Perinatal Streptococcus agalactiae Epidemiology andSurveillance Targets

Lucy L. Furfaro,a Barbara J. Chang,b Matthew S. Paynea

aSchool of Medicine, Division of Obstetrics and Gynaecology, The University of Western Australia,Crawley, Australia

bSchool of Biomedical Sciences, The Marshall Centre for Infectious Diseases Research and Training, TheUniversity of Western Australia, Crawley, Australia

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2IDENTIFICATION AND CLASSIFICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Serotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Global serotype distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Ia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Ib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5V. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5VI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6VII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6VIII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6IX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Nontypeable isolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Surface Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Pulsed-Field Gel Electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Multilocus Sequence Typing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Random Amplified Polymorphic DNA and Repetitive-Sequence-Based PCRs . . . . . . . . . . . 10Multilocus Variant-Number Tandem-Repeat Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10CRISPR Locus 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

FROM TARGETS TO TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13AUTHOR BIOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

SUMMARY Streptococcus agalactiae, or group B streptococcus (GBS), is a majorneonatal pathogen. Recent data have elucidated the global prevalence of maternaland neonatal colonization, but gaps still remain in the epidemiology of this species.A number of phenotypic and genotypic classifications can be used to identify the di-versity of GBS strains, and some are more discriminatory than others. This review ex-plores the main schemes used for GBS epidemiology and further details the targetsfor epidemiological surveillance. Current screening practices across the world pro-vide a unique opportunity to gain detailed information on maternal colonizingstrains and neonatal disease-causing strains, which is vital for monitoring and thera-peutics, if sufficient detail can be extracted. Deciphering which isolates are circulat-ing within specific populations and recording targets within invasive strains are cru-cial steps in monitoring the implementation of therapeutics, such as vaccines, aswell as developing novel therapies against prevalent GBS strains. Having a detailedunderstanding of global GBS epidemiology will prove invaluable for understandingthe pathogenesis of this organism and equipping future prevention strategies forsuccess.

Published 15 August 2018

Citation Furfaro LL, Chang BJ, Payne MS. 2018.Perinatal Streptococcus agalactiaeepidemiology and surveillance targets. ClinMicrobiol Rev 31:e00049-18. https://doi.org/10.1128/CMR.00049-18.

Copyright © 2018 American Society forMicrobiology. All Rights Reserved.

Address correspondence to Lucy L. Furfaro,lucy.furfaro@uwa.edu.au.

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KEYWORDS group B streptococcus, Streptococcus agalactiae, epidemiology,serotype, sequence type, clonal complex, surveillance, vaccine, immunization,perinatal infections

INTRODUCTION

Streptococcus agalactiae is the sole member of the Lancefield group, i.e., group Bstreptococcus (GBS), and therefore is commonly referred to as GBS (1). This Gram-

positive coccus resides as a commensal of the gastrointestinal and genitourinary tractsof humans; however, it has the capacity to cause serious infections. These are oftenopportunistic in nature, affecting the elderly, the immunocompromised, and particu-larly neonates, for which GBS is a major cause of morbidity and mortality (2, 3). Recently,infections of healthy adults have also been reported (4, 5). In the affected populations,the spectrum of disease ranges from sepsis, pneumonia, and meningitis to endocarditis.GBS disease in neonates can be classified based on the time of onset: early-onsetdisease (EOD) occurs in the first week of life (6), while any disease presentation after thisto up to 3 months of life is classified as late-onset disease (LOD) (7). In neonates, themajority of early-onset GBS disease occurs as a result of transmission from a colonizedmother, either through ascending infection or during the process of vaginal birth (8).In contrast, late-onset sepsis is believed to be contracted via nosocomial or community-acquired means (9). Due to the potential for transmission from the mother, universalscreening of pregnant women by either risk-based or culture-based methods has beenimplemented in most countries. In such countries, intrapartum antibiotic prophylaxis(IAP) is administered before delivery to women at risk of GBS disease (delivery at �37weeks of gestation, intrapartum temperature of �38.0°C, or rupture of membranesfor �18 h) or with GBS colonization (10). This widespread treatment strategy hasbeen successful in reducing EOD significantly but has had no effect on LOD (10).Screening for GBS by culture currently involves vaginal and rectal swabs collectedat 35 to 37 weeks of gestation and cultured in selective enrichment media (11).Additionally, diagnostic molecular techniques to detect GBS have also been de-scribed (12). The outcome of this screening is either GBS colonization or absence.However, there is a plethora of other information about these organisms that couldbe obtained during routine screening that may prove vital in furthering ourunderstanding of their epidemiology; as such, we are currently underutilizing thispotentially valuable surveillance source. Expanding our knowledge of current tar-gets through the use of phenotypic and molecular assays to identify and differen-tiate isolates within the population will likely prove essential for future GBSinterventions.

IDENTIFICATION AND CLASSIFICATION

Several methods for identifying and characterizing GBS for epidemiological anddiagnostic purposes have been described (13). These include serotyping (based on thecapsular polysaccharide), typing of surface proteins, multilocus sequence typing(MLST), multilocus variable-number tandem-repeat analysis (MLVA), and, more recently,clustered regularly interspaced short palindromic repeat (CRISPR)-locus assays. All haveadvantages and disadvantages, and all convey different levels of epidemiologic data inthe context of surveillance.

