INTRODUCTION

For decades now, it is known that Group B streptococcus (GBS) is a leading cause of neonatal infection in high-income countries and is associated with frequent morbidity and mortality. Recent estimates suggest that GBS infection is in fact a global problem, with a large fraction of the associated burden in low- and middle-income countries [1▪▪]. Indeed, it was estimated that ∼20 million pregnant women worldwide were colonised by GBS in 2020 and almost 400,000 children presented with either early-onset GBS (EOGBS, presenting 0-6 days after birth) or late-onset GBS (LOGBS, presenting days 7–89 after birth). Furthermore, over 90,000 infant deaths were estimated to occur, nearly half of which in Sub-Saharan Africa. 

Box 1:

no caption available

Much of the clinical research on perinatal GBS infection has been on infant invasive disease. However, this pathogen is also associated with other health outcomes [2] (Fig. 1), including as a causative factor for stillbirths [3], and a risk factor for preterm births [4] and for long-term sequelae in survivors of acute disease [5,6▪▪,7,8,9▪,10▪▪]. It was estimated that 46,200 (95% posterior interval 20,300–111,300) stillbirths resulted from in utero GBS infection in 2020, and up to 518,100 (36,900–1142,300) preterm births might have been associated with GBS colonisation [1▪▪]. The many potential negative consequences of maternal GBS colonisation imply the need for an effective prevention approach that can reduce the risk of multiple outcomes (Fig. 2).

FIGURE 1:

Disease scheme for outcomes of Group B Streptococcus (GBS). The blue solid line arrows indicate later impairment, the black solid line arrows indicate death, and the blue dashed line arrows indicate healthy development. Figure adapted from Lawn JE et al. Clinical Infectious Diseases 2017 (2).

FIGURE 2:

Definitions for GBS outcomes and the potential pathways of prevention comparing intrapartum antibiotic prophylaxis and maternal vaccines. Red indicates no evidence of protection, orange indicates unclear evidence of protection, yellow indicates evidence that it may offer some protection, light green indicates evidence of protection and dark green indicates strong evidence of protection. Definitions adapted from Lawn JE et al. Clinical Infectious Diseases 2017 (2).

Here, we discuss the preventive approach currently in use, intrapartum antibiotic prophylaxis (IAP), which provides protection against EOGBS. Whilst maternal GBS vaccines, that is, vaccines to be given to pregnant women to protect their neonates, are not currently available, they are under development and will also be discussed. The objectives of this review are:

(1) To review the evidence and compare two approaches to identify pregnant women to receive IAP, (2) To update on maternal GBS vaccine development, (3) To discuss the potential impact of these two prevention strategies (IAP and vaccine) on clinical outcomes. GBS SCREENING AND INTRAPARTUM ANTIBIOTIC PROPHYLAXIS

The current approach to prevent GBS disease in early infancy consists of identifying pregnant women whose newborns are at higher risk of developing invasive disease and administering intravenous antibiotics, for at least 4 h, after onset of labor. This strategy, referred to as IAP, has been adopted in 60 of 95 countries included in a recent review [11]. Two different methods are used to identify at-risk newborns: microbiology-based screening and risk factor-based screening (Table 1). In the next subsections, these approaches of IAP are described, and evidence on their comparative effectiveness, discussed.

Table 1 - Comparison of universal microbiology-based and risk factor-based screening for GBS in pregnancy Microbiology-based screening Risk factor-based screening Resources Infrastructure to perform the assay, which will vary depending on culture method or PCR-based method. For intrapartum testing, a 24-h infrastructure needs to be in place. ASM recommends enrichment broth for both methods. For assessment of presence of most risk factors, GBS testing is not required; note however that in settings where history of GBS detection is part of screening, testing infrastructure would have been necessary. Timing Culture based: depends on method, but usually 24–48 h
Molecular biology based: < 2 h if used without enrichment broth step (it can be used for intrapartum screening) No time delays as testing not required. Selection of pregnant women for IAP Based on diagnostic testing. In many countries where this screening approach has been adopted, some risk factors are used in combination with microbiology-based screening to define the population that should receive IAP Based on the presence of risk factors. Antibiotic treatment Penicillin, Ampicillin
First Generation Cephalosporin or Clindamicyn if penicillin allergy
Vancomycin if penicillin allergy and clindamycin resistance Resistance considerations There is only limited evidence of Penicillin resistance in GBS isolates [48–50]. On the other hand, resistance to Clindamycin is frequent in some settings (e.g., 20.8% in the US [20])
Microbiology-based screening to identify at-risk newborns

