Meningitis is a life-threatening infectious disease that can affect all age groups, but especially neonates and children less than 5 years old. Bacterial meningitis can be caused by several pathogens, but among neonates, Group B Streptococcus (GBS, Streptococcus agalactiae) stands out as the leading causative agent of meningitis. The greatest meningitis burden worldwide is reported in children, with 112,000 deaths and 1.28 million cases in 2019. Considering the etiology of neonatal meningitis, viruses are responsible for 37.1% of total cases, followed by GBS (20.4% of total cases) and Neisseria meningitis (9.7% of total cases). GBS can colonize the lower reproductive tract of up to 40% of pregnant women worldwide and is associated with both vertical and horizontal modes of transmission. According to the World Health Organization (WHO), 21.7 million pregnant women are colonized by GBS each year, which leads to 390,000 cases of GBS infection, 91,000 neonatal deaths, more than 46,000 stillbirths, and 518,000 preterm births. Moreover, around 40,000 children who survive GBS infection show neurodevelopmental impairment.

GBS Meningitis

GBS is an opportunistic pathogen that can colonize asymptomatically the gastrointestinal and genital tracts of healthy adults, being part of the intestinal and vaginal microbiomes. The neonatal invasive infections caused by GBS can be classified into early- and late-onset disease according to the timing of symptoms’ onset and mode of transmission. The early-onset GBS disease (EOGBS) is characterized by the onset of symptoms within 7 days after birth and vertical intrapartum transmission due to aspiration of contaminated amniotic or vaginal secretions during labor. The late-onset GBS disease (LOGBS), in turn, is characterized by the beginning of symptoms between 7 and 90 days after birth and horizontal postpartum transmission (hospital environment, the mother or other caregivers, or breastfeeding). Additionally, GBS can ascend from the lower genital tract into the uterus during pregnancy and infect the fetus, causing stillbirths, preterm birth, and miscarriage (prenatal-onset GBS disease). EOGBS and LOGBS differ in their clinical manifestations. Usually, EOD is associated with sepsis and pneumonia and less frequently with meningitis, while LOGBS commonly presents with sepsis and meningitis. Although viruses are the causative agents of most cases of neonatal meningitis, GBS accounts for the highest mortality rates. In 2019, GBS accounted for the highest burden of neonatal deaths due to meningitis (22.8%), followed by Klebsiella pneumoniae (17.1%) and viruses (15.3%). Most of this burden is in low- and middle-income countries, especially in Africa and Asia. GBS can also cause meningitis in adults with underlying conditions (e.g., diabetes, heart disease, cancer, immunocompromising conditions), although the frequency of GBS meningitis in that group is lower. The GBS population is composed of several lineages, but one in specific, the hypervirulent clone CC17 associated with serotype III, is recognized as the major clone causing LOGBS and meningitis. Currently, universal GBS screening of pregnant women in late pregnancy (36-37 weeks of pregnancy) and intrapartum antibiotic prophylaxis (IAP) are recommended to prevent GBS disease. The screening involves taking swab samples from the vagina and rectum, and the pregnant women who test positive for GBS should receive antibiotics during labor (IAP). Penicillin is the drug of choice for IAP, and cefazolin, clindamycin, and vancomycin are options for women with penicillin allergies. However, IAP is effective only to prevent EOGBS but does not prevent the occurrence of LOGBS and prenatal-onset GBS disease. A maternal vaccine is considered the most promising approach to prevent all forms of disease caused by GBS, including meningitis.

Antimicrobial Resistance and GBS

Antimicrobial resistance is a topic of concern for GBS. Penicillin is the drug of choice to treat GBS infections, but penicillin-resistant strains were already detected in Japan, Europe, Canada, and the USA. Clindamycin and erythromycin are recommended to treat patients allergic to penicillin. However, the circulation of GBS strains resistant to clindamycin and erythromycin is a reality, with rates reaching nearly 50% in some regions. Considering this scenario, penicillin-resistant GBS, clindamycin-resistant GBS, and erythromycin-resistant GBS are included in the lists of pathogens that pose a threat to the public health published by the Centers for Disease Control and Prevention (CDC) and the WHO and are targets for the actions taken to tackle antimicrobial resistance.

GBS Can Be Considered a Zoonotic Pathogen?

A foodborne outbreak of invasive disease caused by GBS was reported for the first time in Singapore in 2015. The outbreak was caused by the consumption of farmed freshwater fish contaminated with GBS and affected non-pregnant and younger adults. Septic arthritis and meningitis were the predominant clinical manifestations (146 cases and 5 deaths), and the outbreak was caused by the GBS clone ST283 serotype III. GBS ST283 is a widespread clone in Southeast Asia, but it was already detected in other geographic regions, like Brazil. It causes an infectious disease in fish called streptococcosis and economic losses in aquaculture. This episode highlights the zoonotic role of GBS and its public health importance beyond the neonatal infectious diseases.

The Path Towards a Maternal GBS Vaccine

The WHO, together with many partners, defined a global strategy to tackle bacterial meningitis globally, but especially in LMICs. The global roadmap Defeating Meningitis by 2030 has the vision "Towards a world free of meningitis" and aims to tackle the main causes of bacterial meningitis worldwide. Regarding GBS meningitis, the road map fosters the development of an effective and affordable maternal vaccine, implementation of GBS surveillance strategies, and effective, accessible diagnosis and treatment. In addition, the WHO also published the document “Group B Streptococcus vaccine: full value of vaccine assessment", which describes the global public health rationale for developing GBS vaccines for maternal immunization and informs decision makers and stakeholders. Currently, the vaccine proposals in development are based on two approaches: a multivalent capsular polysaccharide (CPS)-protein conjugate vaccine and protein subunit vaccines. The CPS-based vaccine proposals cover between three and six capsular types, targeting the serotypes most associated with disease. The protein subunit proposals target proteins conserved across all GBS serotypes. A maternal GBS vaccine has not been licensed yet, but there are promising approaches in clinical trials, and it is expected that at least one GBS vaccine will be licensed for maternal immunization very soon.

International GBS Awareness Month

July is recognized as the International GBS Awareness Month, and this is a month dedicated to raising awareness about GBS disease, including GBS neonatal meningitis, among the lay public. The campaign aims to provide information and educate healthcare professionals, the public, parents, and decision-makers about GBS and the risks this pathogen can pose to the health of neonates and their mothers. Usually, nonprofit organizations like Group B Strep International (https://www.groupbstrepinternational.org/) and Group B Strep Support (https://gbsaw.gbss.org.uk/) take the lead in the campaign, but everyone can be involved and make a difference to prevent and tackle GBS meningitis!

By ISID Emerging Leader, Laura Oliveira

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