Serotyping

The capsular polysaccharide (CPS) that encapsulates GBS is a major virulence factor,but it also determines the serotype. A total of 10 serotypes have been identified, withCPS IX being the most recently proposed one (14). Serotypes can be identified throughlatex agglutination and molecular assays, such as multiplex PCR (13, 15–17). As one ofthe first discriminating factors for GBS, the serotypes have been described in theliterature as a way of grouping isolates in an attempt to understand their prevalence inmaternal colonization and neonatal disease. Serotyping provides valuable informationthat allows classification into serologically similar groups, and patterns have emerged

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based on global prevalence. The most common global serotypes include CPS Ia, Ib, II,III, and V. In a perinatal context, however, many studies describe limited serotypetesting (18–20), and others were completed prior to inclusion of CPS IX (21–23). Theseare major limitations in such studies, but there are still numerous studies that haveincluded all known serotypes, and these generally support the overarching predomi-nance of the five main CPS types in a perinatal context (24, 25).

Global serotype distribution. A recent meta-analysis of maternal colonizationdescribed a global data set of serotype prevalences (24). Russell and colleagueshighlighted the regional variation for the less common serotypes, such as CPS IV, VI, VII,VIII, and IX. Prior to this analysis, the general consensus was that approximately 10 to30% of pregnant women were colonized with GBS; this analysis supports previousestimates and suggests that the global colonization rate in pregnant women is 18%,with regional estimates varying from 11 to 35%. South and East Asian countries had thelowest reported prevalences (11 to 12.5%), while the Caribbean was observed to havethe highest prevalence (34.7%) (24). The subsequently estimated neonatal disease ratefor GBS is 0.49 per 1,000 live births globally, with the highest incidence in Africa (1.12per 1,000 live births) and the lowest in Asia (0.30 per 1,000 live births) (25). Fiveserotypes (Ia, Ib, II, III, and V) have been estimated to encompass approximately 98%and 97% of the serotypes identified during maternal colonization and neonatal disease,respectively. This leaves a small proportion of colonization/neonatal disease casesattributable to the remaining five serotypes; however, it is important to highlight theseserotypes, as the dynamic has the potential to shift. Several studies have highlightedthe variation in serotype prevalence globally, and the results are summarized here,along with general trends, for each serotype (Table 1).

Ia. The frequency of different serotypes as colonizers makes determination ofdisease development an extremely difficult task. The asymptomatic colonization insome yet invasive disease progression in others emphasizes the complexity of thehost-GBS interaction. Maternal colonization by serotype Ia is seen globally (24), and itis the most prevalent serotype in maternal disease, according to a limited meta-analysis(including only the United States, United Kingdom, and France) (26). Regarding neo-natal disease, a previous meta-analysis found Ia to be the most frequent serotypecontributing to EOD; however, this global estimate lacked data from Asia (27). The latestanalysis includes Asia, and while overall trends of prevalence remain similar, SouthAmerica is the only region in which CPS Ia predominates over CPS III in cases of EOD(25). In contrast, in East Asia, unlike other regions, the prevalence of Ib surpasses thatof Ia (25).

Ib. East Asia has the largest proportion of neonatal disease attributable to CPS Ib,and within the Asian region, CPS Ib is second only to CPS III in predominance (25). InTaiwan, Lin and colleagues found CPS Ib to account for 21.6% of the isolates collectedfrom a mixed population of pregnant women, neonates, and nonpregnant adults,representing the most common serotype in the study (28). This frequency, however,was largely accounted for by nonpregnant adult invasive disease isolates, whichrepresented 26/29 CPS Ib isolates. Similarly, in South Korea, 22% of GBS serotypescausing infection in adults were identified as Ib (29). Differences in distribution havebeen observed within different cohorts, such as pregnant, neonatal, and adult popu-lations. Maternal colonization with CPS Ib in Mexico and South America has beenreported to be considerably higher than that in other countries (24). On the oppositeend of the spectrum, CPS Ib was the least prevalent serotype, after nontypeable (NT)isolates, to account for maternal disease (in the United States, United Kingdom, andFrance) (26).

II. Serotype II is the fourth most prevalent serotype in maternal disease, accordingto a study including the United States, United Kingdom, and France (26), and is the fifthmost prevalent in neonatal disease worldwide (25). The predominance of this serotypewas observed in pregnant women at the Thai-Myanmar border, where 24% of isolatesrecovered were CPS II, as reported by Turner and others (30). A study in Catalonia,Spain, assessed GBS isolates from pregnant women and pathogenic strains isolated

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TABLE 1 Summary of various serotyping distribution studies that highlight serotype variation, showing the variety of patients, specimens,clinical presentations, and methods useda

Study authors(yr) Location Patients Specimen type(s)

Clinicalpresentation Serotyping method(s) Serotypes Reference

Lin et al. (2016) Central Taiwan Neonates to adults Blood Invasive PCR All 10 28Pregnant women Vaginal and rectal Carriage PCR All 10 28

Uh et al. (2005) South Korea Adults NS Infection Latex agglutination Only Ia, Ib,II to VIII

29

Turner et al.(2012)

Thai-Myanmarborder

Pregnant women Vaginal and rectal Carriage Latex agglutinationand PCR

All 10 30

Lopez et al.(2017)

Catalonia,Spain

Pregnant womenand neonates

NS Carriage NS NS 31

NS Invasive NS NS 31Elikwu et al.