Maternal colonisation with GBS is necessary for the development of invasive disease in the first days after birth, and, consistent with this, epidemiological studies have estimated strong associations between GBS carriage during pregnancy and neonatal disease (e.g., unadjusted odds ratio 17.7 95% confidence interval 1.9–163.5 in [12]). This aspect of the pathogenesis motivates the use of bacterial colonisation testing to identify pregnant women who should receive antibiotics to reduce GBS transmission to neonates.

This screening strategy has been adopted as part of IAP policy by at least 35 countries [11], primarily high-income, and involves collection of rectal and vaginal swabs for GBS detection. Until recently, in the US, the gestational age window for GBS screening was 35 to 37 weeks based on guidance by the Centers for Disease Control and Prevention; this has recently changed and the current recommendation from the American College of Obstetricians and Gynecologists is for microbiological sampling to occur between weeks 36-0/7 and 37-6/7 of gestational age [13▪]. There is variation between countries both in terms of timing and anatomical location of swab sampling [11].

Culture is the most used diagnostic method, with selective enrichment broth medium having higher sensitivity compared to other culture-based methods (see [14▪] for recommendations on sample collection, transport, and detection). Other approaches, however, have promise, including polymerase chain reaction (PCR)-based methods; indeed, recent studies, in various settings, suggest molecular biology methods are sensitive, particularly when a step with selective enrichment broth is used [14▪].

An underlying assumption of the microbiology-based approach is that GBS colonisation at screening time is a good predictor of colonisation at delivery. Three challenges affect this strategy: (1) some GBS carriers will clear their infections by delivery, which implies they will receive antibiotics despite their newborns not being necessarily at higher risk of disease; (2) a fraction of pregnant women who are GBS-colonised at screening might have false negative culture results; (3) some pregnant women who were truly uninfected at screening become colonised by delivery.

Evidence for these different challenges has been reported in various settings. For example, a recent French study suggested ∼40% of pregnant women with evidence of GBS colonisation at 35 to 37 gestational weeks were not colonised at delivery [15] and in 18 US clinical centers, 53% of infants with EOGBS sepsis were born to women with negative GBS screening [16]. Sensitive diagnostic methods with a shorter time-to-result could be used for intrapartum screening, and potentially reduce these problems. PCR-based methods have been assessed in clinical studies (15–17) and their future wider use will likely depend on associated costs [17].

Despite these difficulties in identifying GBS-colonised pregnant women, a recent meta-analysis of observational data estimated microbiology-based screening reduced EOGBS risk by approximately 70% and 60% compared to no preventive policy or risk factor-based approach, respectively [18▪]. However, some studies in that meta-analysis used historical, rather than concurrently recruited, comparator cohorts. In one large study (N = 5144), performed in the US, microbiology-based screening resulted in a lower risk for EOGBS (adjusted relative risk 0.46 95% confidence interval 0.36 – 0.60; reference, risk factor-based screening) [19]. Studies that assessed population-level incidence over long periods of time provide additional observational evidence of the effect of this strategy. For example, in the US [20], the incidence went from 0.37 per 1000 live births in 2006 to 0.23 in 2015; a similar pattern was observed in France [21]. However, this approach of IAP, as well as the risk factor-based approach discussed below, does not affect LOGBS incidence to the same degree or at all [21,22]

Although microbiology-based screening and IAP is an effective approach against infancy GBS disease, several factors complicate its implementation and even in countries where diagnostic methods are widely available, compliance is not perfect. In a study from the US, 85% of pregnant women were screened for GBS colonisation, only half of them were known to be tested at week 35 or later of gestation, and of those who tested positive for GBS carriage 87% received antibiotics [23]. Two recent analyses of American data reported that 21.8% [20] and 37.5% [16] of EOGBS cases did not receive IAP despite indication. Evidence of inadequate policy compliance has also been reported in other high-income countries [24,25]. If coverage is improved, additional reductions in EOGBS incidence should be possible, but may be increasingly expensive per case treated.

