REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10081-1399
Pediatric Infectious Disease
Volume 5 | Issue 3 | Year 2023

“Prevention of Group B Streptococcus by Vaccination,” Will It Transform Maternal and Neonatal Health?

Keyur D Mahajan¹ https://orcid.org/0000-0001-5738-1818

Department of Pediatrics, Deenanath Mangeshkar Hospital and Research Centre, Pune, Maharashtra, India

Corresponding Author: Keyur D Mahajan, Department of Pediatrics, Deenanath Mangeshkar Hospital and Research Centre, Pune, Maharashtra, India, Phone: +91 9850175069, e-mail: drkeyurmahajan@gmail.com

Received on: 26 March 2023; Accepted on: 27 August 2023; Published on: 29 September 2023

ABSTRACT

Objective: Group B Streptococcus (GBS) is a leading cause of sepsis, leading to neonatal mortality and morbidity all over the world. Intrapartum antibiotic prophylaxis is the current main modality for the prevention of perinatal transmission of GBS infection. We want to discuss whether antenatal vaccination is an intervention that can help to reduce the GBS burden and improve maternal and neonatal health.

Conclusion: The GBS vaccine given during pregnancy is undoubtedly the key to lowering newborn mortality, but we must exercise extreme caution while using it. More study is required to fill in the knowledge gaps and better understand the numerous components of prenatal immunization for improving both mother and baby’s health.

How to cite this article: Mahajan KD. “Prevention of Group B Streptococcus by Vaccination,” Will It Transform Maternal and Neonatal Health? Pediatr Inf Dis 2023;5(3):84–89.

Source of support: Nil

Conflict of interest: None

Keywords: Antenatal immunization, Group B Streptococcus, Immunization against group B Streptococcus, Intrapartum antibiotic prophylaxis

INTRODUCTION

Group B Streptococcus (GBS) is a dangerous infection that frequently causes sepsis in newborns.¹^-³ However, until recently, it was still a neglected infection until the World Health Organization (WHO) made aggressive efforts to increase public awareness of the illness burden and the requirement for a vaccine. As a primary cause of meningitis in newborns and young children, the Global Meningitis Roadmap has stated that we must create a superior maternal GBS vaccination.⁴

One of the most varied bacterial groups, the genus Streptococcus, has >50 species.⁵ In the past, the genus Streptococcus was split based on how sheep red blood cells (RBCs) are lysed. On sheep blood agar, β-hemolytic streptococci cause complete hemolysis and the development of a translucent ring around each colony. α-hemolytic streptococci, on the contrary, cause partial red cell damage by producing hydrogen peroxide, resulting in a grayish or green zone near the colonies. γ-hemolytic is the category for nonhemolytic organisms.

Streptococci are categorized using the Lancefield classification,⁶ based on the bacteria’s cell wall’s teichoic acid and polysaccharide antigens. Around 20 groups, from A to H and K to V, are created by alphabetizing groupings of antigenically related organisms.

The GBS is a gram-positive organism, also called Streptococcusagalactiae, which mostly colonizes the vaginal and gastrointestinal tracts and can be detected in the oropharynx.⁷

Burden of GBS

“The London School of Hygiene & Tropical Medicine” released the first “global systematic review and meta-analysis” (2017), which put the incidence of invasive infant GBS illness at 0.49 (95% confidence interval, 0.43–0.56) per thousand live births.¹ Africa had the greatest neonatal GBS incidence risk (1.12), followed by the Caribbean and Latin America (0.49) and Asia (0.49 and 0.30). In review research between 1997 and 2015, Gaurav et al. discovered that 17.9% of women had rectovaginal colonization with GBS on average, with Africa having the highest frequency (22.4%), followed by America (19.7%) and Europe (17.3 and 19.0%).⁷ According to the CDC, one of the most common illnesses and reasons for infant death in the United States of America is GBS.⁸

