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Background Analysis: US FDA Advisory Committee to Discuss Group B Streptococcus (GBS) Vaccines and Hear Report on CBER Lab’s Research Program – MAY 17, 2018 (VRBPAC)
The US FDA has scheduled a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting for Thursday, May 17, 2018, to discuss two topics related to biologic products. Under Topic I, the Committee will discuss approaches for demonstrating effectiveness of group B streptococcus (GBS) vaccines intended for use in pregnant women to protect the newborn infant. Under Topic II, the committee will hear an overview of the research program in the Laboratory of Respiratory Viral Diseases (LRVD), Division of Viral Products, Office of Vaccines Research and Review, CBER, FDA.
Topic I Group B Streptococcus (GBS) Vaccines
Streptococcus agalactiae or group B streptococcus (GBS) is a gram-positive pathogen with polysaccharide capsules that help GBS evade host defense mechanisms by interfering with phagocytic clearance. The capsule polysaccharides can be classified into ten types (Ia, Ib, II, III, IV, V, VI, VII, VIII, IX) based on their structure and antigen makeup. All of these serotypes can cause infections, but five serotypes (Ia, Ib, II, III and V) account for the majority of disease, both in neonates and adults.
GBS is the leading cause of neonatal sepsis and meningitis in many countries and an important cause of disease in pregnant women, as well as in immunocompromised adults and the elderly. Neonatal infections can result in pneumonia, sepsis, meningitis, and in some cases death. GBS is also a commensal organism able to colonize the urogenital and gastrointestinal tracts of 25–40% of healthy women. It has been estimated that, if 20–30% of pregnant women are colonized with GBS, approximately 50% of their infants become colonized and approximately 1% of these infants develop disease. Neonatal infections caused by GBS had an incidence of 0.5–2 per 1000 live births, a mortality rate of 20–25%, and permanent neurologic sequelae in the majority of survivors.
GBS diseases in neonates are classified as early-onset disease (EOD) and late-onset disease (LOD).
EOD occurs in the first 6 days of life and accounts for 60–70% of all GBS neonatal illness. The neonate is usually infected by exposure to GBS during birth when the neonate aspirates contaminated amniotic and vaginal fluids. The bacteria can spread rapidly into the bloodstream, with clinical signs such as pneumonia or sepsis appearing within the first 12 hours in 98% of cases. LOD, occurring between 7–90 days of life, primarily in premature neonates, is characterized by meningitis in up to 50% of cases. It may be acquired from breast milk or from hospital and community sources. LOD has a lower mortality rate than EOD, but a high morbidity rate, with 50% of neonates that survive GBS infection suffering complications, including mental retardation, hearing loss, and speech and language delay.
Intravenous antimicrobial prophylaxis (IAP) and active vaccination are the most common methods of GBS prevention. In the US, IAP is administered to women during labor and delivery, based on a screening approach, which recommends that all pregnant women should be screened for GBS vaginal and rectal colonization at 35–37 weeks of gestation.
Although several vaccines to prevent GBS are in development, none is currently available. in development. Effective vaccines would stimulate the production of functionally active antibodies that could cross the placenta and provide protection against neonatal GBS infection. The most promising vaccine candidates able to confer protection and induce functionally active antibodies are represented by CPS and surface proteins, although to date clinical trials in humans have been conducted only by immunizing subjects with polysaccharide-based vaccines.
Active vaccines in experimental animals have included whole killed GBS, purified bacterial components (generally capsular polysaccharide or purified proteins), or conjugate vaccine preparations. Most studies have used systemic (intramuscular, subcutaneous, or intraperitoneal) vaccination.
GBS capsular polysaccharide (CPS) has been the primary target for vaccine development, although glycoconjugate vaccines (polysaccharides enhanced by covalent conjugation with a carrier protein)
and protein-based vaccines have been studied. Note that polysaccharide-based vaccines typically only provide protection against specific CPS types included in the vaccine or closely related serotypes. With protein-based vaccines, efforts have been made to identify proteins common to all GBS, in order to develop a vaccine that would confer broad protection against GBS.