Risk factor-based screening

The other approach to identify at-risk newborns is based on known risk factors for GBS neonatal infection, including fever, preterm delivery, GBS bacteriuria, prolonged rupture of membranes, and a previous child with EOGBS [11]. The advantage of this strategy compared to microbiology-based screening relates to its lower cost, as no diagnostic tests are performed, and to the potentially lower number of antibiotic doses administered, although similar frequencies of antibiotic use have been reported with the two screening strategies [19].

Fewer countries currently use this approach, including the UK, Denmark, and the Netherlands, among others. There is evidence of EOGBS incidence reduction in some countries (e.g., Sweden [26], Denmark [27], and New Zealand [28]). However, in the Netherlands there was an increase in incidence between 1987 and 2011 (Dutch screening guidelines introduced in 1999) [29], possibly related to the expansion of GBS virulent lineages [30]. A contributing explanation for the limited effectiveness of this approach is the large fraction (∼40%) of early-onset cases in newborns of mothers who do not present risk factors [26,28]. However, this evidence is primarily observational. A large clinical trial currently underway in the UK aims to compare microbiological-based screening using culture at 35 to 37 weeks, intrapartum PCR testing at start of labor, and risk factor-based prevention [31]. As with microbiology-based screening, issues of coverage and compliance are also present in this type of screening.

MATERNAL GBS VACCINE CANDIDATES

Although microbiology-based screening with IAP reduces EOGBS incidence, additional approaches are needed to prevent LOGBS, GBS-associated stillbirth, preterm births, and maternal infections [2]. GBS vaccines are promising. Milestones set in the Defeating Meningitis Roadmap call for licensure and WHO-prequalification of an affordable maternal GBS vaccine by 2026 and vaccine introduction in at least ten countries by 2030 [32▪▪]. As with immunisation with tetanus toxoid, pertussis, and influenza, the protective mechanism of maternal GBS vaccines would involve placental transfer of GBS antibodies to ensure protection when risk of invasive disease is highest [33].

Two vaccine development approaches have been prioritised: vaccines based on capsular polysaccharides and protein-based vaccines. Multivalent capsular polysaccharide vaccines include candidates in various stages of development (Table 2). As six GBS serotypes (Ia, Ib, II, III, IV, V) account for most disease burden [34], Pfizer designed a hexavalent vaccine (GBS6) to target these serotypes; Phase 2 evaluation to assess the safety and immunogenicity in pregnant women is currently underway (NCT03765073) and Phase 3 trials are set to start in 2023 [35]. Another candidate, developed by PATH, a global public health non-profit organization, and Inventprise, a vaccine manufacturer, to address the need for low-cost vaccines, is a multivalent vaccine currently in Phase 1 development [36].

Table 2 - GBS vaccine candidates in the development pathway Vaccine candidate Serotype target Preclinical Phase 1 Phase 2 Trials in Pregnant Women Phase 3 Trial locations Polysaccharide conjugate vaccines  Monovalent and bivalent conjugates (TT / CRM197 CPS) TT monovalent: Ia, Ib, II, III, IVa, V, VIa, VIIa, VIIIa
TT bivalent: II, III
CRM197 monovalent: V √ √ √ √ No longer in development  Trivalent CRM197-CPS conjugates Ia, Ib, III √ √ √ √ No longer in development  Pentavalent TT CPS conjugates TBC √ √ TBC  Hexavalent CRM197-CPS conjugates Ia, Ib, II, III, IV, V √ √ √ √ √b South Africa, UK, US, Uganda  Biotinylated CPS conjugates √ Protein-based vaccines  N-terminal domains of the Rib and AlphaC proteins N/A √ √ √ √ √b Denmark, South Africa, Uganda, UK  Pilus proteins √  Other proteins √

aOnly in preclinical trials.

bPlanned for 2023.TBC, to be confirmed.