Globally, GBS is estimated by the WHO to be responsible for 91,000 newborn fatalities annually, 518,000 preterm births, and 46,000 stillbirths.⁹ Nearly 40,000 infants also have chronic conditions such as cerebral palsy, hearing loss, or visual loss. Gonçalves et al. projections of the regional and worldwide burden indicate that in 2020, it is expected that >200,000 infants will have early onset GBS infection (EOGBS) and roughly 160,000 will have late-onset GBS infection. With a large range of uncertainty, they pegged the possible annual burden of preterm births linked to GBS at 0.5 million.¹⁰

Each year, about 20 million pregnant women worldwide carry GBS. Additionally, most of them go unrecognized and untreated. Two geographical areas, that is, sub-Saharan Africa and Central/South Asia, bear more than half of this weight. According to a WHO survey, the top five countries by the number of pregnant women colonized were China (1,934,900), India (2,466,500), the United States (942,800), Nigeria (1,060,000), and Indonesia (799,100).¹¹ With approximately 10 million pregnant women affected together, there is a high chance that these women will transmit this virus to their neonates and unborn children (Fig. 1).

Fig. 1: No. of pregnant women carrying GBS every year by region all over the world (in millions)

Group B Streptococcus (GBS) Risk Factors

Early-onset disease is an invasive GBS disease when it is identified within the first week of life (EOD). It is understood that invasive GBS disease is called late-onset disease when it usually manifests during the first week and third month of birth (LOD). The colonization of the maternal vaginal system with GBS during childbirth is the most significant risk factor for neonates acquiring an early-onset invasive GBS infection.¹²^,¹³

An important contributor to early-onset GBS illness is a positive GBS urinary tract infection.¹² Black race and young maternal age are also linked to a greater risk of invasive GBS in newborns. Other risk factors for early-onset GBS illness include preterm labor (37 weeks), prolonged membrane rupture (>18 hours), and maternal fever during labor. Without any preventative interventions, there is a 1–2% chance that newborns delivered to mothers who have GBS colonization will have early-onset GBS.¹²

Chemoprophylaxis for GBS in Pregnant Women

The backbone of defense against early-onset GBS for the past few years has been giving mothers antibiotic prophylaxis during labor and delivery. Finding female patients who will benefit from antibiotic prophylaxis is crucial.

All pregnant women should get antepartum screening at 36 weeks of gestation for GBS, regardless of the method of delivery, in accordance with CDC recommendations based on ACOG recommendations,¹⁴ unless intrapartum antibiotic prophylaxis for GBS is indicated due to GBS bacteriuria anytime throughout the pregnancy or due to a history of a previous newborn who had the infection. The 5-week window for reliable culture results under the revised suggested screening schedule helps to include births that take place until at least 41, 0/7 weeks into the pregnancy.

When a pregnancy-related GBS rectovaginal culture is positive, or there is a history of delivering a child who had an early-onset GBS infection, and there is GBS bacteriuria at any point throughout the pregnancy, then intrapartum antibiotic prophylaxis is advised.¹⁴

Why do we need a Vaccine Against GBS?

Early-onset GBS infection (EOGBS) in infants cannot be completely prevented by antibiotic chemoprophylaxis, notwithstanding how effective it is. Because genital tract colonization can be transient, even a strong prenatal care program for GBS culture screening would not be able to detect all women who have the infection during labor.¹²

Due to logistical challenges and limited access to high-quality healthcare in low- and low-middle-income countries, we can only undertake antenatal GBS culture screening programs in some countries. Additionally, 60% of cases of early-onset GBS infection in newborns are born to mothers who had negative GBS cultures at 35–37 weeks of pregnancy.¹² What if a GBS strain develops in the future that is resistant to medications that are now on the market? The incidence of neonatal invasive GBS infections will thereafter abruptly rise. To accommodate persons from low- to low-middle-income nations, a significantly less expensive alternative is required to maternal intrapartum screening and antimicrobial prophylaxis.

