Why do we need to step forward towards a maternal GBS-vaccine?
By May Murra, Aarhus University Hospital, Denmark and Dr Eleni Vergadi, University of Crete, Medical School
Global impact of GBS in mothers, neonates, and infants
Globally, around 20% of pregnant women (approximately 20 million women each year) are colonized with Group B Streptococcus (Streptococcus agalactiae, GBS) in rectum or vagina. GBS can be transmitted to the fetus during pregnancy, and to the neonate during or after delivery.
GBS infection within the first week of life (day 0-6) is defined as early-onset disease (EOD), while late-onset disease (LOD) occurs between the first week and third month of life. Invasive GBS infections may lead to pneumonia, sepsis, and/or meningitis, causing significant mortality, morbidity and long-term neurodevelopmental sequelae.
Invasive GBS disease remains a non-negligible problem nowadays; a recent “Full Value of Vaccine assessment from the World Health Organization” estimated an annual number of 41,000 maternal GBS-sepsis cases, 392,000 EOD and LOD cases resulting in 91,000 deaths and 40,000 cases with neurodevelopmental impairment. Furthermore, GBS was estimated to cause 46,000 stillbirths and 518,000 preterm births every year.
Current prevention strategies against neonatal GBS infections
- Intrapartum antibiotic prophylaxis (IAP)
High-income countries (HICs) introduced IAP during labor in the late 90’s to prevent GBS-infections in neonates. IAP is indicated by a specific prevention strategy: Some countries have a universal screening approach, where pregnant women are screened for recto-vaginal carriage of GBS in the 35-37th week of pregnancy and given IAP during labor. Other countries have a risk-based screening labor to reduce the use of IAP.
Why do we need a maternal GBS vaccine?
IAP has been efficient in reducing the incidence of EOD up to 80% in high income-countries, but IAP is not feasible in low-and middle-income countries due to the lack of infrastructure for prenatal care, and the fact that many births occur outside of a health-care setting. Furthermore, a recent study by Lohrmann F, et al, led by the DEVANI (Design of a Vaccine Against Neonatal Infections) Study Group (Prevention of group B streptococcal neonatal disease revisited. The DEVANI European project – PubMed (nih.gov)) revealed important limitations of both prevention strategies, and significant lack of adherence of health care professionals to existing recommendations.
Additionally, IAP has no impact on maternal sepsis, preterm birth, stillbirth nor LOD, which are a major GBS-caused burden globally. Thus, even full adherence to antenatal screening would miss a relevant number of EOD and LOD cases, rendering the advert of a maternal GBS vaccine as the most promising prophylactic approach against GBS neonatal disease.
The advantages of a maternal GBS vaccine
Currently, maternal vaccines against GBS are being developed as an alternative to GBS-screening and IAP.
IAP increases the risk of Penicillin-resistant GBS-isolates, which have been reported from Japan, the USA, Canada, China, England, Germany, Italy, and Korea.
A GBS-vaccine during pregnancy would facilitate protection of the fetus and infant by placentally transferred antibodies and thereby have an impact on both EOD cases but also preterm birth, stillbirths and LOD, which IAP have no effect on.
Watch video on GBS vaccines from IMPRINT : Group B Strep Vaccines – Animation – ISSAD.org
Development of GBS-vaccines
GBS express a type-specific capsular polysaccharide (CPS), one of the most important GBS virulence factors. To date, ten serotypes have been described (Ia, Ib, II to IX).
In 1976, Baker et al. published a study among women colonized with GBS serotype III which showed an association between low maternal serotype III-specific IgG concentrations and infant susceptibility to EOD caused by serotype III strains.
Since the 1980’s, the development of a vaccine against GBS have been taking place. By maternal immunization, the fetus and newborn would gain protection against severe GBS-infections through transplacental transfer of maternal antibodies against GBS.
Currently, the most advanced GBS-vaccines in trial are the GBS6 vaccine by Pfizer and the GBS-NN vaccine by MinervaX.
The 6-valent vaccine (GBS6) targets the CPS serotypes Ia, Ib, II, III, IV, and V which accounts for 95-98% of the disease-causing isolates worldwide.
The GBS-vaccine by MinervaX uses the GBS-NN as the antigen. Thisis a fusion protein consisting of the N-terminal domains of the GBS proteins AlphaC and Rib, members of the alpha-like protein (AlpN) family also containing Alp1–Alp4. The AlpNs are allelic variants, and at least one Alp was detected in 99.3% of 6,340 sequenced invasive GBS isolates collected in the USA during the period of 2015–2017.
Both vaccines shows promising results and have reached clinical trials in pregnant women.
The strongest evidence to support the licensure of a GBS-vaccine, would be a randomized, double-blind placebo-controlled trial with endpoints defined as EOD, LOD and GBS-associated stillbirth. However, the phase III trials GBS-vaccines would require a major study with inclusion of 40,000 – 180,000 women-infant-dyads for, because the incidence of iGBS is low.
An alternative licensure pathway would be to identify robust correlates of protection associated with risk reduction. This have previously been done for the licensure of meningococcal vaccines and high-valency pneumococcal vaccines. Evidence to support licensure based on immunogenicity studies and correlates of protection is a priority and much work in this area is ongoing.
A general correlation between high maternal GBS antibody concentrations and reduced risk of GBS disease in newborn babies has been observed in several seroepidemiological studies. Regulatory approval based on an immune threshold of protection derived from natural history studies is feasible and could accelerate the licensure of a GBS-vaccine.
We hope that we will soon have a licensure for a maternal GBS vaccine that will allow us to step forward in the prevention of fetal and neonatal invasive GBS disease.