Protein subunit vaccines could potentially cover more GBS strains and address concerns surrounding potential serotype replacement, as described for capsular polysaccharide pneumococcal vaccines [37], or capsular switching, which has been observed with natural GBS infection [38]. While several protein-based vaccines are in preclinical development, one candidate, developed by Minervax, targeting the N-terminal domain of the family of alpha-like surface proteins (GBS-NN) was found safe and immunogenic in nonpregnant women (Table 2), and is now in Phase 2 trials to evaluate immunogenicity and safety in pregnant women (NCT04596878, NCT05154578).

In 2022, the vaccine candidates GBS6 and GBS-NN were awarded PRIME status by the European Medicines Agency, which means enhanced support for the development as GBS vaccines are considered an unmet need [39–41]. Phase 3 trials are expected to start for both vaccines in 2023 [35,41].

Complexities in developing pregnancy vaccines, misconceptions regarding the success of IAP, and key data gaps in the global burden have contributed to the sluggish advancement of GBS vaccines [42]. As vaccine development progresses, a potential obstacle to licensure is the sample size needed in a Phase 3 trial to assess efficacy against invasive disease. Indeed, it has been estimated that such a trial would require 30,000–1800,000 participants, depending on vaccine efficacy and disease incidence, and would therefore require significant time and resources [37]. A recent review summarised the potential paths to licensure for GBS vaccines [43▪▪]. Compared to the conventional approval pathway, an accelerated approval pathway by regulatory authorities, such as the US Food and Drug Administration or the Medicines and Healthcare Products Regulatory Agency, might lead to licensure of a GBS vaccine based on a surrogate immunological endpoint and use in pregnant women. Such an approach was favourably discussed during the Vaccine and Related Biological Products Advisory Committee in May 2018 and could allow licensure based on serocorrelate of protection followed by a confirmatory effectiveness study postlicensure. Alternatively, an immunological endpoint could be nested in a trial with a clinical endpoint, where trial size would be based on the clinical endpoint, and immunogenicity results could be used for accelerated approval, before efficacy estimates based on disease become available [43▪▪]. Both approaches rely on validated serological correlates of protection using standardised assays. For this reason, a consortium was established to develop standardised assays and reagents. The results of these interlaboratory studies have shown good agreement between laboratories using standard reference reagents and protocols [44]. Serocorrelates of protection studies using natural immune sera are currently underway in the UK, USA, South Africa, and in the PREPARE consortium (Malawi, Uganda, Netherlands, France, Italy) to establish the concentration of antibodies associated with a risk reduction threshold for invasive disease [45].

POTENTIAL IMPACT OF PREVENTION STRATEGIES

IAP prevents the outcome with peak incidence immediately after birth, early-onset disease. However, even in Europe and North America, where policy coverage is highest, thousands of EOGBS cases still occur every year. Equally importantly, risk of LOGBS, which more often presents as meningitis, is not reduced by IAP. Given the risk of moderate/severe neurodevelopmental impairment after GBS meningitis, estimated at 20.7% (95% posterior interval 16.1–25.6) [1▪▪], it is possible that even where IAP has reduced EOGBS, considerable burden will persist due to acute LOGBS and the associated long-term sequelae. Other outcomes, including GBS-associated preterm births and stillbirths are not likely to be impacted by IAP, although surveillance data from the US suggest reduced incidence of maternal disease after IAP implementation [22].

A maternal GBS vaccine on the other hand could potentially prevent both EOGBS and LOGBS. Indeed, according to an estimation in the Group B streptococcus Full Value of Vaccine Assessment[46▪▪], ∼87,000 late-onset cases and ∼127,000 early-onset cases estimated to occur annually under current IAP coverage could be prevented if a vaccine with 80% efficacy were deployed globally, and as a consequence, ∼20,000 moderate/severe impairment cases would be averted. Although questions remain on how GBS colonisation increase risk of prematurity or lead to stillbirth, if maternal vaccines enhance GBS clearance, or prevent colonisation in pregnancy, vaccination could prevent these outcomes. It has been estimated that a vaccine with 80% efficacy could potentially prevent 23,000 GBS-related stillbirths.