When the “Product Development for Vaccines Advisory Committee” met in 2015, the WHO selected a GBS vaccine for maternal immunization as a top priority.⁹ Because GBS infection has a serious impact on public health, developing a vaccine against it is essential.¹⁵ The maternal vaccine for GBS is intended to provide effective protection against invasive GBS disease to neonates who cannot get IAP or in circumstances where IAP is insufficient or impossible if given during pregnancy.

In all settings and distant places, compared to antepartum GBS screening, culturing, and IAP delivery, the vaccine is a more practicable choice. The effectiveness of maternal immunization in preventing illnesses, including influenza, tetanus, and pertussis in early babies has already been demonstrated.¹⁶^-¹⁸ We predict that RSV and GBS will soon be implemented as promising options for maternal immunization programs aimed at avoiding illness in newborns.

Capsular Polysaccharide Conjugate Vaccines

The virulence factors that GBS expresses include evasion factors, adhesion factors, pore-forming toxins, and factors that deter or promote resistance to an antimicrobial peptide. The most noticeable and extensively researched virulence factor is capsular polysaccharides (CPS). By making the host’s immune system easier to evade, it functions as a virulence factor. GBS is divided into many strains based on surface CPS that are “IX, Ia, Ib, II, III, IV, V, VI, VII, and VIII.”¹⁹^,²⁰

Different antigens can contribute to the development of GBS protective immunity. The GBS capsular polysaccharide antigens are the most significant and extensively researched. According to a recent meta-analysis by Madrid et al., serotype III is the most frequent serotype to cause invasive illness in babies. Moreover, the five most prevalent GBS serotypes account for about 97% of all invasive infections worldwide (“Ia, Ib, II, III, and V”).²¹

In their investigation, Baker and Kasper discovered a correlation between maternal antibodies and protection against severe GBS infection in newborns, which they hypothesized was caused by the transplacental transfer of maternal immunoglobulin G (IgG).²² These important findings prompted the researchers to look for a CPS vaccination for expectant mothers, which would provide adequate protection against GBS infection in neonates.

Numerous studies show that compared to unconjugated vaccinations, CPS-conjugated vaccines have substantially greater immunogenicity and high antibody levels.²³^-²⁶ Polysaccharides are “T cell-dependent antigens,” and in order to elicit memory and protective B cell response as a vaccine, they must be conjugated to a protein carrier. Tetanus toxoid was initially employed, but “CRM197,” a benign variant of “diphtheria toxin,” is now the preferred method.

Monovalent vaccinations for “Ia, Ib, II, III, and V” were investigated when the GBS vaccine was still in its early stages of development.²³^-²⁶ The attention switched to the creation of multivalent vaccinations once it was discovered that single-serotype immunizations typically do not present cross-reactive protection against different serotypes.²⁷

“The trivalent CRM197 conjugate vaccine (Ia, Ib, and III)” was investigated in the trial listed as NCT01193920 in the ClinicalTrials.gov database.²⁸^,²⁹ Higher CPS-specific antibodies in newborn children were found in phase I/II in pregnant women’s trials with no safety issues. Following this success, a larger trial with the hexavalent vaccine (“Ia, Ib, II, III, IV, V”), coupled with “CRM197” and administered with/without aluminum phosphate, was registered as NCT03170609 to protect against at least 98% of GBS isolates causing neonatal invasive disease.³⁰ At all dosages studied, with or without aluminum phosphate, this vaccination was well tolerated and produced potent CPS-specific IgG responses. These results prompted the current “phase I/II trial (NCT03765073),” which is being conducted in South Africa to assess the immunogenicity and safety in both pregnant/nonpregnant women.³¹

The number of dosages needed during pregnancy to achieve full immunity is the subject of few investigations. The immunogenicity and safety of the second dose of the “trivalent vaccine” were assessed in a study (NCT02690181).³² They discovered that after the second dosage was administered, antibody levels in previously immunized women increased by >200 times. A small number of women who had undetectable antibody levels following the first dose also displayed a large rise in antibodies following the second. These findings need to be further examined, but they indicated that we might need to revaccinate a woman in her following pregnancies.

