Every Country, Every Family: Time to Act for Group B Streptococcal Disease Worldwide.

The global burden of Group B Streptococcus (GBS) was estimated for 2015 prompting inclusion of GBS as a priority in the Global Meningitis Roadmap. New estimates for the year 2020 and a WHO report analysing the full value of GBS maternal vaccines has been launched to advance evidence based decision making for multiple stakeholders. In this first of a 10-article supplement, we discuss the following (1) gaps in evidence and action, (2) new evidence in this supplement, and (3) what actions can be taken now and key research gaps ahead. We call for investment in the research pipeline, notably description, development, and delivery, in order to accelerate progress and address the large burden of GBS for every family in every country

WHO consultation on group B Streptococcus vaccine development: Report from a meeting held on 27-28 April 2016.

Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality-assured standardized antibody assays to identify correlates of protection

Coadministration of a 9-Valent Human Papillomavirus Vaccine With Meningococcal and Tdap Vaccines

BACKGROUND: This study in 11- to 15-year-old boys and girls compared the immunogenicity and safety of GARDASIL 9 (9-valent human papillomavirus [9vHPV] vaccine) administered either concomitantly or nonconcomitantly with 2 vaccines routinely administered in this age group (Menactra [MCV4; Neisseria meningitidis serotypes A/C/Y/W-135] or Adacel [Tdap; diphtheria/tetanus/acellular pertussis]). METHODS: Participants received 9vHPV vaccine at day 1 and months 2 and 6; the concomitant group (n = 621) received MCV4/Tdap concomitantly with 9vHPV vaccine at day 1; the nonconcomitant group (n = 620) received MCV4/Tdap at month 1. Antibodies to HPV-, MCV4-, and Tdap-relevant antigens were determined. Injection-site and systemic adverse events (AEs) were monitored for 15 days after any vaccination; serious AEs were monitored throughout the study. RESULTS: The geometric mean titers for all HPV types in 9vHPV vaccine 4 weeks after dose 3, proportion of subjects with a fourfold rise or greater in titers for 4 N meningitidis serotypes 4 weeks after injection with MCV4, proportion of subjects with antibody titers to diphtheria and tetanus ≥0.1 IU/mL, and geometric mean titers for pertussis antigens 4 weeks after injection with Tdap were all noninferior in the concomitant group compared with the nonconcomitant group. Injection-site swelling occurred more frequently in the concomitant group. There were no vaccine-related serious AEs. CONCLUSIONS: Concomitant administration of 9vHPV vaccine with MCV4/Tdap was generally well tolerated and did not interfere with the antibody response to any of these vaccines. This strategy would minimize the number of visits required to deliver each vaccine individually

Vaccines for maternal immunization against Group B Streptococcus disease: WHO perspectives on case ascertainment and case definitions.

Group B Streptococcus (GBS) is an important cause of disease in young infants, stillbirths, pregnant and post-partum women. GBS vaccines for maternal immunization are in development aiming to reduce this burden. Standardisation of case definitions and ascertainment methodologies for GBS disease is needed to support future trials of maternal GBS vaccines. Considerations presented here may also serve to promote consistency in observational studies and surveillance, to better establish disease burden. The World Health Organization convened a working group to provide consensus guidance for case ascertainment and case definitions of GBS disease in stillbirths, infants, pregnant and post-partum women, with feedback sought from external stakeholders. In intervention studies, case capture and case ascertainment for GBS disease should be based on antenatal recruitment of women, with active follow-up, systematic clinical assessment, standardised sampling strategies and optimised laboratory methods. Confirmed cases of invasive GBS disease in stillbirths or infants should be included in a primary composite endpoint for vaccine efficacy studies, with GBS cultured from a usually sterile body site (may be post-mortem). For additional endpoints, or observational studies, confirmed cases of GBS sepsis in pregnant and post-partum women should be assessed. Culture independent diagnostic tests (CIDTs) may detect additional presumed cases, however, the use of these diagnostics needs further evaluation. Efficacy of vaccination against maternal and neonatal GBS colonisation, and maternal GBS urinary tract infection could be included as additional, separate, endpoints and/or in observational studies. Whilst the focus here is on specific GBS disease outcomes, intervention studies also present an opportunity to establish the contribution of GBS across adverse perinatal outcomes, including all-cause stillbirth, preterm birth and neonatal encephalopathy

Preparing to introduce new maternal immunizations in low- and lower-middle-income countries: A report from the Bill & Melinda Gates Foundation convening "Allies in Maternal and Newborn Care"; May 3-4, 2018.