Maternal GBS vaccine use could also have the additional benefit of reducing antibiotic administration for IAP and treatment of vaccine-prevented early-onset and late-onset cases. If we assumed two scenarios – one in which microbiology-based screening using culture rather than PCR-based intrapartum testing [47] would eventually be adopted universally in the absence of an effective vaccine, and a second scenario where, with deployment of a vaccine, IAP would no longer be in use; in the second scenario up to ∼20 million pregnant women would not need to receive IAP every year. In reality, both scenarios are unlikely for different reasons: (1) adoption of microbiology-based screening is not feasible in many settings in the near-future, (2) in many countries a large fraction of births still happens at home, which precludes intrapartum antibiotics; (3) it is unclear whether vaccine availability would lead to discontinuation of IAP policy. For example, it is conceivable that for newborns at high risk of disease, for example, preterm infants, IAP would still be beneficial in further reducing risk. GBS vaccine deployment would likely reduce the global number of IAP- and disease treatment-related antibiotic doses administered, potentially slowing spread of antimicrobial resistance, and preventing possible, but still under-researched consequences to the microbiome.

CONCLUSION

For the last three decades, IAP has saved lives of children who may otherwise have developed EOGBS in some higher income settings, and this strategy could be improved by better policy coverage and by improvements in diagnostic methods. However, common and serious clinical consequences of maternal GBS colonisation (notably LOGBS, stillbirths, and preterm birth) are not prevented by IAP. Maternal vaccines, which may potentially provide protection against the different presentations of this infection and are feasible to scale, could have a major impact on disease burden, in particular in limited resourced settings, where incidence is high, and IAP is challenging to implement. A recently published WHO report [46▪▪], which calls for the development of maternal GBS vaccines to reduce GBS burden, has increased momentum for development of GBS vaccine candidates, many of which have been stuck in the pipeline for decades.

Acknowledgements

We are grateful to the following research groups, with whom we have collaborated on GBS research epidemiological studies: the GBS Danish and Dutch collaborative group for long-term outcomes, and the GBS low-income and middle-income country collaborative group for long-term outcomes. We also would like to thank members of the WHO Scientific Advisory Group, ISSAD Committee (issad.org), Ajoke Sobanjo-ter Meulen, and Kate Fay.