The first clinical trials for GBS vaccines were conducted by investigators under the auspices of the National Institutes of Health (NIH). Trials with plain CPS-based vaccines demonstrated that they were well-tolerated but only modestly immunogenic. Trials with GBS polysaccharide-protein conjugate protein also have been administered to healthy adults and pregnant women. Novartis, now GlaxoSmithKline (GSK), was the first manufacturer to conduct clinical trials with a new CPS-conjugate vaccine. Early clinical trials were NCT01193920 (Phase 1/2 trial), NCT01446289 (Phase 2 trial), and NCT02046148 (Phase 2 trial). Another manufacturer, MinervaX, has conducted a Phase 1 trial (NCT02459262) with a protein vaccine (GBS-NN) made from the N-terminal domains of the Rib and AlphaC surface proteins of GBS.
Several regulatory issues are involved in the development of GBS vaccines. One issue is that these vaccines would be the first vaccines to be developed specifically for use in pregnant women and their regulatory pathway also will impact the approach of additional vaccines developed for pregnancy. Another issue is whether large-scale randomized, placebo-controlled trials will be required or whether approval can be based on serological correlates of protection; that is, the correlation of serotype-specific CPS antibody levels and GBS disease in newborns. It is likely that endpoints in clinical trials would focus on the impact of the vaccines against EOD, LOD and maternal disease, as well as potential surrogate endpoint of impact on colonization.
In June 2016, the FDA hosted a webinar on the use of vaccines during pregnancy to benefit both the mother and the infant. In that webinar, the FDA noted that, in order to approve a vaccine for use in pregnancy to protect the infant, the vaccine would need to demonstrate that the vaccine is safe and effective, and to show protection in infants. They also said that the clinical development program would need to be specifically designed for pregnant women and the infant. The nonclinical development would need to include a description of the manufacturing process of the vaccine; appropriate product characterization to determine acceptability of candidate vaccines for clinical studies; and toxicology studies in animals, including reproductive and developmental toxicology. Clinical safety evaluation would need to focus on potential adverse events in the mother, potential complications specific to pregnancy and obstetric complications, and infant outcomes data. In the FDA’s webinar slides, they discuss effectiveness, saying that, for diseases with low incidence, it may not be feasible to directly measure a vaccine’s effectiveness in preventing disease in newborn infants in clinical trials. They also said that, for vaccines already recommended for use in pregnancy, controlled clinical trials present challenges. The FDA acknowledges that alternative clinical trial designs may be needed to determine the effectiveness of vaccines used during pregnancy to protect the infant.
The FDA convened a meeting of the VRPBAC on November 13, 2015 to discuss the topic of “Considerations for evaluation of the safety and effectiveness of vaccines administered to pregnant women to protect the infant.” In the 2015 VRBPAC meeting, the topic did not focus on a specific disease. The published Committee meeting minutes noted that VRBPAC discussed that serological markers may be acceptable to infer vaccine effectiveness to protect the infant from disease. However, they said that the adequacy of using serological endpoints as markers of passive protection in the infant will depend on the vaccine used in maternal immunization programs. Furthermore, the duration and type of safety follow-up of the infant as well as safety assessments in the mother will depend on the vaccine under investigation and disease targeted. The Committee noted the challenges with safety follow-up in infants, as infants are seen by different providers. Also, the need for clinical studies to assess potential immune interference with childhood vaccines depends on the vaccine antigen used for maternal immunization. Observational studies using existing databases to evaluate the effectiveness of currently licensed vaccines recommended for use in pregnancy to protect the infant from disease could be used, however, potential challenges with this approach need to be considered.”
Topic II Laboratory of Respiratory Viral Diseases (LRVD) Research Program
The Committee will hear an overview of the research program in the Laboratory of Respiratory Viral Diseases (LRVD), Division of Viral Products, Office of Vaccines Research and Review at CBER. Presenters from the Laboratory, Division, and Office will provide overviews of their areas, Following the presentations, the meeting will be closed to permit discussion where disclosure would constitute a clearly unwarranted invasion of personal privacy (5 U.S.C. 552b(c)(6)). The recommendations of the advisory committee regarding the progress of the investigator’s research, along with other information, will be used in making personnel and staffing decisions regarding individual scientists.
Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s (if applicable) briefing materials.
Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.
METADATA: Sponsor: none Drug Name: none Drug Class: vaccine Indication: Group B Streptococcus
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