“Prevention of Group B Streptococcus by Vaccination,” Will It Transform Maternal and Neonatal Health?
Corresponding Author: Keyur D Mahajan, Department of Pediatrics, Deenanath Mangeshkar Hospital and Research Centre, Pune, Maharashtra, India, Phone: +91 9850175069, e-mail: firstname.lastname@example.org
Received on: 26 March 2023; Accepted on: 27 August 2023; Published on: 29 September 2023
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
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).
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.
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 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.
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.
|Name of organism||Zakariya et al.45||Marwah et al.46||Bhat et al.47||DeNIS collaboration48||Pavan Kumar et al.49|
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.
Keyur D Mahajan https://orcid.org/0000-0001-5738-1818
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