New strategies will be critical to reduce infant mortality and severe morbidity - there are still 5.2 million newborn deaths and stillbirths each year. The decline in newborn mortality has not kept pace with the reduction in under-five deaths and is slowest in low- and lower-middle-income countries (LMICs). Maternal immunization is a promising intervention to protect infants when they are most vulnerable - in utero and their first few months of life, before they can receive their own vaccines. Successfully introducing new vaccines for pregnant women in LMICs will require collaboration between two fields - (1) immunization and (2) maternal, newborn and child health - that use different service delivery approaches, operate under different policy and funding paradigms, and are not always integrated. In May 2018, stakeholders from these distinct communities convened to identify challenges and opportunities associated with delivering new maternal immunizations. Participants agreed that antenatal care is a logical platform. However, in many resource-constrained settings, antenatal care providers are already overburdened, and most women do not receive the recommended number of antenatal visits. Implementing maternal immunization could help increase antenatal care attendance by offering an additional safe and effective intervention that women value. Substantial effort is needed to demonstrate the benefits of maternal immunization to decision-makers and providers, and to ensure that countries and health systems are ready for introduction. To that end, participants identified the following priorities: assure coherence of policies for introducing new vaccines for pregnant women and strengthen maternal health interventions; generate demand for existing, recommended, and new maternal vaccines; conduct socio-behavioral, health systems and implementation research to shape optimal vaccine delivery strategies; and strengthen antenatal and perinatal care quality. To achieve these aims, collaboration across fields will be essential. Given that new maternal vaccines are advancing in clinical development, time is of the essence

Acting on sex and gender in medical innovation is good for business.

Lavanya Vijayasingham and colleagues argue that as well as improving safety and efficacy, considering sex and gender related factors in medical research can have commercial benefit

Immunization in pregnancy clinical research in low- and middle-income countries - Study design, regulatory and safety considerations.

Immunization of pregnant women is a promising public health strategy to reduce morbidity and mortality among both the mothers and their infants. Establishing safety and efficacy of vaccines generally uses a hybrid design between a conventional interventional study and an observational study that requires enrolling thousands of study participants to detect an unknown number of uncommon events. Historically, enrollment of pregnant women in clinical research studies encountered many barriers based on risk aversion, lack of knowledge, and regulatory ambiguity. Conducting research enrolling pregnant women in low- and middle-income countries can have additional factors to address such as limited availability of baseline epidemiologic data on disease burden and maternal and neonatal outcomes during and after pregnancy; challenges in recruiting and retaining pregnant women in research studies, variability in applying and interpreting assessment methods, and variability in locally acceptable and available infrastructure. Some measures to address these challenges include adjustment of study design, tailoring recruitment, consent process, retention strategies, operational and logistical processes, and the use of definitions and data collection methods that will align with efforts globally

Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis. RESULTS: We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%-38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%-22%) with moderate to severe NDI. CONCLUSIONS: GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities

Neonatal Encephalopathy with Group B Streptococcal Disease Worldwide:Systematic Review, Investigator Group Datasets, and Meta-analysis

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of child mortality and longer-term impairment. Infection can sensitize the newborn brain to injury; however, the role of group B streptococcal (GBS) disease has not been reviewed. This paper is the ninth in an 11-article series estimating the burden of GBS disease; here we aim to assess the proportion of GBS in NE cases. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups reporting GBS-associated NE. Meta-analyses estimated the proportion of GBS disease in NE and mortality risk. UK population-level data estimated the incidence of GBS-associated NE. RESULTS: Four published and 25 unpublished datasets were identified from 13 countries (N = 10436). The proportion of NE associated with GBS was 0.58% (95% confidence interval [CI], 0.18%-.98%). Mortality was significantly increased in GBS-associated NE vs NE alone (risk ratio, 2.07 [95% CI, 1.47-2.91]). This equates to a UK incidence of GBS-associated NE of 0.019 per 1000 live births. CONCLUSIONS: The consistent increased proportion of GBS disease in NE and significant increased risk of mortality provides evidence that GBS infection contributes to NE. Increased information regarding this and other organisms is important to inform interventions, especially in low- and middle-resource contexts