(2016)Nigeria Pregnant women Vaginal and rectal Carriage PCR All 10 32

Foster-Nyarko etal. (2016)

Gambia Infants Nasopharyngeal Carriage Latex agglutinationand PCR

All 10 33

Romain et al.(2017)

France Neonates andinfants

Blood andcerebrospinalfluid

Invasive NS (French NationalReference Centrefor Streptococci)

Only Ia to V 35

Bjorsdottir et al.(2016)

Iceland Adults Blood and synovialfluid

Invasive Latex agglutination All 10 36

Teatero et al.(2017)

Toronto,Canada

Pregnant women Vaginal and rectal Carriage PCR and latexagglutination

All 10 37

Teatero et al.(2015)

Toronto,Canada

Neonates to adults Blood, cerebrospinalfluid, and tissue

Invasive PCR and latexagglutination

All 10 38

Ferrieri et al.(2013)

Minnesota,USA

Infants Blood, cerebrospinalfluid, bone, joint,and postmortemsamples fromliver and lung

Invasive Immunoprecipitation All 10 39

Blumberg et al.(1996)

Atlanta, GA,USA

Infants to adults Blood, peritonealfluid, andcerebrospinalfluid

Invasive Capillary precipitin Only Ia, Ib,II to V

41

Belard et al.(2015)

Gabon Pregnant women Vaginal and rectal Carriage Latex agglutination All 10 42

Suara et al.(1994)

Gambia Pregnant women Vaginal and rectal Carriage Capillary precipitin Only I to VI 43

Neonates Throat, rectal, andumbilical

Carriage Capillary precipitin Only I to VI 43

Shabayek et al.(2014)

Egypt Pregnant andnonpregnantwomen

Vaginal Carriage PCR and latexagglutination

All 10 44

Lachenauer et al.(1999)

Japan Pregnant women Vaginal Carriage Inhibition enzyme-linkedimmunosorbentassay

Only Ia, Ib,II to VIII

45

Eskandrian et al.(2015)

Malaysia Neonates andadults

Vaginal and urine Carriage PCR and latexagglutination

Only Ia, Ib,II to VII

18

Blood, wound andskin ulcers,tracheal andgastric aspirates

Invasive/infection

PCR and latexagglutination

Only Ia, Ib,II to VII

18

Suhaimi et al.(2017)

Malaysia Neonates to adults(80� yr)

Vaginal, urine, andplacental

Carriage PCR and latexagglutination

All 10 46

Blood and tissue Invasive PCR and latexagglutination

All 10 46

Dutra et al.(2014)

Brazil Pregnant women Vaginal and perianal Carriage Capillary precipitin Only Ia, Ib,II to VIII

19

Adults Blood, urine, andmale genital tractdischarge

Invasive/infection

Capillary precipitin Only Ia, Ib,II to VIII

19

Chaudhary et al.(2017)

India Pregnant women Vaginal and rectal Carriage Latex agglutination All 10 49

(Continued on next page)

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from neonates with sepsis and found that serotypes Ia and II were significantly morefrequent than others as colonizing strains (31). Colonization of Nigerian pregnantwomen also showed a predominance of serotype Ia, while serotype II accounted for71.4% of the neonatal colonizing isolates (32). Likewise, GBS isolated from the naso-pharynxes of Gambian neonatal carriers found the highest prevalences of CPS V and II(33).

III. CPS III is well known for its association with disease, in particular EOD, and it hasbeen reported thoroughly worldwide and remains the leading cause of neonataldisease (25). Maternal prevalences differ by continent or region, as Africa, Australia, andNew Zealand have much higher prevalences, while the Middle East, Eastern Europe,South Asia (including India and Bangladesh), and Central America have lower rates (24).In coastal Kenya, CPS III accounted for the majority of maternal colonizing isolates and70% of the neonatal disease strains (34). In France, serotype III accounted for 83.9% ofinfant meningitis cases caused by GBS infection (35). The temporal dynamics of thisserotype were reported for adult invasive infections in Iceland, where the only signif-icant decline in serotype prevalence over the 39-year period was for CPS III (36). Thisobservation contrasts with those for other populations, such as neonates, in which it isattributed to the majority of invasive disease cases (25).

IV. Serotype IV is less prevalent globally than the other main serotypes (Ia, Ib, II, III,and V). Recent studies, however, have noticed the emergence of this serotype, partic-ularly in Canada and the United States (37–39). These studies also reported evidence ofcapsular switching relevant to this serotype, a concern for targeted therapies. Thepresence of serotype IV within a predominantly CPS III cluster of isolates from Francewas suggested to have occurred through capsular switching (40), and capsular switch-ing to serotype IV within clonal complex 17 was also reported in Kenya (34), whichfurther supports this as a cause for concern.

V. Early studies reporting the emergence of CPS V noted a close genetic relationshipamong the strains of this serotype and its recovery from all populations, but more sofrom nonpregnant adults (41). It is recognized as the third most prevalent serotypeassociated with maternal disease in the United States, United Kingdom, and France (26).Africa, more specifically West Africa, has a higher frequency of CPS V maternal coloni-zation than those of other regions, such as North America, Australia, and New Zealand,which have much lower prevalences (24). In Gabon, approximately one-third of strainsisolated from pregnant women were CPS V (42). This supports previous observations ofCPS V predominance by other studies of Gambian mothers and their infants and ofpregnant women in Egypt (43, 44).

TABLE 1 (Continued)

Study authors(yr) Location Patients Specimen type(s)

Clinicalpresentation Serotyping method(s) Serotypes Reference

Islam et al.(2016)

Bangladesh Neonates Umbilical cord Carriage PCR All 10 50

Ekelund et al.(2003)

Denmark Neonates to adults(80� yr)

Blood Invasive Precipitin test Only Ia, Ib,II to VIII

51

Paoletti et al.(1999)

Boston, MA,USA

Neonates andadults

Genitourinary tract,others NS

NS Precipitin test Only Ia, Ib,II, III, V,VI, VIII

52

Yan et al. (2016) China Pregnant women NS Carriage PCR All 10 53Toyofuku et al.

(2017)Japan Neonates Nasopharyngeal and

rectalCarriage PCR Only Ia, Ib,

II to VIII54

Slotved et al.(2017)

Ghana Pregnant women Vaginal and rectal Carriage Latex agglutination All 10 47

Gudjonsdottir etal. (2015)

Sweden Neonates andadults

Blood, cerebrospinalfluid, and synovialfluid

Invasive Latex agglutination All 10 55

Takahara et al.(2015)

Japan Neonate (casestudy)

Blood andcerebrospinalfluid

Invasive Latex agglutination All 10 56

aNS, not stated.

