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Group B streptococcal disease is the most common cause of bacterial sepsis and menin-gitis in newborns in developed countries and a common cause in the developing world; the disease is of en fatal and frequently causes se-vere sequelae in survivors (1). Group B strep-tococcal infections are unusual in that the majority of cases occur in newborn infants who acquire the pathogen from their moth-ers at birth (2). T erefore, development of an ef ective vaccine for maternal immuniza-tion could eliminate neonatal mortality and severe morbidity associated with this disease.

Before the introduction of conjugate vaccines—which are created by binding a poorly immunogenic poly-saccharide antigen to a carrier protein to build an ef ective immunogen—the majority of cases of bacterial meningitis and sepsis in children were caused by Haemophilus inf u-enzae type b (Hib), pneumo-coccal, and meningococcal species. Routine vaccination with Hib-, pneumococcal-, and meningococcal-saccharide conjugates has nearly elimi-nated these diseases (1, 3, 4). To further accomplish to-tal control of meningococcal disease, a protein-based vaccine against serogroup B meningococcus was recently approved by the European Medicines Agency (5).

Although Group B streptococcus (GBS) has been recognized as the major cause of infant bacterial meningitis and sepsis in

developed countries since the 1970s (6–9), it is the only remaining major cause of bac-terial sepsis and meningitis in children for which no vaccine is commercially available yet. A protective role for capsular polysac-charide-specif c antibodies was demonstrat-ed several years ago in animal models of infection (10) and in humans (11). A conju-gate GBS vaccine is now in clinical trials in order to assess safety and immunogenicity. Here, we report on a symposium held in Siena, Italy, in which participants discussed

the impact of GBS and potential approaches to maternal immunization with conjugate vaccines for the prevention of perinatal group B streptococcal disease.

GROUP B STREPTOCOCCAL DISEASEGBS is a β-hemolytic Gram-positive encap-sulated bacterium that exists as a normal part of the human gastrointestinal (GI) f ora and colonizes the vagina in 10 to 50% of women. Bacteria can reach the newborn through the birth canal and cause disease

(12). T e classic presentation of early-onset disease (EOD) includes overwhelming re-spiratory distress, cardiovascular instabili-ty, pneumonia, sepsis, and meningitis, of en ending in death. EOD of en appears during the f rst hours af er birth, with most cases occurring within 24 to 48 hours and the re-maining within the f rst 7 days of life. Risk factors for infection are prolonged rupture of membranes (rupture of the amniotic membrane at least 18 hours before delivery of an infant), prematurity, maternal fever, GBS infection in a previous child, and black race (13, 14).

GBS also causes late-onset disease (LOD), which presents between 1 week and 3 months of life and peaks in frequency at about 1 month of age. LOD can be acquired from the mother by colonization of the infant during birth, and case reports have also identif ed breast milk as a source of infection. Nosocomial transmission has been reported as well (15). T e majority of EOD cases present as sepsis, whereas meningitis is more frequent for LOD (16), and in some geographical settings, the number of such cases can equal or exceed the number of cases presenting as sepsis (17, 18).

As with EOD, prematurity appears to be an important risk factor for LOD, and incidence is higher among black infants. Apart from timing of colonization, the factors that in% u-ence whether an infant will develop EOD or LOD are unknown.

Despite early antimicrobial treat-ment and improvement in neonatal intensive care in many countries, up to 10% of GBS infections are lethal, and 25 to 35% of surviving infants with meningitis experience per-manent neurological sequelae (19). Mortality in patients with EOD in-creases with prematurity, reaching 24.1% of the cases in infants younger than 24 weeks gestation, then de-creasing to 13.9% in infants between 24 and 37 weeks and to 5.7% in those

older than 37 weeks gestational age (17).GBS also causes maternal infections, in-

cluding bacteremia, chorioamnionitis, uri-nary tract infections, endometritis, and sep-tic abortion, and morbidity and mortality in the elderly and in immunocompromised adults (16).

Recently it has been demonstrated that selected strains of GBS lacking the hemo-lysin repressor CovR/S accelerate the fail-ure of the amniotic barrier and allow GBS to penetrate the chorioamniotic membrane

B A C T E R I A L D I S E A S E

Preventing Newborn Infection with Maternal ImmunizationSteven Black,1 Immaculada Margarit,2 Rino Rappuoli2*

*Corresponding Author. E-mail: rino.rappuoli@novartis.com

1Center for Global Health, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA. 2Novartis Vaccines, 53000 Siena, Italy.

