Collaboration within the global vaccine safety surveillance ecosystem during the COVID-19 pandemic: lessons learnt and key recommendations from the COVAX Vaccine Safety Working Group.

This analysis describes the successes, challenges and opportunities to improve global vaccine safety surveillance as observed by the Vaccine Safety Working Group from its role as a platform of exchange for stakeholders responsible for monitoring the safety of vaccines distributed through the COVAX mechanism. Three key elements considered to be essential for ongoing and future pandemic preparedness for vaccine developers in their interaction with other members of the vaccine safety ecosystem are (1) the availability of infrastructure and capacity for active vaccine safety surveillance in low-income and middle-income countries (LMICs), including the advancement of concepts of safety surveillance and risk management to vaccine developers and manufacturers from LMICs; (2) more comprehensive mechanisms to ensure timely exchange of vaccine safety data and/or knowledge gaps between public health authorities and vaccine developers and manufacturers; and (3) further implementation of the concept of regulatory reliance in pharmacovigilance. These aims would both conserve valuable resources and allow for more equitable access to vaccine safety information and for benefit/risk decision-making.

Improvement of Pediatric Drug Development: Regulatory and Practical Frameworks.

PURPOSE: A dearth in pediatric drug development often leaves pediatricians with no alternative but to prescribe unlicensed or off-label drugs with a resultant increased risk of adverse events. We present the current status of pediatric drug development and, based on our data analysis, clarify the problems in this area. Further action is proposed to improve the drug development that has pediatric therapeutic orphan status. METHODS: We analyzed all Phase II/III and Phase III trials in ClinicalTrials.gov that only included pediatric participants (<18 years old) between 2006 and 2014. Performance index, an indicator of pediatric drug development, was calculated by dividing the annual number of pediatric clinical trials by million pediatric populations acquired from Census.gov. Effects of the 2 Japanese premiums introduced in 2010, for the enhancement of pediatric drug development, were analyzed by comparing mean performance index prepremiums (2006-2009) and postpremiums (2010-2014) among Japan, the European Union, and the United States. The European Union Clinical Trials Register and published reports from the European Medicines Agency were also surveyed to investigate the Paediatric Committee effect on pediatric clinical trials in the European Union. FINDINGS: Mean difference of the performance index in prepremiums and postpremiums between Japan and the European Union were 0.296 (P < 0.001) and 0.066 (P = 0.498), respectively. Those between Japan and the United States were 0.560 (P < 0.001) and 0.281 (P = 0.002), indicating that pediatric drug development in Japan was more active after the introduction of these premiums, even reaching the level of the European Union. The Pediatric Regulation and the Paediatric Committee promoted pediatric drug development in the European Union. The registered number of clinical trials that includes at least 1 participants <18 years old in the European Union Clinical Trials Register increased by 247 trials (from 672) in the 1000 days after regulation. The ratio of pediatric clinical trials with an approved Paediatric Investigation Plan increased to >15% after 2008. IMPLICATIONS: Recruitment and ethical obstacles make conducting pediatric clinical trials challenging. An improved operational framework for conducting clinical trials should mirror the ever-improving regulatory framework that incentivizes investment in pediatric clinical trials. Technological approaches, enhancements in electronic medical record systems, and community approaches that actively incorporate input from physicians, researchers, and patients could offer a sustainable solution to recruitment of pediatric study participants. The key therefore is to improve pediatric pharmacotherapy collaboration among industry, government, academia, and community. Expanding the regulatory steps taken in the European Union, United States, and Japan and using innovative clinical trial tools can move pediatric pharmacotherapy out of its current therapeutic orphan state.

Summary of knowledge gaps related to quality and efficacy of current influenza vaccines.

Influenza viruses are a public health threat, as they are pathogenic, highly transmissible and prone to genetic changes. For decades vaccination strategies have been based on trivalent inactivated vaccines, which are regulated by specific guidelines. The progress in scientific knowledge and the lessons learned from the A(H1N1)2009 pandemic have highlighted further the need to improve current guidelines, including the immunogenicity criteria set by the CHMP in 1997, and to promote the discussion on the shortcomings encountered, e.g. the evaluation of vaccine efficacy in the paediatric and elderly populations, the measurement of the naivety of a population, the impact of prior immunity on subsequent vaccinations, and the technical issues with the serological assays for detection of immunity and immunogenicity. The authors attempted to summarise and tackle key gaps in the existing evidence concerning quality and efficacy of influenza vaccines, aiming at favouring a common understanding and a coordinated approach across stakeholders.

A Belgian consensus-statement on growing-up milks for children 12-36 months old.

