Official batch control of influenza vaccines: Is it still useful?

INTRODUCTION: The governmental quality control of human vaccines is a long established tradition in many European countries. In Germany, vaccines have been controlled by a governmental agency since 1935. In the beginning, vaccine production and control was a purely national activity. However, that changed fundamentally in 1994 when the so-called Official Control Authority Batch Release Network (OCABR) was implemented shortly after the establishment of the European Union. Today, Official Medicinal Control Laboratories (OMCLs) are part of the European OCABR Network. In many European countries, OMCLs experimentally test every batch of human vaccines before they enter the market. We wanted to gain insights into the benefits of batch release by the Network and address the question whether batch release is still useful. This question was investigated in the context of influenza vaccines. METHODS: Notifications on influenza vaccines circulated from 2006 to 2016 within the OCABR network were compiled and organized into 32 cases. The impact of these findings was evaluated, and the communication pathways between companies and respective European control laboratories were examined. RESULTS: Approximately 5850 batches were tested by the OMCL network between 2006 and 2016. Among these, notifications belonging to 32 cases were observed. The predominant proportion of the circulated notifications related to manufacturing issues. In most cases, the manufacturer itself had withdrawn the batches before they entered the market. However, in three cases, batches of insufficient quality were detected by the respective European Control Laboratory leading to withdrawal of 13 batches. CONCLUSION: 13 batches which did not meet the specifications of influenza vaccine were detected by the OMCL network between 2006 and 2016 which would not have been identified by the manufacturer. This demonstrates the impact of governmental batch release. Together with the intrinsic values of the OCABR system and keeping in mind that vaccines are given to healthy often young individuals, governmental batch release of influenza vaccines is still justified.

New bone post-processing tools in forensic imaging: a multi-reader feasibility study to evaluate detection time and diagnostic accuracy in rib fracture assessment.

PURPOSE: The aim of this multi-reader feasibility study was to evaluate new post-processing CT imaging tools in rib fracture assessment of forensic cases by analyzing detection time and diagnostic accuracy. MATERIALS AND METHODS: Thirty autopsy cases (20 with and 10 without rib fractures in autopsy) were randomly selected and included in this study. All cases received a native whole body CT scan prior to the autopsy procedure, which included dissection and careful evaluation of each rib. In addition to standard transverse sections (modality A), CT images were subjected to a reconstruction algorithm to compute axial labelling of the ribs (modality B) as well as "unfolding" visualizations of the rib cage (modality C, "eagle tool"). Three radiologists with different clinical and forensic experience who were blinded to autopsy results evaluated all cases in a random manner of modality and case. RESULTS: Rib fracture assessment of each reader was evaluated compared to autopsy and a CT consensus read as radiologic reference. A detailed evaluation of relevant test parameters revealed a better accordance to the CT consensus read as to the autopsy. Modality C was the significantly quickest rib fracture detection modality despite slightly reduced statistic test parameters compared to modalities A and B. CONCLUSION: Modern CT post-processing software is able to shorten reading time and to increase sensitivity and specificity compared to standard autopsy alone. The eagle tool as an easy to use tool is suited for an initial rib fracture screening prior to autopsy and can therefore be beneficial for forensic pathologists.

Considerations of strategies to provide influenza vaccine year round.

There is potential for influenza vaccine programmes to make a substantial impact on severe disease in low-resource settings, however questions around vaccine composition and programmatic issues will require special attention. Some countries may benefit from immunization programmes that provide year-round supply of vaccine; however the best way to ensure adequate vaccine supply has yet to be determined. In this report, we discuss vaccine composition, availability, and programmatic issues that must be considered when developing year-round influenza immunization programmes. We then explore how these considerations have influenced immunization practices in the Latin American region as a case study. We identify three different approaches to achieve year-round supply: (1) alternating between Northern Hemisphere and Southern Hemisphere formulations, (2) extending the expiration date to permit extended use of a single hemisphere formulation, and (3) local vaccine manufacture with production timelines that align with local epidemiology. Each approach has its challenges and opportunities. The growing data suggesting high influenza disease burden in low resource countries underscores the compelling public health need to determine the best strategies for vaccine delivery.

[From the licensure of vaccines to the recommendation of the Standing Committee on Vaccination in Germany : criteria for the assessment of benefits and risks]. / Von der Zulassung von Impfstoffen zur Empfehlung durch die Ständige Impfkommission in Deutschland : Kriterien zur objektiven Bewertung von Nutzen und Risiken.