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VI. Considered one of the rarer serotypes (with VII, VIII, and IX), CPS VI is oftenreported in Asian countries, in particular Japan (45) and Malaysia (18, 46). While globalcolonization estimates place CPS VI in the minority, this serotype is thought to accountfor as much as 20% of serotypes observed in Southeast Asian pregnant women (24).

VII. Similarly, CPS VII is less well represented across the globe (24). Interestingly, itwas found to be the most common serotype in southern Ghana, in the first study toreport such serotype prevalence in pregnant women from West Africa (47). A numberof Malaysian studies observed serotype VII isolates in their cohorts, ranging from 1.7%to 21.4% of serotypes (18, 46, 48). This supports the observation of intracountryvariation that was similarly reported (although not for CPS VII) for serotypes in differentregions of Brazil (19). A study of maternal colonization in India observed CPS VIIaccounting for 6.7% of the serotypes and having a higher prevalence than that of CPSIb, which is indicative of Asian countries yet shows a unique distribution (49). Morerecently, Islam et al. observed that 37.1% of the GBS specimens isolated in Bangladeshfrom newborn umbilical cord areas (colonizing isolates) belonged to CPS VII (50).

VIII. Serotype VIII is strongly associated with Japan, with an early study reporting ahigh frequency in pregnant women (45). That study found a 35.6% prevalence of CPSVIII among serotypes, followed by CPS VI (also considered rare globally), amongcolonizing isolates from Japanese pregnant women (45). Thereafter, incidences of itspresence began to be described outside Japan. In Denmark, seven instances of invasivedisease isolates belonging to CPS VIII among nonpregnant adults were reported from1999 to 2002 (51). Also, one isolate colonizing a pregnant woman in Maryland wasrecognized as CPS VIII (52). Lately, the frequency of CPS VIII is generally low outsideJapan, and studies often describe few isolates (53, 54).

IX. The newest serotype, described in 2007, has had fewer chances for descriptionin the literature; however, in the last decade, studies have adopted new techniques,and now most test for all serotypes. As mentioned above, a study in southern Ghanaobserved CPS IX as having the second highest prevalence, behind CPS VII (47). ASwedish study assessed changes in serotype distribution over time for invasive disease(neonatal and adult populations) and suggested that circulating serotypes remainedstable from 1990 onwards; however, the study noted an increase in CPS VII to IX (55).Additionally, a case study in Japan described an incidence of ultra-late-onset sepsiscaused by CPS IX, and this demonstrates its capacity to play a role in disease (56).

Nontypeable isolates. Numerous serotyping studies result in isolates that do notrepresent any of the defined types and are thus considered nontypeable (NT). It is notknown whether this is a result of technique specificity or whether such isolates mayrepresent novel serotypes; either way, NT isolates may potentially skew the availabledata. Capsule loss and lack of expression are both potential contributors to this NTcategory (57, 58). One study assessed a collection of GBS isolates classified as NT byserological methods and went on to characterize them by a number of differenttechniques (immunodiffusion, pulsed-field gel electrophoresis [PFGE], and multilocussequence typing) (59). This resulted in all isolates being serotyped and found torepresent all types, excluding IV and VII to IX, with instances of multiple serotypes perisolate, which has been described previously (52). This may represent an incidence ofcapsular switching, a phenomenon that involves the genetic exchange of capsulargenes and thus enables expression of alternative capsule types, and it is proposed thatsuch horizontal transfer may be responsible for the capsular locus diversity (60–62). Ina former study by Ramaswamy and colleagues, 80% of isolates containing multipleserotypes contained a type V CPS-specific gene, and the authors proposed that thisserotype may have an association with increased competency and ability to acquireDNA (59). This is an interesting notion, but given that GBS is not thought to be naturallytransformable, the idea that capsular switching may result from increased competenceof CPS V seems unlikely; however, capsular switching has been reported by others (37,40, 63, 64). This is a concern for development of vaccines targeting the capsule, as thishas been an issue for the naturally transformable organism Streptococcus pneumoniaedue to capsular switching (65, 66).

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One of the major limiting factors in discussing GBS serotype distribution is that adirect comparison between studies can be difficult due to the number of differentstudy parameters assessed, such as specimen type and study population, and theadded complexity of various serotyping methodologies. For optimal surveillance out-comes, data on all types of patient cohorts are vital to completing the broader pictureof GBS epidemiology. Increasing our understanding of prevalent isolates associatedwith specific body sites and their potential to cause disease by monitoring theserotypes is the first step toward narrowing down invasive strain targets and surveyingthe serotype distribution dynamics.

Surface Proteins

In addition to the CPS, proteins are also present on the surfaces of GBS cells, andstudies have shown that antibodies against both CPS and surface proteins are protec-tive against GBS infection (67–69). The alpha-like protein (Alp) family proteins areamong the well-characterized GBS surface proteins and are significant virulence factors.These include alpha-C protein, Rib, Alp2, Alp3, Alp4, and epsilon (Alp1) and are encodedby the bca, rib, alp2, alp3, alp4, and epsilon/alp1 genes, respectively (70). Detection ofthe expressed surface proteins by serology or the presence of their genes by moleculartechniques, such as PCR or sequencing, can be used as another grouping tool. The Cantigen was the first identified surface protein antigen and has been found in numer-ous GBS strains, except for serotype III strains (71). Alps have been present in themajority of GBS isolates, but non-Alp isolates do exist. A total of 1.1% of isolates in onestudy were non-Alp isolates, and all were associated with invasive bloodstream infec-tions (72). Smith and others examined associations between the common serotypes (Ia,Ib, II, III, and V) and specific genes. They found that most genes tested (sbp1, bca, bac,rib, brp, pag, and psp) were common in only one or two serotypes, except for bca, whichwas present in �50% of all serotype Ib, II, and V strains (73). A review of several surfaceproteins reported correlations for alpha protein presence in CPS Ia, Ib, and II strains, yetit was found almost never in CPS III and only rarely in CPS V strains. Rib is expressed bythe large majority of CPS III, many CPS II, and a few CPS V strains. Alp3 is expressed byCPS V and VIII strains and Alp2, more rarely, by CPS Ia, III, and V strains (70).