Financial support and sponsorship

This work was supported by a grant (INV-00908) from the Bill & Melinda Gates Foundation to the London School of Hygiene & Tropical Medicine (PI, Joy Lawn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1▪▪. Gonçalves BP, Procter SR, Paul P, et al. Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden. The Lancet Global Health 2022; 10:e807–e819. 2. Lawn JE, Bianchi Jassir F, Russell N, et al. Group B streptococcal disease worldwide for pregnant women, stillbirths and children: why, what and how to undertake estimates? Clin Infect Dis 2017; 65: (suppl_2): S89–S99. 3. Seale AC, Blencowe H, Bianchi-Jassir F, et al. Stillbirth with group B streptococcus disease worldwide: systematic review and meta-analyses. Clin Infect Dis 2017; 65:S125–S132. 4. Bianchi-Jassir F, Seale AC, Kohli-Lynch M, et al. Preterm birth associated with group B streptococcus maternal colonization worldwide: systematic review and meta-analyses. Clin Infect Dis 2017; 65:S133–S142. 5. Harden LM, Leahy S, Lala SG, et al. South African of invasive group B Streptococcus disease aged 5 to 8 years. Clin Infect Dis 2022; 74:S5–13. 6▪▪. Horváth-Puhó E, Kassel MN van, Gonçalves BP, et al. Mortality, neurodevelopmental impairments, and economic outcomes after invasive group B streptococcal disease in early infancy in Denmark and the Netherlands: a national matched cohort study. Lancet Child & Adolesc Health 2021; 5:398–407. 7. John HB, Arumugam A, Priya M, et al. South Indian children's neurodevelopmental outcomes after group B streptococcus invasive disease: a matched-cohort study. Clin Infect Dis 2022; 74:S24–34. 8. Bramugy J, Mucasse H, Massora S, et al. Short- and long-term outcomes of group B Streptococcus invasive disease in Mozambican children: results of a matched cohort and retrospective observational study and implications for future vaccine introduction. Clin Infect Dis 2022; 74:S14–S23. 9▪. Chandna J, Liu W-H, Dangor Z, et al. Emotional and behavioral outcomes in childhood for survivors of invasive group B Streptococcus disease in infancy: findings from 5 low- and middle-income countries. Clin Infect Dis 2022; 74:S35–S43. 10▪▪. Paul P, Chandna J, Procter SR, et al. Neurodevelopmental and growth outcomes after invasive Group B Streptococcus in early infancy: A multicountry matched cohort study in South Africa, Mozambique, India, Kenya, and Argentina. EClinicalMedicine 2022; 47:101358. 11. Le Doare K, O’Driscoll M, Turner K, et al. Intrapartum antibiotic chemoprophylaxis policies for the prevention of group B streptococcal disease worldwide: systematic review. Clin Infect Dis 2017; 65:S143–S151. 12. Oddie S, Embleton ND. Risk factors for early onset neonatal group B streptococcal sepsis: case-control study. BMJ 2002; 325:308. 13▪. The American College of Obstetricians and Gynecologists’ (ACOG) Committee. Prevention of Group B Streptococcal Early-Onset Disease in Newborns. 2020. https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2020/02/prevention-of-group-b-streptococcal-early-onset-disease-in-newborns. 14▪. Guidelines for the Detection and Identification of Group B Streptococcus. 2021. https://asm.org/Guideline/Guidelines-for-the-Detection-and-Identification-of. 15. Plainvert C, El Alaoui F, Tazi A, et al. Intrapartum group B Streptococcus screening in the labor ward by Xpert® GBS real-time PCR. Eur J Clin Microbiol Infect Dis 2018; 37:265–270. 16. Stoll BJ, Puopolo KM, Hansen NI, et al. Early-onset neonatal sepsis 2015 to 2017, the rise of Escherichia coli, and the need for novel prevention strategies. JAMA Pediatr 2020; 174:e200593. 17. El Helali N, Giovangrandi Y, Guyot K, et al. Cost and effectiveness of intrapartum group B streptococcus polymerase chain reaction screening for term deliveries. Obstetr Gynecol 2012; 119:822–829. 18▪. Hasperhoven G, Al-Nasiry S, Bekker V, et al. Universal screening versus risk-based protocols for antibiotic prophylaxis during childbirth to prevent early-onset group B streptococcal disease: a systematic review and meta-analysis. BJOG: Int J Obstet Gy 2020; 127:680–691. 19. Schrag SJ, Zell ER, Lynfield R, et al. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. N Engl J Med 2002; 347:233–239. 20. Nanduri SA, Petit S, Smelser C, et al. Epidemiology of invasive early-onset and late-onset group B streptococcal disease in the United States, 2006 to 2015: multistate laboratory and population-based surveillance. JAMA Pediatr 2019; 173:224–233. 21. Romain A-S, Cohen R, Plainvert C, et al. Clinical and laboratory features of group B streptococcus meningitis in infants and newborns: study of 848 cases in France, 2001–2014. Clin Infect Dis 2018; 66:857–864. 22. Schrag S. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 2000; 342:15–20. 23. Van Dyke MK, Phares CR, Lynfield R, et al. Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med 2009; 360:2626–2636. 