P E R S P E C T I V E

Group B streptococcal disease is a common cause of bacterial sepsis in newborns and is often fatal. To protect these babies, a vaccination program must target pregnant women for immunization so that the resulting antibodies can be passively delivered from the mother to the fetus. Scientists met in Siena, Italy, to discuss potential approaches to maternal immunization for the prevention of perinatal group B streptococcal disease.

Fig. 1. Mapping neonatal disease. The estimated number of cases of GBS infection per 1000 live births in infants <90 days of age is indicated in diff erent colors. Countries in gray do not have incidence data avail-able. Adapted from data reviewed by Edmond et al. (21).

0 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80

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barrier and gain access to the fetus (20). T is provides a pathophysiologic basis for the previously demonstrated ability of GBS to cause maternal chorioamnionitis, as well as to gain access to the fetus and cause EOD.

GLOBAL EPIDEMIOLOGYPerinatal GBS disease is a global problem, although surveillance data to document the true disease burden have been dif cult to obtain (Fig. 1) (21). Factors that likely con-tribute to underestimation of cases include the lability of the organism in the laborato-ry, the small volumes of blood available for cultures from infants, use of nonautomated culture methods, poor surveillance, and barriers to health care access, especially in developing countries (22).

When women with vaginal GBS de-liver, about 50% of their infants become colonized as well (23). Nearly 2% of these colonized infants go on to develop early-onset GBS disease. T e incidence of EOD in the United States has declined from 1.7 cases per 1000 live births in the early 1990s to 0.35 cases per 1000 live births in 2005, af er implementation of universal antenatal culture screening and antibiotic prophylaxis (16). Conversely, the incidence of LOD (0.4 cases per 1000 live births) has remained unchanged over the past 20 years (24). In many preterm infants, EOD may not be immediately recognized because its early symptoms can be mistaken for those of hyaline membrane disease. In the UK, the incidence of LOD is 0.24 cases/1000 live births (17). Among infants with GBS meningitis, 13% of survivors have severe disabilities, and an additional 17% have moderate disabilities (25).

Because of a paucity of reliable surveil-lance data, there is only limited evidence that suggests that the disease burden in de-veloping countries is higher than that in the developed world. A recent meta-analysis and global review (21) revealed that only a few studies met preestablished inclusion

criteria. Zero incidence of early-onset peri-natal GBS infection was reported in India, where surveillance was poor, whereas inci-dence in South Africa is approximately f ve times higher than that observed in the UK or the United States (26). In countries that use screening and intrapartum prophylaxis, EOD has been greatly reduced, but LOD in-cidence has remained untouched by this in-tervention. It is likely that if robust surveil-lance data were available, the incidence rates in developing countries would be similar to those in the United States before the use of screening and intrapartum prophylaxis.

VACCINOLOGYIn 1976, Baker and Kasper noted a corre-lation between the absence of type-specif c anticapsular maternal antibody and suscep-tibility to GBS infection (11). T is suggests that placental transfer of maternal antibody for a specif c serotype is associated with protection (27). T is observation led to the early consideration of maternal vaccination as a possible means of protecting infants from disease. In the 1970s and 1980s, pure polysaccharide vaccines were considered, but when these were evaluated in adults, they were insuf ciently immunogenic, with an overall response rate of 63% (28). Recog-nizing the success of polysaccharide conju-gate vaccines for Hib, scientists have turned their attention to the development of a con-jugate vaccine for maternal immunization.

Vaccines have now been developed against GBS serotypes Ia, Ib, II, III, and V by conjugating the capsular polysaccha-rides from GBS with tetanus toxoid. For each GBS serotype, functional activity has been demonstrated in vitro for vaccine-induced antibodies (29). In vitro func-tional testing correlated well with standard enzyme-linked immunosorbent assay test-ing (30). In phase 1 clinical trials, these vaccines were well tolerated in adults, with no serious adverse events reported. In an-other phase 1 trial, a type III tetanus toxoid

conjugate vaccine was administered safely to healthy pregnant women. In separate phase 2 evaluations, GBS type Ia and type V vaccines were administered to seronega-tive women, who responded with a robust response of at least a 1 µg/ml increase in type-specif c antibody 1 month af er receipt of vaccine. By 1 year af er vaccination, an-tibody levels had declined to approximately half the peak level. A comprehensive review describing the above-mentioned trials and their results was published in 2011 (31).