Pulsed-Field Gel Electrophoresis

Pulsed-field gel electrophoresis (PFGE) is another molecular method that distin-guishes isolates with greater discrimination than that of serotyping for evaluation ofgenetic relatedness. It involves nucleic acid digestion with one or more restrictionenzymes (often SmaI in the case of GBS) to produce fragment profiles on an agarosegel, after which the profiles are then compared for similarity and grouped accordingly(74). Fasola and colleagues described this method for use in GBS in 1993, and Bensonand Ferrieri later reported an updated and more rapid PFGE technique for GBS,reducing the workflow from 6 to 8 days to 3 days total (75, 76). PFGE profile correlationswith serotypes have shown variation; Skjaervold et al. observed homogeneity for Ib, III,and V strains, while IV, Ia, and II strains were heterogenous (77). This suggests thatserotype grouping does not permit an understanding of close genetic relationships.While a greater depth of genetic relationship can be observed using PFGE than usingserological typing, there are limitations with this method. Due to the lack of a uniformtyping system with respect to naming, PFGE analyses can be difficult to comparebetween studies: what may be PFGE clone A in one study could be clone 37 in another(78, 79). Therefore, pattern and band sizes must be used for comparison betweenstudies. In this respect, it is mainly useful for comparison within a study to see diversityamong isolates and modes of transmission. For example, mother and infant paired GBSspecimen fragment profiles were observed to have common patterns, highlightingvertical transmission (80). In the past, identifying fragment banding on gels wassubjective and lacked accuracy in the reporting of band sizes, making comparisonacross studies difficult. The idea of using restriction enzymes with minimal cutting sitesaims to reduce this by producing fewer fragments for visualization on the gel (74).

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Regardless of any limitations, PFGE has identified variation within and across serotypesand has led to the progression of the molecular epidemiology of GBS.

Multilocus Sequence Typing

Jones and colleagues developed the multilocus sequence typing (MLST) method forGBS by using seven defined housekeeping genes (adhP, atr, glcK, glnA, pheS, sdhA, andtkt) (81). The MLST database was produced by Jolley and colleagues and currentlyincludes over 4,000 GBS isolates (82). Allelic variations among housekeeping genesallow the determination of different sequence types (STs). These STs can then beclustered into clonal complexes (CCs), which are conservatively defined by membershaving no more than one allelic difference from other members of the cluster.

The MLST database is a valuable resource that enables sharing of data; the publiclyavailable information for GBS includes a range of criteria to assess, including thecountry of origin, serotype, and specimen type. Although there remains a reportingbias, in that only submitted information is available, the data represent a mix of globalinformation which is very useful. An audit of the GBS MLST database (https://pubmlst.org/sagalactiae/) found a total of 4,131 isolates from 38 different countries. Of these,3,949 isolates had been assigned an ST (n � 635). Twelve STs account for 73% of theGBS isolates with available MLST data (Fig. 1). The remaining STs (27%) each account forless than 1% of all isolates, and 525 STs have a single isolate submitted to the database.

Having access to the location of each isolate’s origin enabled categorization of STsby continent (Fig. 2). This highlighted gaps in the global data, with no isolates fromAustralia and New Zealand available, unless they are not stated (categorized as“unknown”). Examining the main contributors within each continent, Netherlands (n �

FIG 1 Frequencies of the 12 most prevalent GBS sequence types available from the MLST database,which includes a total of 635 sequence types (remaining STs account for �1% each).

FIG 2 Contributions by continent of GBS isolates available in the MLST database, as percentages of allisolates (South America represents 0.1% and is therefore not visible).

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1,230/1,610 isolates), Kenya (n � 1,133/1,172 isolates), Japan (n � 490/550 isolates),United States (n � 325/491 isolates), and Brazil (n � 3/5 isolates) have submitted themost isolates within Europe, Africa, Asia, North America, and South America, respec-tively.

Associations between ST and serotype have been reported in the literature, with someshowing a strong correlation and others very little; this is also observed in the MLSTdatabase (Fig. 3). Ramaswamy et al. observed a correlation between CPS III and ST-17 andbetween CPS Ib and ST-12, and they found that CPS V was represented in all STs except forST-17 (59). Similar trends are observed within the MLST database, where each of the mostprevalent STs appears to be dominated by a particular serotype (Fig. 3). The serotypevariability in some instances, for example, ST-1, may be suggestive of discordance withserotype profiling. Trends observed by various studies reveal a variable serotype presencewithin ST-1, variation between CPS Ib and II within ST-10, and a predominance of CPS IIIwithin ST-17 and ST-19 and of CPS Ia within ST-23 (83, 84). Within the clonal complexes,homogeneity of serotypes is evident in the CC-17 group, with all isolates representing CPSIII, except for a small proportion with unspecified serotypes. Similarly, within CC-19, ST-182includes CPS III only, but other STs in this complex show variation, especially ST-28, whichis predominantly CPS V (Fig. 3). From an evolutionary perspective, caution must be takenwhen inferring phylogenetic relationships, as suggested by Sorensen et al., due to theindication that different segments of the GBS genome evolved independently (85). Withthis in mind, MLST is perhaps not the best method for describing evolutionary relationships,but for the purposes of epidemiology at the current scale, it should be acceptable now thatwe are aware of these factors.