Capsular Polysaccharide (CPS) Vaccine Problems

This multivalent CPS conjugate vaccination has some gaps; it only provides serotype-specific immunity.

People of different ethnicities may respond differently to vaccinations, and different geographical regions have distinct circulating strains. Additionally, we must keep in mind that different local guidelines may be necessary.

What if serotypes’ infectivity is changed/switched or they get replaced?
What if the nonencapsulated strain of GBS arrives?
When administered in combination, other conjugate vaccines, such as those for meningococcal, pneumococcal, and type B Haemophilus influenzae, may impair the vaccine’s potential to elicit an immunological response.

A recent study in mice using two (“synthetic vaccine”) models shows that immunization using the “tetanus toxoid” as a carrier with preexisting immunity against it, can decrease the immunological response to the synthetic epitopes conjugated with the same carrier.³³ This impact may have significant repercussions for the creation of synthetic vaccinations because the majority of humanity has been exposed to this antigen.

Protein Vaccines

Researchers are also working to create nonserotype-specific vaccinations to address these issues connected to various serotypes. Researchers are investigating alternatives to polysaccharide vaccines, such as protein antigens, that can trigger a powerful immune response that is expressed in practically all strains and protect against disease. Protein antigens, as opposed to polysaccharide antigens, can trigger T cell-dept protective antibody response that results in long-lasting immunity.

Reverse vaccinology has long been a key component of creating vaccines of the future.²⁷ Whole genome analysis enables us to access all of its antigens completely and aids in the discovery of fresh protein vaccine candidates.³⁴^,³⁵ The Neisseria meningitis serogroup B vaccine introduced this idea first (MenB).³⁶ The complete genome sequences of eight clinical GBS strains were used by Maione et al.³⁴ Four possible vaccine-candidate protein antigens were identified by researchers while working on their concept through several mouse model tests.³⁵ In order to create better vaccines that elicit higher levels of maternal antibodies and higher levels of newborn antibodies, researchers are adopting unique designs.³⁷ It is crucial to have an extremely immunogenic vaccine for the protection of these tiny ones against invasive GBS infection because the maternal–fetal transfer is disrupted in preterm infants.

Vaccination in Pregnancy

The safety of vaccinations given during pregnancy must be carefully assessed for both mother and fetus before the introduction of each new vaccine. A vaccine’s successful rollout is influenced by many important elements. One essential component of that is patient education. Mothers should receive the immunization and feel safe doing so. They should be informed of the seriousness of the condition, how it affects their unborn children, and the potential advantages of the vaccine. The vaccine ought to be reasonably priced and widely available.

During antenatal time, a mother may have some ailments, including gestational diabetes, gestational hypertension, obesity, HIV infection, smoking, and other illnesses, including malaria, which could affect how the vaccine reacts. For instance, cord IgG levels are lower in babies delivered to mothers who have HIV infection, malaria infection, or hypergammaglobulinemia than in babies born to women who do not have these illnesses.³⁸^-⁴⁰ In-depth research must be done on each of these potential vaccine-interfering factors, and effective vaccination regimens for such mothers must be developed.

To give the infant the greatest benefits during its most vulnerable time, the best immunization scheduling during pregnancy needs to be thoroughly researched. Given that prematurity is a substantial risk factor for invasive GBS disease in infants, the possibility of having a premature baby should also be taken into account when choosing the right time for immunization.

Cost-effectiveness

Cost-effectiveness research was conducted on routine maternal immunization during pregnancy by Oster et al.⁴¹ They discovered that screening and intrapartum antibiotic prophylaxis, along with the inclusion of a trivalent GBS vaccine, could lower the incidence of disease of GBS in babies while having a similar cost-effectiveness to recently developed vaccines.

According to WHO recommendations, GBS maternal immunization can also be financially advantageous in South Africa.⁴² According to this study, without IAP, simply GBS immunization would contribute to a reduction in baby GBS cases between 30 and 54% as compared to doing nothing, assuming vaccine efficiency varied between 50 and 90% and coverage of roughly 75%. Another study found that, in comparison to other recently launched vaccines in sub-Saharan Africa, maternal immunization might be a cost-effective intervention.⁴³ To assess these findings in other LIC and LMICs, we need further information.

