262). The participants included 240 healthy women who were immunised with one or two doses of GBS-NN, generating an elevated level of GBS-NN specific antibodies by over-30 fold (62). GBS expresses either one of two-allelic serine-rich repeat 1 (Srr1) and serine rich-repeat 2(Srr2) proteins (63), both of which can bind to fibrinogen Aα through the “dock, lock and latch” mechanism, thus contributing to the pathogenesis of GBS meningitis and GBS colonisation of the vaginal surface (63–65). The antigenic latch domain consisting of 13 amino acids in both Srr1 and Srr2, was shown to play a significant role in GBS pathogenesis. Murine models have exhibited serotype-independent protection against GBS infection after being vaccinated with the latch-peptide vaccine (66). C5a peptidase, which is a GBS virulence factor was also considered as a universal protein vaccine or a carrier of GBS-CPS (67). C5a peptidase encapsulated within microspheres composed of lactic acid and glycolic acid co-polymer triggered systemic and mucosal immune responses in murine models, thus protecting them against multiple GBS serotypes (68,69). Another type of surface protein is the pilus proteins, which, in preclinical studies, were found to induce the immune response against different GBS serotypes (18,70).
Next steps, new perspectives
To summarise, the leading GBS vaccines under investigation are CPS conjugate vaccines. The most advanced candidates are hexavalent vaccines including serotypes Ia, Ib, II, III, IV, and V, which are now in phase I/II trials. Immunogenicity and safety of these candidates has been demonstrated in non-pregnant and, more recently, in pregnant women (71).
Several obstacles exist in moving the most advanced vaccines into phase III clinical trials. Given the relative low incidence of GBS disease in Europe and the USA, large numbers of participants would be needed to determine vaccine efficacy (72). In addition, obstacles exist in determining what concentration of antibody is required to protect the infant for the duration of the period at risk (around the 3 first months) as there are currently no internationally recognised immune markers with which to interpret individual study results (73). Therefore, a serocorrelate of protection against GBS is needed to accelerate the licensure of a vaccine. The standardisation of assays to measure antibodies against GBS is crucial for the establishment of serological correlates of protection and for the development of GBS vaccines. The GASTON consortium was recently set up with this aim (49).
On the other hand, efforts to identify common proteins to all GBS strains have been made in order to find a vaccine that confers protection against all GBS serotypes. New molecular techniques, such as multi-locus sequence type (MLST) and whole-genome sequencing (WGS), have allowed us to better characterise the GBS structure, as well as to identify the virulent lineages. It is important to understand the genetic lineages that are more likely to cause GBS disease to define vaccine targets.
Other areas for future research
As mentioned above, it is important to establish rates of maternal colonisation and GBS disease worldwide, as well as to understand the relationship between colonisation and invasive infection, as this will assist assessments of vaccine efficacy. Regional serotype distribution is also required, especially from many LMIC were very few data is available.
Once a vaccine is licensed, the number and timing of doses for optimum coverage during pregnancy and the number of doses required for full protection needs to be determined. Furthermore, there are other knowledge gaps that remain unanswered regarding the placental transfer of vaccine-induced immune responses in special populations, such as women infected with HIV, malaria, syphilis and hepatitis B among others. These infections, highly prevalent in LMIC, may alter the immune response to vaccines and impair the antibody transfer across the placenta. A phase II trial using a GBS trivalent vaccine (Ia, Ib, III) undertaken in Malawi and South Africa among 270 pregnant women with or without HIV infection (NCT01412801) showed that immune response to vaccines and serotype-specific antibody concentrations in infants at birth were lower in the HIV infected group (74). Maternal immunisation policies require understanding of the role of these endemic infections in generating immune responses that ensure an adequate protection of infants in these challenging environments (75) (76).
Finally, cost-effectiveness evaluation is required. This depends on disease incidence and vaccine efficacy, amongst other parameters. In high income countries, where GBS disease is well characterized, it has been shown that a maternal vaccine would be more cost-effective compared to IAP and doing nothing. A population-based economic analysis in the USA concluded that vaccinating 80% of pregnant women with a vaccine that prevents 80% of cases among infants born at or after 34 weeks of gestation would prevent approximately 4100 neonatal cases annually with a net savings of $131 million (77). A study in South Africa also concluded that GBS maternal vaccination would be very cost-effective by WHO guidelines. Assuming that vaccine efficacy varies from 50% to 90% with a 75% coverage, GBS immunisation alone, without IAP prevention, would prevent 30-54% of infant GBS cases compared to doing nothing. In contrast, risk factor based-IAP alone prevents 10% of infant GBS cases compared to doing nothing. Furthermore, at a vaccination cost between $10 and $30, and mid-range efficacy vaccine introduction costs range from $676 to $2390 per disability-adjusted life-year (DALY) averted ($US 2010), compared to doing nothing (78). A modeling study of different sub-Saharan African countries showed that maternal GBS immunisation could be a cost-effective intervention, with cost-effectiveness ratios similar to other recently introduced vaccines. 37 African countries were clustered in four different groups according to their economic and health resources and public health outcomes. One country of each cluster was chosen as representative: Guinea-Bissau, Uganda, Nigeria and Ghana. At equal coverage to that of pregnant women that attend four or more antenatal visits and with vaccine efficacy of 70%, maternal vaccination would prevent one-third of GBS cases in Uganda and Nigeria, 42-43% in Guinea-Bissau and 55-57% in Ghana. For a vaccine price of $7 per dose, maternal vaccination would cost from $320 to $350 per DALY averted in Guinea-Bissau, Nigeria and Ghana, as well as $573 in Uganda. The vaccine would be less cost-effective in Uganda as neonatal mortality seems to be lower. However, the causes of mortality are unknown as well as the incidence of GBS disease (79). These studies, together with more epidemiological data in LMIC, might raise the impact resulting from a vaccine prevention strategy.
Data provided in this review demonstrate that obtaining a vaccine for pregnant women is the most promising strategy to prevent neonatal and infant GBS disease. Although several gaps in knowledge prevent the optimal design of an effective vaccine, key research areas are identified, and great efforts are being made to accelerate licensing. Consensus among public health institutions and sponsors is a priority to allow this breakthrough that will help reduce neonatal and infant mortality, especially in the most vulnerable populations.
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