Recurring themes in the literature include the numerous studies that have describedthe association between ST-17 and invasive neonatal disease (83, 86–90) and, further,the relationship between this lineage and meningitis (91). Neonatal invasive isolatescollected over a 10-year period in Sweden showed variation in genotype prevalenceover time and in different regions, in particular the emergence of CC-1 and subsequentdisappearance of CC-23 (88). These temporal changes emphasize the importance ofunderstanding GBS epidemiology and tracking changes in prevalence worldwide: ST-17may expand and/or other STs may become hypervirulent over time.

The MLST profiling scheme is publicly available and curated, making it an invaluableepidemiology resource. If the database were treated like a repository, the epidemio-logical surveillance would be greatly enhanced, which would be desirable for targetedtherapeutics assessment.

FIG 3 Serotype distribution within each sequence type, using the public MLST database for GBS, for the12 most represented sequence types within the database, as well as their corresponding clonalcomplexes (CCs), where appropriate.

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Random Amplified Polymorphic DNA and Repetitive-Sequence-Based PCRs

Random amplified polymorphic DNA PCR (RAPD-PCR) and repetitive-sequence-based PCR (rep-PCR) are techniques that rely on the amplification of DNA via randomprimers (RAPD-PCR) (92) or repetitive sequence target primers (rep-PCR) and result ingenomic fingerprinting profiles, as the generated amplicons lead to strain-specific bandpatterns on an electrophoretic gel.

The RAPD assay has been used in a number of genotyping contexts, such asevolution and genetic relatedness (93), epidemiology (46, 94), transmission (95), andisolate variation within individual patients (96–98). One study examined RAPD profilesof GBS isolates from a number of sites, such as blood, cerebrospinal fluid, and maternalbreast milk, in cases of LOD in neonates (n � 4) (96). It found identical banding profilesfor all sample types from individual patients and differing types between patients, butthis was representative of a small sample size. Likewise, Brzychczy-Wloch et al. usedRAPD-PCR to suggest that GBS isolates from colonized neonates originated from thecolonized mothers, regardless of mode of delivery, as they had identical genotypicprofiles (99). While detection of identical clones via RAPD profiles can suggest verticaltransmission, other studies have used this to demonstrate horizontal transmission inneonates born to noncolonized mothers that likely acquired GBS from the hospitalenvironment, as identical profiles were observed in other hospital wards (100).

Toresani et al. found 16 profiles for 21 GBS isolates tested by RAPD assay, and further-more, successive samples from two patients showed different genotype profiles, suggest-ing reinfection (97). In contrast, El Aila et al. compared culture methods and genotypedmultiple isolates collected from individual patients. RAPD testing of 118 isolates from 32pregnant women resulted in 66 genotype profiles, including cases of multiple differentgenotypes at each site (vagina and rectum), demonstrating that assumed reinfection maybe due to a lack of initial identification (98). This highlights the use of RAPD assay forsingle-center studies and its integration with high-resolution capillary electrophoresis,which enhances accuracy and provides digital fingerprints (98).

Numerous studies have observed correlations between RAPD profiles and clusteringof strains with resistant phenotypes (101, 102). The results from a study of macrolide-resistant GBS isolates suggested that PFGE was a more precise tool than RAPD-PCR foranalyzing molecular epidemiology (95). In contrast, Zhang and colleagues (103) foundthat the clustering of the isolates by RAPD-PCR was in concordance with previous PFGEfindings suggesting that clusters could be serotype specific (80).

The great advantages of RAPD assay are a relatively short procedure time and asimple methodology, which make it a suitable tool for suggesting clonal relatedness inclinical settings and for monitoring transmission. Comparison between studies can bedifficult, however, particularly if different primers are used. The random nature of thisprofiling technique provides variation and enables discrimination between clones, butsimilar to the PFGE technique, due to the lack of specific targets, the information thisprovides beyond strain similarity is somewhat limited unless further genetic analysis isundertaken.

The literature assessing rep-PCR for GBS is limited, with one study comparing therep-PCR Diversilab system with MLST and PFGE by using clinical adult and neonatal GBSisolates (n � 179) (104). The clustering concordances of PFGE and rep-PCR weresimilarly low, but PFGE had a greater discriminatory power than that of rep-PCR (104).One study compared both RAPD-PCR and rep-PCR techniques to genotype GBS isolatesfrom fish and observed RAPD-PCR to have a greater level of variability than that ofrep-PCR between strains, with 13 and 9 profiles, respectively (105). This is not support-ive of the use of rep-PCR over other methods tested, including MLST and PFGE. rep-PCRtyping is notorious for its susceptibility to minor variations in experimental conditionsand reagents, resulting in poor reproducibility (106, 107).