Indian Scenario

In India, there is a lot of controversy around the rates of baby-invasive GBS disease and maternal GBS colonization. To quantify the global burden of GBS disease for stillbirths, pregnant women, and children, a study was carried out in 2017.¹ According to the report, India had the maximum number of infant GBS cases (31,000; the range of uncertainty: 0–75,000) and GBS-related mortality (13,000; the range of uncertainty: 5,000–23,000). However, these were estimates with a high degree of uncertainty that were based on a model rather than actual data. Ghia and Rambhad made an effort to investigate the incidence of maternal GBS colonization in India.⁴⁴ They investigated various research assessing the frequency of GBS colonization in expectant mothers. They discovered that the prevalence of GBS colonization ranged from 2 to 62%, and its transfer to their neonates ranged from 6.7 to 11.1%.

The bacteriological profile for early-onset sepsis in India was very different from that in high-income nations when we sought to investigate it. Table 1 below shows the distribution of organisms isolated in various locations of India, broken down by percentage.

**Table 1:** Bacteriological profile for early-onset neonatal sepsis in India
Name of organism	Zakariya et al.⁴⁵	Marwah et al.⁴⁶	Bhat et al.⁴⁷	DeNIS collaboration⁴⁸	Pavan Kumar et al.⁴⁹
Acinetobacter spp.	5%	13%	14.4%	22%
Escherichia coli	0%	16%	4.4%	14%	11%
Klebsiella pneumoniae	74%	15%	31.4%	17%	21%
Streptococcus pneumoniae	5%
CONS	8%			15%
Enterobacter spp.	5%		2.2%	4%
Pseudomonas spp.			33.2%	7%	3.5%
GBS	0%	0%	0%	1%
Staphylococcus aureus		51%	9.2%	12%	36%
Others		5%	5.2%	3%	30%

DeNIS, Delhi Neonatal Infection Study collaboration; CONS, coagulase-negative staphylococci

The problem with GBS is that it is difficult to culture in routine laboratory settings. It needs selective enrichment broths like LIM broth or Trans-Vag broth. Also, if any growth is seen, it needs to be subcultured on nonselective 5% sheep blood agar plates.⁵⁰ In India, the prevalence of GBS is about 1%, as indicated in various studies shown above. This may be an underestimation of actual prevalence due to improper culture techniques and insufficient laboratory support. But, even if we consider a 1% prevalence, compared to other nations, the total number of maternal GBS diseases will be large because of the extremely crowded population. These findings underline once again the need to comprehend the local demography of the organism causing early-onset sepsis and make appropriate plans.

In India, we must consider how the GBS vaccine can help lessen the overall incidence of early-onset sepsis in newborns. To further comprehend locally circulating strains, more research is required. For Indian situations, a cost-benefit analysis should be performed. The vaccine should undergo local trials to determine its efficacy. Additionally, if the vaccine is successful, we must have a plan for distributing it to the expected 300 million childbearing women worldwide in 2020.⁵¹

Future of GBS Vaccine

As previously said, additional research is required to check the prevalence of GBS illness and maternal colonization rates across all nations, including developing and LMIC nations, where scant data is available. We require research to pinpoint the precise relationship between maternal colonization and invasive infection to evaluate the effectiveness of the vaccine. Once the vaccine is approved for use, more research will be required to determine whether the vaccine-induced immune responses are altered in special conditions like HIV, syphilis, malaria, and hepatitis B. Additionally, more research is required to determine the precise dose regimen, timing throughout pregnancy, and requirement for a booster during succeeding pregnancies. We must be very certain of a vaccine’s efficacy, dosing regimen, and potential side effects—both short-term and long-term—before introducing it to a population that will be affected on such a huge scale, particularly pregnant women.

