En route towards prevention of neonatal group B streptococcal disease
Authors: Reinhard Berner
Journal: The Lancet Infectious Diseases (2016)

In The Lancet Infectious Diseases Robert Heyderman and colleagues1Heyderman RS Madhi SA French N et al.Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial.Lancet Infect Dis. 2016; (published online Feb 8.)http://dx.doi.org/10.1016/S1473-3099(15)00484-3Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar report on a phase 2 clinical trial comparing the safety and immunogenicity of a trivalent glycoconjugate vaccine directed against group B streptococci (GBS) in pregnant HIV-infected and uninfected women in Malawi and South Africa. In my opinion the most important message of this Article is that finally—more than 40 years after the magnitude of neonatal GBS disease was first recognised—a promising vaccine against GBS is studied in the target group of pregnant women; and in particular, it is tested in women with HIV in sub-Saharan Africa where the disease burden is supposed to be highest. During the early 1970s, the attention to GBS changed greatly when three hallmark manuscripts reported simultaneously that GBS had emerged as the leading pathogen in neonatal sepsis in the USA.2Schuchat A Group B streptococcal disease: from trials and tribulations to triumph and trepidation.Clin Infect Dis. 2001; 33: 751-756Crossref PubMed Scopus (64) Google Scholar At present, GBS is one of the most important pathogens worldwide, leading to neonatal sepsis, death, and disability.3Edmond 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: 547-556Summary Full Text Full Text PDF PubMed Scopus (453) Google Scholar In sub-Saharan Africa—and particularly in pregnant women with HIV—the risk for invasive neonatal GBS disease is supposed to be many times higher than in the USA and Europe. In the 1990s, a first milestone towards successful containment was reached when consensus recommendations for the prevention of neonatal GBS disease were issued by the key professional organisations in the USA, the American College of Obstetricians and the American Academy of Pediatrics, together with the Centers for Disease Control and Prevention. In brief, the recommendations were to screen pregnant women for GBS colonisation (screening-based approach), and to give intrapartum antibiotic prophylaxis to women positive for GBS or to women with specific risk factors (risk-based approach). Consequently, from 1993 to 1998, the incidence of neonatal early onset GBS disease (which is defined as occurring between days 0 to 7 postpartum) decreased by 65%.4Schrag SJ Zywicki S Farley MM et al.Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis.N Engl J Med. 2000; 342: 15-20Crossref PubMed Scopus (838) Google Scholar In fact, intrapartum antibiotic prophylaxis proved successful but was bought dearly—doubling the rate of antibiotic use during labour. Moreover, the incidence of neonatal late-onset GBS sepsis (occurring from day 8 to 90) remained fairly unaffected. In the 1980s, clinician scientists Carol Baker and Dennis Kasper began investigating polysaccharide-based GBS vaccines.5Baker CJ Kasper DL Group B streptococcal vaccines.Rev Infect Dis. 1985; 7: 458-467Crossref PubMed Scopus (117) Google Scholar As early as 1988, they were able to show that maternal immunisation against GBS is feasible.6Baker CJ Rench MA Edwards MS Carpenter RJ Hays BM Kasper DL Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus.N Engl J Med. 1988; 19: 1180-1185Crossref Scopus (251) Google Scholar However, the immunogenicity of GBS polysaccharide-based vaccines was weak. By contrast, conjugate vaccines prepared with GBS type-specific capsular polysaccharides coupled to protein antigens proved to induce stronger immune responses than GBS vaccines based only on polysaccharides, and were first tested in a phase 1 trial in 1996.7Kasper D Paoletti L Wessels M et al.Immune response to type III group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine.J Clin Invest. 