Multilocus Variant-Number Tandem-Repeat Assay

Various bacterial species have been typed through the detection of variable-number tandem repeats (VNTRs), which is based on the repeated sequences that

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make up DNA at different loci and that are found throughout bacterial genomes(108). As the name suggests, these VNTR loci vary in repeat number, allowing for anassay of a combination of several VNTR loci to generate different strain-specificprofiles. This is known as a multilocus variant-number tandem-repeat analysis(MLVA) and has a principle similar to that of MLST; however, rather than house-keeping genes, MLVA uses VNTR loci (109). This typing scheme was developed forGBS by Radtke and colleagues and includes five of the most diverse loci (SATR1[110], SATR2, SATR3 [111], SATR4 [112], and SATR5 [113]) (109). The authors foundclustering by CPS/surface protein typing or MLST to generally correspond with theMLVA profiles, but the latter was more discriminatory. A total of 126 GBS isolatestested were profiled as having 70 different MLVA types (MTs), compared to 36 STsby MLST and 19 CPS/protein types. A specific number of 15 repeats within SATR2was observed to correspond with serotype IX. Additionally, for one of the threedescribed SATR3 alleles, all isolates of that allele (except one) belonged to ST-17,known to account for a large proportion of neonatal infections (81, 88). Other MLSTgroups were more dispersed, including CPS V/ST-1, for which SATR5 resolved intoa number of profiles. This is interesting due to the often homogeneous reports ofthis subgroup in other studies (28, 77). The SATR1 locus is considered to becomposed of clustered regularly interspaced short palindromic repeats (CRISPR),and this worked efficiently as part of the MLVA scheme.

Additional MLVA schemes have been reported, one of which used six VNTR loci,including three described by Radtke et al. (109, 114). Similar results were observed inthat study, with greater isolate discrimination reported with the MLVA technique (98types) than with MLST (51 types). The clustering patterns observed for MLVA typesshowed similarity to MLST CCs; in particular, all human strains of MLST CC-17 appearedin MLVA cluster 9 (114). This scheme was able to categorize MLST CC-23 into twoclusters, one accounting for CPS III and the other for CPS Ia, which highlights thisscheme’s ability to distinguish strain variability within lineages (114).

A study of commensal GBS colonization of nonpregnant women of reproductiveage utilized MLVA for genotyping and observed 15 types among the 86 GBS isolates(115). For pregnant women, 30 MTs from a total of 41 GBS isolates were observed,which suggested a highly diverse population structure (116). The MTs are difficultto compare between studies, though, as there is no mention of a database in whichnaming conventions are uniformly enforced; however, a database has been createdfor this purpose (http://www.mlva.net) but unfortunately does not include GBS.

CRISPR Locus 1

Lastly, the molecular target which was mentioned above as one of the loci of theMLVA scheme is CRISPR as well as Cas (CRISPR-associated proteins). These are knownfor their role in bacterial host defense and adaptive immunity against foreign invadingDNA, such as bacteriophages and mobile genetic elements (117). The genetic arrange-ment that this system follows results in a polarized orientation, which allows trackingof ancestral invasions over time (118). In GBS, two CRISPR-Cas systems have beenidentified, including a type II-A system (ubiquitous and functional) and a type I-Csystem (rare and often incomplete), associated with CRIPSR locus 1 (CRISPR1) andCRISPR2, respectively (119, 120). The ubiquitous nature of CRISPR1 makes it an attrac-tive molecular marker with which to track changes in the genome. The highly con-served direct repeats form the spacers between introduced genetic materials and cantherefore be monitored for changes. Using this method, Beauruelle and others wereable to monitor the vaginal GBS colonization of 100 women over an 11-year period(121). This extensive study highlights the influence of genetic variables that alter theseorganisms over time, for example, bacteriophage infection. This is an example of newepidemiological markers that may assist in understanding these bacteria, their coloni-zation, and their pathogenic tendencies.

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FROM TARGETS TO TREATMENT

The purpose of the targets and molecular assays presented above is to understandthe population of GBS with respect to colonization and disease; by distinguishingdifferences between strains, we can begin to associate specific features with clinicaloutcomes. Equally, by identifying similarities that are represented across the majority orthe entire population of GBS strains, we can target these bacteria more broadly. Withinantenatal settings, the current preventative measures for GBS include antenatal GBSscreening (risk or culture based) and subsequent intrapartum antibiotic prophylaxisprior to delivery. This has resulted in reductions in EOD rates as reported by the Centersfor Disease Control and Prevention and is also recommended in other countries (10, 11,122, 123). Unfortunately, no change in LOD has been observed with such preventativestrategies; however, this is likely due to the nature of transmission (nosocomial orcommunity acquired) (124).

Due to the recommended IAP, antibiotic exposure has become widespread, but thepotential for resulting adverse events is unclear, as highlighted in a recent systematicreview (125). While consistency is lacking for data on development of antimicrobialresistance and long-term adverse events as a result of IAP for GBS, infant microbiomedisruption has been observed by numerous studies (126–132). However, due to the lackof high-level (species) taxonomic data and the myriad other methodological problemsthat are still rampant in microbiome studies (lack of negative controls and properselection of primer sets) (133), with the current data it remains unclear what impact thismay have on neonates. With the potential implications in mind, however, it is importantto examine alternative preventative and therapeutic strategies.

Maternal GBS vaccination has been proposed as an alternative preventative strategydue to the ability of maternal IgG to cross the placenta and provide immunity for thefetus (134). Baker and Kasper identified an association between deficient maternalantibody levels and the occurrence of neonatal GBS infection. That study also detectedGBS antibody titers in the umbilical cord sera of three healthy neonates born tomothers with demonstrable antibody levels (60 to 80% of the maternal levels weredetected), suggesting transplacental transfer and illustrating the potential for a mater-nal vaccine (135). The benefit of maternal vaccination has since been described, and anumber of GBS vaccines have been developed (134, 136–138).