The GBS vaccine given during pregnancy is undoubtedly the key to lowering newborn mortality, but we must exercise extreme caution while using it. To fill in the knowledge gaps and better understand the numerous components of prenatal immunization for the improvement of both mother and baby health, more study is required.

ORCID

Keyur D Mahajan https://orcid.org/0000-0001-5738-1818

REFERENCES

1. Seale AC, Bianchi-Jassir F, Russell NJ, et al. Estimates of the burden of group B streptococcal disease worldwide for pregnant women, stillbirths, and children. Clin Infect Dis 2017;65(Suppl 2):S200–S219. DOI: 10.1093/cid/cix664

2. Edmond KM, Kortsalioudaki C, Scott S, et al. Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis. Lancet 2012;379(9815):547–556. DOI: 10.1016/s0140-6736(11)61651-6

3. Sigaúque B, Kobayashi M, Vubil D, et al. Invasive bacterial disease trends and characterization of group B streptococcal isolates among young infants in southern Mozambique 2001-2015. PLoS One 2018;13(1):e0191193. DOI: 10.1371/journal.pone.0191193

4. Venkatesan P. Defeating meningitis by 2030: the WHO roadmap. Lancet Infect Dis 2021;21(12):1635. DOI: 10.1016/S1473-3099(21)00712-X

5. Principles and Practice of Pediatric Infectious Diseases. 5th edition. Elsevier Health Sciences; 2018.

6. al. PAe. Lancefield-classification of streptococcus. In: Altmeyer HD Peter, Neumann Herbert, Przuntek Horst, Gerken Guido Günther Heinrich, Gatermann Sören G. editor. ALTMEYERS ENCYCLOPEDIA2023.

7. Gaurav K, Marianne CC, Elizabeth M, et al. Prevalence of maternal colonisation with group B streptococcus: a systematic review and meta-analysis. Lancet Infect Dis 2016;16(9):1076–1084. DOI: 10.1016/S1473-3099(16)30055-X

8. (CDC) CfDCaP. Group B Strep (GBS) Fast Facts. https://www.cdc.gov/groupbstrep/about/fast-facts.html#:~:text=In%20the%20United%20States%2C%20GBS,who%20develop%20GBS%20disease%20die.

9. Giersing BK, Modjarrad K, Kaslow DC, et al. Report from the World Health Organization’s Product Development for Vaccines Advisory Committee (PDVAC) meeting, Geneva, 7-9th Sep 2015. Vaccine 2016;34(26):2865–2869. DOI: 10.1016/j.vaccine.2016.02.078

10. Gonçalves BP, Procter SR, Paul P, et al. Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden. Lancet Glob Health 2022;10(6):e807–e819. DOI: 10.1016/s2214-109x(22)00093-6

11. WHO, Immunization VaB. Group B Streptococcus. Vaccine: full value vaccine assessment. 3 November 2021. https://www.lshtm.ac.uk/newsevents/news/2021/urgent-need-vaccine-prevent-deadly-group-b-streptococcus

12. Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(Rr-10):1–36.

13. Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect 2014;68(Suppl 1):S24–S32. DOI: 10.1016/j.jinf.2013.09.011

14. Prevention of group B streptococcal early-onset disease in newborns: ACOG Committee Opinion, Number 797. Obstet Gynecol 2020;135(2):e51–e72. DOI: 10.1097/aog.0000000000003668

15. 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(50):7391–7393. DOI: 10.1016/j.vaccine.2017.09.087

16. Thwaites CL, Beeching NJ, Newton CR. Maternal and neonatal tetanus. Lancet 2015;385(9965):362–370. DOI: 10.1016/s0140-6736(14)60236-1

17. Campbell H, Gupta S, Dolan GP, et al. Review of vaccination in pregnancy to prevent pertussis in early infancy. J Med Microbiol 2018;67(10):1426–1456. DOI: 10.1099/jmm.0.000829

18. Baxter R, Bartlett J, Fireman B, et al. Effectiveness of vaccination during pregnancy to prevent infant pertussis. Pediatrics 2017;139(5):e20164091. DOI: 10.1542/peds.2016-4091