Until recently, all studies of conjugate GBS vaccines had been conducted in aca-demic settings. Recognizing that involve-ment of a commercial vaccine company would be required to make protection against group B streptococcal disease a practical reality, Novartis began the devel-opment of a conjugate GBS vaccine that contains CRM197 conjugates for GBS se-rotypes Ia, Ib, and III. Preclinical studies of this vaccine in pregnant mice revealed 73 to 93% protection against a lethal chal-lenge in their of spring. T is vaccine is now in phase 2 clinical trials (31), with a phase 3 ef cacy trial being planned. On-going preliminary analyses indicate that all regimens and dosages have been well tolerated and immunogenic in both non-pregnant and pregnant women. T e po-tential coverage (in percent) of such a tri-valent vaccine is shown in Table 1, based on available epidemiological data for the United States, Germany, the UK, South Africa, and Malawi (16, 17).

Another GBS vaccine, which contains serotypes Ia, Ib, II, III, and V, as well as a combination of pilus proteins broadly rep-resented in the GBS population (32, 33), is in the preclinical development stage.

MATERNAL IMMUNIZATIONAlthough maternal immunization has been extraordinarily successful in the preven-tion of neonatal tetanus and immuniza-tion of pregnant women is now routinely

Table 1. Serotype survey. Shown is the potential coverage (percent) of a trivalent GBS vaccine in various countries. Data are extrapolated from (16) and (21).

Early-onset disease Late-onset disease

Serotype USA Germany UK S Africa Malawi USA Germany UK S Africa Malawi

Ia 30 17 32 23 26 24 11 17 14 20

Ib 7 5 6 5 7 7 4 7 0 4

III 28 58 37 58 52 51 77 67 84 72

Trivalent (Ia+Ib+III) 65 80 75 86 85 82 92 92 98 96

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recommended in the United States for pre-vention of in% uenza in both the infant and mother, data on the safety and ef ective-ness of maternal immunization from ran-domized clinical trials are rare, and most data come from observational studies and administrative databases (34). Recently, a randomized comparative trial of an in% u-enza vaccine versus a pneumococcal poly-saccharide vaccine demonstrated the safety and ef ectiveness of both of these vaccines in pregnant women (35). In 2011, the U.S. Advisory Committee on Immunization Practices added the adult booster vaccine Tdap (against tetanus, diphtheria, and per-tussis) to the list of vaccines that should be routinely administered during pregnancy in order to prevent neonatal and young infant deaths and hospitalizations associ-ated with these diseases. No concerning patterns of pregnancy outcomes have been reported. Last, data on a more limited number of pregnant women showed that pneumococcal and meningococcal poly-saccharide vaccines are safe and immuno-genic (36).

All of the above-mentioned vaccines were shown to be ef ective and safe in non-pregnant adults before their use in preg-nancy. In contrast, for GBS neonatal sepsis the primary target population for a GBS

vaccine is pregnant women, and one could not rely on demonstration of safety and ef-fectiveness in nonpregnant women to eval-uate and license this vaccine. However, the knowledge that we have gained through extensive use of tetanus toxoid and, more recently, the in% uenza vaccine is reassur-ing on two counts. First, infrastructure now exists in many countries to vaccinate pregnant women, and this infrastructure should be easily adaptable to a new GBS vaccine program. Second, the extensive experience with in% uenza and tetanus vac-cines has demonstrated that vaccination of pregnant women is both safe and ef ca-cious in preventing neonatal disease.

CURRENT LANDSCAPE AND THE FUTUREPerinatal group B streptococcal disease is a global problem (Fig. 1), and epidemiologi-cal data from many countries are either of poor quality or unavailable. T erefore, cre-ating disease awareness and prioritization of infant GBS disease as a public health problem in much of the world will require basic work to demonstrate the epidemiol-ogy of GBS in those settings.