While no vaccines against GBS are currently licensed and available, several polysaccha-ride conjugate and surface protein vaccines are under trial (137, 138). Through comparisonof the vaccine targets with the global GBS epidemiology, we can identify areas of vaccinecoverage. Numerous studies that have identified the less commonly recognized serotypeswithin their populations have raised concern about vaccinations targeting specific sero-types, such as Ia, Ib, and III, all of which are included in the trivalent vaccine currentlyfurthest along in progress, with completion of a phase Ib/2 clinical trial (ClinicalTrials.govnumber NCT01193920) (139, 140). A review by Lin et al. describes such challenges faced bycapsule-based conjugate vaccines against GBS, in addition to dealing with the potential forserotype replacement and capsular switching (138). More recently, a pentavalent vaccinetargeting serotypes Ia, Ib, II, III, and V commenced a phase I trial on healthy volunteers(ClinicalTrials.gov number NCT03170609); if successful, this may be an effective GBS vaccineoutside Asia, as it covers the five major circulating serotypes in the United States, Europe,and Australia (24).

Alternative vaccination strategies have focused on proteins. Surface proteins havebeen included as vaccine targets in addition to capsule types, and given the variety ofcirculating serotypes described, these may provide a broader, more universal target toexploit, which would be ideal for vaccine development (137). Although few surfaceproteins are conserved across all strains, Maione and colleagues provided evidence ofprotein vaccination in female mice with the ability to elicit protection in 43 to 80% ofcases of GBS challenge to pups born to the vaccinated mother (141). Four proteins,including a conserved Sip protein (SAG0032) encoded within the core genome ofstrains, were included in this study, in addition to three other antigens (SAG1404,

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SAG0645, and SAG0649) which had a variable presence in the genome (141). Studies inhumans have been described by Heath (137) and include multiple studies of monova-lent, one bivalent, and several trivalent CPS-based vaccines, all in the proof-of-conceptstage involving trials in pregnant women. A bivalent vaccine including the N-terminaldomains of the surface proteins alpha-C and Rib is currently in development by MinervaXand has completed phase I clinical trials (ClinicalTrials.gov number NCT02459262). Larssonet al. reported the association between low protein alpha and Rib antibodies and theoccurrence of neonatal invasive infection (142). While the type of vaccine is importantin terms of coverage, the implementation is equally important in considering access,especially in low-income settings and developing countries, where screening andwidespread prophylaxis are often not practical (143). Based on the World HealthOrganization guidelines, GBS vaccination, particularly in South Africa, would be verycost-effective (144). In developed countries, such as the United States, Kim and othersevaluated the cost-effectiveness of a maternal vaccine compared to screening/IAP(145). They concluded that �70% vaccine efficacy in addition to IAP for unvaccinatedwomen would prevent more disease than current strategies, with a similar economicburden (145). Epidemiological data about GBS are invaluable not only for vaccinedevelopment and success but also for other future targeted therapeutic agents, such asbacteriophage therapy (146).

CONCLUSIONS

This review describes different commonly used and emerging techniques to defineGBS epidemiology and phylogeny. Some traditional targets, such as serotypes, arewidely reported but lack the level of definition that other molecular targets can providewith respect to genetic relatedness and pathogenic features. The difficulty lies inrecognizing these targets and widely reporting them to provide a comparable basis forglobal surveillance. It is likely that future epidemiological efforts to monitor GBS willinclude the reporting of a combination of these targets and will in turn refine theassociation between these different components. The epidemiology of GBS providesinsight into the adaptation and evolution of these organisms through examination oftheir genetic relatedness and population structure. Understanding GBS as an oppor-tunistic pathogen is one aspect to arise from the proposed surveillance efforts; anotheris guidance for development of future therapeutics. Vaccines based on serotypescommonly found in one area may not include prevalent serotypes of another due tothe geographic variation observed even at the regional level. To vet these coverageissues, surveillance of different targets within GBS is required to monitor prevalentisolates in all populations. Additionally, following vaccine implementation, this willprovide a platform to monitor shifts in GBS dynamics and to identify emergingpathogen types before outbreaks occur. Broader coverage may result from proteinvaccine development, which further emphasizes the importance of characterization ofa range of targets. The targets outlined here each have individual relevance, althoughuniformity in reporting profiles would be ideal for global comparisons. Currently, MLST,while less discriminatory than MLVA, comprises the only method with an establisheddatabase to enable this comparison and provide the added confidence of curation.

ACKNOWLEDGMENTSL.L.F. is supported by an Australian Government Research Training Program Schol-

arship and a Professor Gordon King Postgraduate Scholarship, provided by the Womenand Infants Research Foundation. M.S.P. is supported by an NHMRC project grant (grant1077931).

We have no conflicts of interest.

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Lucy L. Furfaro is currently completing herPh.D. at the University of Western Australiaand previously completed her B.S. and Hon-ors programs at the University of WesternAustralia. Her research interests include peri-natal microbiology, with a focus on group Bstreptococcus and treatment alternatives toantibiotics, such as bacteriophage therapy.This area of research has been pursued overthe last 4 years as part of Honors and post-graduate studies.

Barbara J. Chang received her Ph.D. fromMonash University, Australia, followed bypostdoctoral positions at the University ofCalgary, Canada. Currently, she is the Direc-tor of Postgraduate Programs in InfectiousDiseases at the School of Biomedical Sci-ences at the University of Western Australia.Her research interests include the biologyand genetics of bacteriophages, anti-quorum-sensing agents, and bacterial pathogens, in-cluding Clostridium difficile, Moraxella ca-tarrhalis, and group B streptococcus.

Matthew S. Payne was awarded his Ph.D. inmolecular microbiology from the Universityof Queensland, Australia, and has since con-ducted postdoctoral research at Kings Col-lege London, United Kingdom, and La TrobeUniversity, Australia. Dr. Payne is currently atThe University of Western Australia, wherehe is focused on preventing infection-mediated preterm birth. His research inter-ests include the microbiology of pretermbirth, microbial metagenomics, Ureaplasmaand Mycoplasma spp., and antibiotic and nonantibiotic treatment reg-imens for prevention of preterm birth and neonatal sepsis.

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