19. Ferrieri P, Flores AE. Surface protein expression in group B streptococcal invasive isolates. Adv Exp Med Biol 1997;418:635–637. DOI: 10.1007/978-1-4899-1825-3_148

20. Slotved HC, Kong F, Lambertsen L, et al. Serotype IX, a proposed new streptococcus agalactiae serotype. J Clin Microbiol 2007;45(9):2929–2936. DOI: 10.1128/jcm.00117-07

21. Madrid L, Seale AC, Kohli-Lynch M, et al. Infant group B streptococcal disease incidence and serotypes worldwide: systematic review and meta-analyses. Clin Infect Dis 2017;65(Suppl 2):S160–S172. DOI:10.1093/cid/cix656

22. Baker CJ, Kasper DL. Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection. N Engl J Med 1976;294(14):753–756. DOI: 10.1056/nejm197604012941404

23. Wessels MR, Paoletti LC, Kasper DL, et al. Immunogenicity in animals of a polysaccharide-protein conjugate vaccine against type III group B streptococcus. J Clin Invest 1990;86(5):1428–1433. DOI: 10.1172/jci114858

24. Lagergard T, Shiloach J, Robbins JB, et al. Synthesis and immunological properties of conjugates composed of group B streptococcus type III capsular polysaccharide covalently bound to tetanus toxoid. Infect Immun 1990;58(3):687–694. DOI: 10.1128/iai.58.3.687-694.1990

25. Paoletti LC, Kasper DL, Michon F, et al. An oligosaccharide-tetanus toxoid conjugate vaccine against type III group B streptococcus. J Biol Chem 1990;265(30):18278–18283.

26. Paoletti LC, Wessels MR, Michon F, et al. Group B streptococcus type II polysaccharide-tetanus toxoid conjugate vaccine. Infect Immun 1992;60(10):4009–4014. DOI: 10.1128/iai.60.10.4009-4014.1992

27. Seib KL, Zhao X, Rappuoli R. Developing vaccines in the era of genomics: a decade of reverse vaccinology. Clin Microbiol Infect 2012;18(Suppl 5):109–116. DOI: 10.1111/j.1469-0691.2012.03939.x

28. Swamy GK, Metz TD, Edwards KM, et al. Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in pregnant women and their infants: results from a randomized placebo-controlled phase II trial. Vaccine 2020;38(44):6930–6940. DOI: 10.1016/j.vaccine.2020.08.056

29. Madhi SA, Cutland CL, Jose L, et al. Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial. Lancet Infect Dis 2016;16(8):923–934. DOI: 10.1016/s1473-3099(16)00152-3

30. Absalon J, Segall N, Block SL, et al. Safety and immunogenicity of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 1/2, randomised, placebo-controlled, observer-blinded, dose-escalation trial. Lancet Infect Dis 2021;21(2):263–274. DOI: 10.1016/s1473-3099(20)30478-3

31. Pfizer CG. Trial to Evaluate the Safety, Tolerability, and Immunogenicity of a Multivalent Group B Streptococcus Vaccine in Healthy Nonpregnant Women and Pregnant Women and Their Infants. 2023. Accessed March 22, 2023. Available from: https://clinicaltrials.gov/ct2/show/NCT03765073

32. Leroux-Roels G, Bebia Z, Maes C, et al. Safety and immunogenicity of a second dose of an investigational maternal trivalent group B streptococcus vaccine in nonpregnant women 4-6 years after a first dose: results from a phase 2 trial. Clin Infect Dis 2020;70(12):2570–2579. DOI: 10.1093/cid/ciz737

33. Schutze MP, Leclerc C, Jolivet M, et al. Carrier-induced epitopic suppression, a major issue for future synthetic vaccines. J Immunol 1985;135(4):2319–2322.