Vaccines are among the most effective preventive measures in modern medicine and have led to a dramatic decline and-for a few diseases-even to the elimination of severely infectious diseases. There are some particularities of the risk-benefit assessment of vaccines compared with that of therapeutic drugs. These include the fact that vaccines are applied to healthy individuals with the aim of preventing an infectious disease, while therapeutic drugs are administered to sick people to cure them of an already acquired disease. The acceptable level of risk associated with the application of a vaccine is therefore much lower. In addition, high vaccination coverage can lead to population-level effects (e.g., the indirect protection of unvaccinated individuals) that can confer additional benefits to the population overall. When a marketing authorization application (MAA) for a novel vaccine is evaluated, conclusions are made regarding its quality, safety, and efficacy, and a benefit-risk assessment is carried out accordingly. In contrast, when deciding on the introduction of a new vaccine into a national immunization program or on a recommendation for a specific risk-group, the focus is shifted to considerations of how a licensed vaccine can be best used in a population (e.g., which immunization strategy is most effective in preventing deaths or hospitalizations, or in reducing treatment costs for the health care system). Stringent assessment criteria have been developed that require a robust safety analysis before a new vaccine is administered to humans for the first time in pre-licensure studies. Similarly, criteria are applied for calculating the benefit-risk ratio at the time of the licensure of a new vaccine in addition to during the entire post-licensure period. However, when deciding if and how a licensed vaccine can best be integrated into an existing immunization program, additional criteria are applied that are different, yet complementary to those applied for granting a marketing authorization. These decisions require-in addition to considerations of vaccine quality, vaccine efficacy and safety-conclusions regarding population-level effects combined with an integrative analysis of the local context (e.g., local epidemiology, cost-effectiveness, and acceptance by the population). To serve these objectives, national authorities such as the Standing Committee on Vaccination in Germany (STIKO) have been established to integrate globally developed vaccines into the national context of immunization strategies.

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 global regulatory science agenda for vaccines.

The Decade of Vaccines Collaboration and development of the Global Vaccine Action Plan provides a catalyst and unique opportunity for regulators worldwide to develop and propose a global regulatory science agenda for vaccines. Regulatory oversight is critical to allow access to vaccines that are safe, effective, and of assured quality. Methods used by regulators need to constantly evolve so that scientific and technological advances are applied to address challenges such as new products and technologies, and also to provide an increased understanding of benefits and risks of existing products. Regulatory science builds on high-quality basic research, and encompasses at least two broad categories. First, there is laboratory-based regulatory science. Illustrative examples include development of correlates of immunity; or correlates of safety; or of improved product characterization and potency assays. Included in such science would be tools to standardize assays used for regulatory purposes. Second, there is science to develop regulatory processes. Illustrative examples include adaptive clinical trial designs; or tools to analyze the benefit-risk decision-making process of regulators; or novel pharmacovigilance methodologies. Included in such science would be initiatives to standardize regulatory processes (e.g., definitions of terms for adverse events [AEs] following immunization). The aim of a global regulatory science agenda is to transform current national efforts, mainly by well-resourced regulatory agencies, into a coordinated action plan to support global immunization goals. This article provides examples of how regulatory science has, in the past, contributed to improved access to vaccines, and identifies gaps that could be addressed through a global regulatory science agenda. The article also identifies challenges to implementing a regulatory science agenda and proposes strategies and actions to fill these gaps. A global regulatory science agenda will enable regulators, academics, and other stakeholders to converge around transformative actions for innovation in the regulatory process to support global immunization goals.

Enhancing the reproducibility of serological methods used to evaluate immunogenicity of pandemic H1N1 influenza vaccines-an effective EU regulatory approach.

Haemagglutination-inhibition (HI) and virus neutralisation (VN) assays are routinely applied to evaluate influenza vaccine immunogenicity for regulatory approval. Despite their frequent use both assays are currently only poorly standardised causing considerable inter-laboratory variation of serological results that is particularly evident for pandemic influenza vaccines. The present study was conducted in association with the European Medicines Agency (EMA) to directly compare assay variability between vaccine manufacturer's and European regulatory agency's laboratories in an influenza pandemic scenario. To this end, a defined subset of H1N1 pdm clinical trial sera from all manufacturers that had applied at EMA for approval of pandemic H1N1 vaccines were re-tested by the National Institute for Biological Standards and Control (for HI) and the Paul Ehrlich Institute (for VN). Comparative analysis of test results determined for almost 2000 serum samples revealed a marked inter-laboratory variation for HI titres (up to 5.8-fold) and even more for neutralisation titres (up to 7.0-fold). When the absolute titres were adjusted relative to the calibrated International Antibody Standard 09/194 variation was drastically reduced and acceptable agreement of results from different laboratories could be achieved. Hence, inclusion of an appropriate calibrated antibody standard for adjustment of original titres is a powerful tool to substantially increase reproducibility of serological results from different laboratories and to significantly improve regulatory evaluation of influenza vaccine efficacy.

Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469.

The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic ß-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).

Stability of vaccines - bridging from stability data to continuous safety and efficacy throughout shelf life - an always reliable approach?

Stability studies are important tools to reliably ensure that efficacy and safety of medicinal products will remain unchanged from release of drug product until the end of shelf life. For complex medicinal products such as biological medicinal products, including vaccines, design and conduct of such studies requires particularly careful considerations in order to ensure that technical data resulting from stability studies are indeed indicative for unchanged clinical performance. Ideally, relevance of specifications controlled by stability studies as well as definition of shelf life should be justified by acceptable clinical data obtained with product at the end of the shelf life claimed.

Vaccination safety update.

INTRODUCTION: In Germany, a large number of biased reports against vaccination have recently been published in all of the news media, and particularly on the internet. This paper discusses the safety profile of modern vaccines and their continuous surveillance and shows why the current criticism of vaccination on safety grounds is unjustified. METHODS: The authors have performed a selective literature search to enable a proper distinction to be drawn between scientifically justified and unjustified reports on the potential adverse effects of vaccination. RESULTS: At present, the safety of a new vaccine must be demonstrated in large-scale clinical trials before the product is licensed. After licensing, the safety of new vaccines is constantly monitored, and the results of monitoring are published. DISCUSSION: An examination of these data reveals that the expressed doubts about the safety of vaccines are unjustified.