In the absence of an available vaccine, the United States began, in 2002, routine universal prenatal GBS screening with

administration of intrapartum antibiotic prophylaxis for women who test positive. A recent review of this program indicated that 85% of pregnancies are now screened and that 98% of these women have results available at delivery, with more than 80% of these women receiving appropriate anti-biotic prophylaxis (37). T ere are, however, gaps with this program. Only a minority of preterm infants, who are at higher risk for GBS disease, received screening before delivery, and only slightly more than half of these women received intrapartum anti-biotic prophylaxis before delivery. In addi-tion, although antibiotic resistance has not been an issue to date, if ampicillin-resistant GBS strains become prevalent, this will ad-versely impact the viability of intrapartum prophylaxis programs because ampicillin is the mainstay of these programs. Currently, in the United States more than 60% of EOD cases occur in women who tested negative for GBS colonization when screened and hence did not receive antibiotic prophy-laxis. Because screening normally occurs weeks before delivery, these cases of EOD may result from new colonization and are not preventable with the current screening program. Perhaps the biggest drawback is that this screening approach has no impact on late-onset GBS disease.

Last, the logistical coordination re-quired to implement such a screening and follow-up system is only available in a few developed countries, leaving the rest of the world without a viable approach for prevention of GBS disease. T erefore, al-ternative approaches are needed, such as maternal vaccination, which would have broad applicability without the logistical constraints of prenatal screening and anti-biotic prophylaxis.

Symposium participants reached a con-sensus: Perinatal group B streptococcal disease remains a substantial global health problem. Recommendations of the work-ing groups as to how to best approach this problem are summarized in Table 2. T e success of prenatal maternal immuniza-tion programs for tetanus and in% uenza as well as the potential for future availability of immunogenic conjugate vaccines make this an ideal time to move forward with the development of a GBS vaccine.

SUPPLEMENTARY MATERIALSwww.sciencetranslationalmedicine.org/cgi/content/full/5/195/195ps12/DC1Table S1. Novartis patents pertaining to GBS vaccine development.

Table 2. Needs assessment and recommendations.

Working group Needs and recommendations

GBS epidemiology and vaccine need in developed countries

• Standardize surveillance data throughout Europe

• Raise awareness of GBS disease

GBS epidemiology and vaccine need in developing countries

• Standardize surveillance worldwide

• Arrange PCR or culture-free testing

• Set up studies to assess true disease burden

Moving forward with a maternal immunization platform

• Collect epidemiology data to drive decision-making

• Evaluate the impact of maternal immunization on natural infection and response to vaccines in infants

• Assess duration of protection provided to infants by maternal immunization

• Study correlates of protection to estimate extent of achievable protection in infants

• Educate mothers, providers, and public health offi cials about the need for vaccination and vaccine safety

Optimal phase 3 trial design for a GBS vaccine in pregnant women

• A trial should simulate real-world use of vaccine to assess potential impact

• Defi ne optimal time in pregnancy to vaccinate

• Assess impact not only on GBS disease but other pregnancy outcomes such as prematurity

• Identify sites with large disease burden but adequate laboratory facilities

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Acknowledgments: Phase 2 trials NCT01446289 and NCT01412801 are ongoing. For other trial information, see (31). Competing interests: S.B. is a paid consultant for Novar-tis Vaccines and Diagnostics. Novartis patents that pertain to the development of the GBS vaccine are listed in table S1.

Citation: S. Black, I. Margarit, R. Rappuoli, Preventing new-born infection with maternal immunization. Sci. Transl. Med. 5, 195ps11 (2013).

10.1126/scitranslmed.3005451

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Preventing Newborn Infection with Maternal ImmunizationSteven Black, Immaculada Margarit and Rino Rappuoli

DOI: 10.1126/scitranslmed.3005451, 195ps11195ps11.5Sci Transl Med

ARTICLE TOOLS http://stm.sciencemag.org/content/5/195/195ps11

MATERIALSSUPPLEMENTARY http://stm.sciencemag.org/content/suppl/2013/07/22/5.195.195ps11.DC1

CONTENTRELATED

http://stm.sciencemag.org/content/scitransmed/8/345/345ps14.fullhttp://stm.sciencemag.org/content/scitransmed/6/249/249ra109.fullhttp://stm.sciencemag.org/content/scitransmed/5/204/204ed16.fullhttp://stm.sciencemag.org/content/scitransmed/3/91/91ra62.fullhttp://stm.sciencemag.org/content/scitransmed/4/128/128cm4.fullhttp://stm.sciencemag.org/content/scitransmed/4/123/123ps5.full

REFERENCES

http://stm.sciencemag.org/content/5/195/195ps11#BIBLThis article cites 36 articles, 7 of which you can access for free

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(ISSN 1946-6242) is published by the American Association for the Advancement ofScience Translational Medicine

Copyright © 2013, American Association for the Advancement of Science

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