34. Maione D, Margarit I, Rinaudo CD, et al. Identification of a universal group B streptococcus vaccine by multiple genome screen. Science 2005;309(5731):148–150. DOI: 10.1126/science.1109869

35. Lauer P, Rinaudo CD, Soriani M, et al. Genome analysis reveals pili in group B streptococcus. Science 2005;309(5731):105. DOI: 10.1126/science.1111563

36. Pizza M, Scarlato V, Masignani V, et al. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 2000;287(5459):1816–1820. DOI: 10.1126/science.287.5459.1816

37. Margarit I, Rinaudo CD, Galeotti CL, et al. Preventing bacterial infections with pilus-based vaccines: the group B streptococcus paradigm. J Infect Dis 2009;199(1):108–115. DOI: 10.1086/595564

38. Abu-Raya B, Kollmann TR, Marchant A, et al. The immune system of HIV-exposed uninfected infants. Front Immunol 2016;7:383. DOI:10.3389/fimmu.2016.00383

39. Dechavanne C, Cottrell G, Garcia A, et al. Placental malaria: decreased transfer of maternal antibodies directed to plasmodium falciparum and impact on the incidence of febrile infections in infants. PLoS One 2015;10(12):e0145464. DOI: 10.1371/journal.pone.0145464

40. Okoko BJ, Wesumperuma LH, Ota MO, et al. The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and IgG subclasses in a rural West African population. J Infect Dis 2001;184(5):627-632. DOI: 10.1086/322808

41. Oster G, Edelsberg J, Hennegan K, et al. Prevention of group B streptococcal disease in the first 3 months of life: would routine maternal immunization during pregnancy be cost-effective? Vaccine 2014;32(37):4778–4785. DOI: 10.1016/j.vaccine.2014.06.003

42. Kim SY, Russell LB, Park J, et al. Cost-effectiveness of a potential group B streptococcal vaccine program for pregnant women in South Africa. Vaccine 2014;32(17):1954–1963. DOI: 10.1016/j.vaccine.2014.01.062

43. Russell LB, Kim SY, Cosgriff B, et al. Cost-effectiveness of maternal GBS immunization in low-income sub-Saharan Africa. Vaccine 2017;35(49 Pt B):6905–6914. DOI: 10.1016/j.vaccine.2017.07.108

44. Ghia C, Rambhad G. Disease burden due to group B streptococcus in the Indian population and the need for a vaccine—a narrative review. Ther Adv Infect Dis 2021;8:20499361211045253. DOI:10.1177/20499361211045253

45. Zakariya BP, Bhat V, Harish BN, et al. Neonatal sepsis in a tertiary care hospital in South India: bacteriological profile and antibiotic sensitivity pattern. Indian J Pediatr 2011;78(4):413–417. DOI: 10.1007/s12098-010-0314-8

46. Marwah P, Chawla D, Chander J, et al. Bacteriological profile of neonatal sepsis in a tertiary-care hospital of Northern India. Indian Pediatr 2015;52(2):158–159.

47. Bhat YR, Lewis LE, K EV. Bacterial isolates of early-onset neonatal sepsis and their antibiotic susceptibility pattern between 1998 and 2004: an audit from a center in India. Ital J Pediatr 2011;37:32. DOI: 10.1186/1824-7288-37-32

48. Investigators of the Delhi Neonatal Infection Study (DeNIS) collaboration. Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study. Lancet Glob Health 2016;4(10):e752–e760. DOI: 10.1016/s2214-109x(16)30148-6

49. Pavan Kumar DV, Mohan J, Rakesh PS, et al. Bacteriological profile of neonatal sepsis in a secondary care hospital in rural Tamil Nadu, Southern India. J Family Med Prim Care 2017;6(4):735–738. DOI:10.4103/jfmpc.jfmpc_66_17

50. Recommendations for Collection and Culture of Clinical Specimens from Pregnant Women for Group B Streptococcus Minnesota Department of Health 2003.

51. Davanzo J, Dogo H, Grammich CA. Demographic Trends, Policy Influences, and Economic Effects in China and India Through 2025. 2011.

________________________
© The Author(s). 2023 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.