1996; 98: 2308-2314Crossref PubMed Scopus (224) Google Scholar Since then, not much progress has been made. For almost half a century, invasive disease due to GBS has been recognised as a threat to the health of newborn infants and their mothers in both rich and resource-poor countries. But the development of GBS vaccines has been hampered for decades by many obstacles, not least by the scarcity of sponsorship by industrial partners. Heyderman and colleagues' study, together with concurrent phase 2 trials, constitutes an important step forward towards prevention of neonatal GBS sepsis.1Heyderman RS Madhi SA French N et al.Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial.Lancet Infect Dis. 2016; (published online Feb 8.)http://dx.doi.org/10.1016/S1473-3099(15)00484-3Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 8Nuccitelli A Rinaudo CD Maione D Group B streptococcus vaccine: state of the art.Ther Adv Vaccines. 2015; 3: 76-90Crossref PubMed Google Scholar, 9Madhi SA, Leroux-Roels G, Koen A, et al. Safety and immunogenicity of an investigational maternal trivalent vaccine to prevent perinatal group B streptococcus (GBS) infection. 31st ESPID meeting; Milan; May 28–June 1, 2013.Google Scholar However, questions remain. Why is the vaccine less immunogenic in women with HIV? Is immunogenicity affected by baseline antibody concentrations as it seems to be, and if so, could antibody concentrations in turn be affected by GBS carriage rates, at least of specific serotypes? Finally, researchers still need to determine the dosage of the vaccine and whether a booster dose should be used. Nevertheless, the results of this trial1Heyderman RS Madhi SA French N et al.Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial.Lancet Infect Dis. 2016; (published online Feb 8.)http://dx.doi.org/10.1016/S1473-3099(15)00484-3Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar show that prevention of neonatal GBS infection by vaccination is feasible in women with and without HIV. Maternal immunisation has the potential to protect the pregnant woman, fetus, and newborn infant from vaccine preventable diseases. Maternal IgG is actively transported across the placenta, providing passive immunity. At present, inactivated influenza, tetanus toxoid, and acellular pertussis vaccines are recommended during pregnancy.10Chu HY Englund JA Maternal immunization.Clin Infect Dis. 2014; 59: 560-568Crossref PubMed Scopus (99) Google Scholar The time has come to further develop GBS vaccines, to address issues not covered in the present study, and to initiate larger studies designed to prove not only immunogenicity but also protection from disease and mortality.8Nuccitelli A Rinaudo CD Maione D Group B streptococcus vaccine: state of the art.Ther Adv Vaccines. 2015; 3: 76-90Crossref PubMed Google Scholar, 11Edwards MS Group B streptococcal conjugate vaccine: a timely concept for which the time has come.Hum Vaccin. 2008; 4: 444-448Crossref PubMed Scopus (47) Google Scholar Heyderman and colleagues' study is also relevant beyond neonatal sepsis; GBS has emerged as an important bacterial pathogen in general. In the USA, GBS is now ranked second (18%) after pneumococci (58%) among causative agents leading to bacterial meningitis across all age groups, having surpassed meningococci (13·9%) and Haemophilus influenzae type b (6·7%).12Thigpen MC Whitney CG Messonnier NE et al.Bacterial meningitis in the United States, 1998–2007.N Engl J Med. 2011; 364: 2016-2025Crossref PubMed Scopus (671) Google Scholar Therefore, a forthcoming GBS vaccine would hopefully, not only save thousands of lives of newborn babies, but also lives of children, adults, and elderly people. The trial by Heyderman and colleagues adds substantially towards the realisation of this vision. I was part of the EU-funded (7th framework programme) project DEVANI (Design of a vaccine to immunize neonates against GBS infections through a durable maternal immune response), of which Novartis Vaccines & Diagnostics was part of the project team. Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trialThe vaccine was less immunogenic in women infected with HIV than it was in those not infected, irrespective of CD4 cell count, resulting in lower levels of serotype-specific maternal antibody transferred to infants, which could reduce vaccine protection against invasive GBS disease. A validated assay and correlate of protection is needed to understand the potential protective value of this vaccine. Full-Text PDF Open Access