24. Yamaguchi K, Ohashi K. Management of group b streptococcus-positive pregnant women at maternity homes in JAPAN: a questionnaire survey of compliance among midwives. Matern Health, Neonatol and Perinatol 2018; 4:4. 25. Kunze M, Zumstein K, Markfeld-Erol F, et al. Comparison of pre and intrapartum screening of group B streptococci and adherence to screening guidelines: a cohort study. Eur J Pediatr 2015; 174:827–835. 26. Hakansson S, Axemo P, Bremme K, et al. Group B streptococcal carriage in Sweden: a national study on risk factors for mother and infant colonisation. Acta Obstetricia et Gynecologica Scandinavica 2008; 87:50–58. 27. Andersen J, Christensen R, Hertel J. Clinical features and epidemiology of septicaemia and meningitis in neonates due to Streptococcus agalactiae in Copenhagen County, Denmark: a 10 year survey from 1992 to 2001. Acta Paediatr 2004; 93:1334–1339. 28. Darlow BA, Voss L, Lennon DR, et al. Early-onset neonatal group B streptococcus sepsis following national risk-based prevention guidelines. Aust New Zealand J Obstetr Gynaecol 2016; 56:69–74. 29. Bekker V, Bijlsma MW, van de Beek D, et al. Incidence of invasive group B streptococcal disease and pathogen genotype distribution in newborn babies in the Netherlands over 25 years: a nationwide surveillance study. Lancet Infect Dis 2014; 14:1083–1089. 30. Jamrozy D, Bijlsma MW, de Goffau MC, et al. Increasing incidence of group B streptococcus neonatal infections in the Netherlands is associated with clonal expansion of CC17 and CC23. Sci Rep 2020; 10:9539. 31. Nottingham Clinical Trials Unit. GBS3 Trial n.d. Available at: https://www.gbs3trial.ac.uk/home.aspx (Accessed on December 15, 2022). 32▪▪. World Defeating meningitis by 2030: a global road map. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240026407 n.d. 33. Palmeira P, Quinello C, Silveira-Lessa AL, et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012; 2012:1–13. 34. Bianchi-Jassir F, Paul P, To K-N, et al. Systematic review of Group B Streptococcal capsular types, sequence types and surface proteins as potential vaccine candidates. Vaccine 2020; 38:6682–6694. 35. Bill & Melinda Gates Foundation Announces New Commitments for Vaccine Candidates With the Potential to Reduce Newborn and Infant Deaths in Lower-Income Countries n.d. 36. Invenprise. Product Pipeline n.d. Available at: https://inventprise.com/?page_id=1677 (Accessed on December 21, 2022). 37. Vekemans J, Crofts J, Baker CJ, et al. The role of immune correlates of protection on the pathway to licensure, policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations. Vaccine 2019; 37:3190–3198. 38. Bellais S, Six A, Fouet A, et al. Capsular switching in group B streptococcus CC17 hypervirulent clone: a future challenge for polysaccharide vaccine development. J Infect Dis 2012; 206:1745–1752. 40. FDA Grants Breakthrough Therapy Designation to Pfizer's Group B Streptococcus Vaccine Candidate to Help Prevent Infection in Infants Via Immunization of Pregnant Women. https://www.pfizer.com/news/press-release/press-release-detail/fda-grants-breakthrough-therapy-designation-pfizers-group-b. 42. Vekemans J, Moorthy V, Friede M, et al. Maternal immunization against Group B streptococcus: World Health Organization research and development technological roadmap and preferred product characteristics. Vaccine 2019; 37:7391–7393. 43▪▪. Absalon J, Simon R, Radley D, et al. Advances towards licensure of a maternal vaccine for the prevention of invasive group B streptococcus disease in infants: a discussion of different approaches. Human Vaccines & Immunotherapeut 2022; 18:2037350. 44. Kirsty LeDoare. Interlaboratory comparison of a multiplex immunoassay for the assignment of antibody concentrations against select Group B Streptococcus polysaccharides in human sera. 2021. Presented at 2nd International Symposium on Streptococcus agalactiae Disease (ISSAD) (Poster). https://www.issad.org/wp-content/uploads/2021/12/23.-Kirsty-Le-Doare-1.pdf. 45. Welcome to PREPARE. St George,s University. https://gbsprepare.org/ 46▪▪. Group B streptococcus vaccine: full value of vaccine assessment. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240037526. 47. Helmig RB, Gertsen JB. Intrapartum PCR-assay for detection of Group B Streptococci (GBS). Eur J Obstet Gynecol Reprod Biol X 2019; 4:100081. 48. Burcham LR, Spencer BL, Keeler LR, et al. Determinants of Group B streptococcal virulence potential amongst vaginal clinical isolates from pregnant women. PLoS ONE 2019; 14:e0226699. 49. Matani C, Trezzi M, Matteini A, et al. Streptococcus agalactiae: prevalence of antimicrobial resistance in vaginal and rectal swabs in Italian pregnant women. Infez Med 2016; 24:217–221. 50. Gizachew M, Tiruneh M, Moges F, et al. Streptococcus agalactiae maternal colonization, antibiotic resistance and serotype profiles in Africa: a meta-analysis. Ann Clin Microbiol Antimicrob 2019; 18:14.