UNLABELLED: Growing-up milks (GUM) are milk-based drinks with low protein and added minerals and vitamins intended for children 12-36 months. Since the advantages of GUM are heavily debated, we reviewed the literature. A literature search was done using the classic databases (Pubmed, Embase, Cochrane) on the use of GUM in 12- to 36-month-old young children. Only limited data are available. GUM have a highly variable composition as their marketing is not regulated. Nevertheless, all papers conclude that GUM help to cover nutritional requirements of 12- to 36-month-old infants. CONCLUSION: Appropriate intakes of macro- and micronutrients in 1- to 3-year-old children have long-term health benefits. Present diets offered to toddlers do in general not meet the requirements. Supplemented foods are therefore helpful, of which GUM is a possibility.

The risks of risk aversion in drug regulation.

Drugs are approved by regulatory agencies on the basis of their assessment of whether the available evidence indicates that the benefits of the drug outweigh its risks. In recent years, regulatory agencies have been criticized both for being overly tolerant of risks or being excessively risk-averse, which reflects the challenge in determining an appropriate balance between benefit and risk with the limited data that is typically available before drug approval. The negative consequences of regulatory tolerance in allowing drugs onto the market that turn out to be unsafe are obvious, but the potential for adverse effects on public health owing to the absence of new drugs because of regulatory risk-aversion is less apparent. Here, we discuss the consequences of regulatory risk-aversion for public health and suggest what might be done to best align acceptance of risk and uncertainty by regulators with the interests of public health.

Lessons learnt from pandemic A(H1N1) 2009 influenza vaccination. Highlights of a European workshop in Brussels (22 March 2010).

This European workshop identified a number of lessons learnt in the field of vaccine licensure, prioritization of target groups, communication on pandemic vaccines, implementation of vaccination and safety monitoring. The mild severity of the pandemic A(H1N1) 2009 influenza virus influenced the perception of pandemic vaccines, as previous pandemic preparedness had anticipated a more virulent virus. This vaccination experience provides an important opportunity for research on the long-term immunogenicity and safety of pandemic vaccines in pregnant women and children, as well as on the long-term safety of adjuvants. Preparedness for future pandemics could involve improved decision-making on target groups and increased communication on vaccine safety.

Development of medicines for children in Europe: ethical implications.

Ethics of clinical trials in children have been a longstanding topic for debate. Children are vulnerable, unable to consent to participation in trials from a legal perspective and deserve to be protected. Ethical principles and the European legal framework define the safeguards that need to be put in place in any paediatric trial, be it performed in developed or in developing countries. It was considered that children should not be included in trials for ethical reasons. However, there is an ethical need to study medicines as data obtained in adults cannot be extrapolated to children. It is our collective responsibility to obtain sufficient information to be able to prescribe medicines safely whilst protecting children who are exposed in the trials. Future European paediatric regulations should encourage the development of medicines in high-quality ethical research and ensure availability of information to the public.

Isolation and characterization of enteroaggregative Escherichia coli (EAggEC) by genotypic and phenotypic markers, isolated from diarrheal children in Congo.

OBJECTIVE: To determine the prevalence of enteroaggregative Escherichia coli (EAggEC) in African diarrheal children in Lwiro, Congo, to characterize EAggEC isolates by possible genotypic and phenotypic markers, and to evaluate the EAggEC probe pCVD432 in identifying EAggEC. METHODS: The Hep-2 cell adhesion assay and colony-blot hybridization assays were carried out for the identification of EAggEC. O:H serotyping, biotyping, antibiogram and plasmid-profile analysis were done. To detect the E. coli LT and ST, ELISA tests were used and, for VT, a vero cell assay was used. RESULTS: EAggEC strains were isolated from 56 out of 115 diarrheal children (48.7%): the organism was present alone and presumed to cause diarrhea in 22 (19.1%) cases. The rest of the cases were associated with two or more diarrheagenic E. coli strains. EAggEC strains were isolated from 25% of total diarrheal children (first day of isolation) and 8.86% of age-matched healthy individuals (p<0.03). This isolation rate was significantly higher than the one found for other diarrheagenic E. coli strains. In parallel, we evaluated the sensitivity and specificity of EAggEC probe pCVD432, and found that it had 56% sensitivity with 100% specificity compared with the Hep-2 cell test. EAggEC isolates were characterized by serotyping, biotyping, antibiotic resistance pattern, plasmid profiling and toxin production analysis. They did not produce any one of these classical toxins and nor did they relate to any particular serotypes. Plasmid analysis of the 79 EAggEC isolates (n=315) showed seven different profiles. Ten resistance patterns were identified and 34 strains were sensitive to all drugs. There was no association between plasmid profiles and antibiotic resistance patterns. All 16 classical E. coli biotypes were found in this small EAggEC population. CONCLUSIONS: EAggEC has been emerging as a cause of childhood diarrhea in African children in Congo. From the accumulated data it was found that there is a great heterogeneity in EAggEC populations.