Pandemic influenza vaccine & narcolepsy: Simulations on the potential impact of bias

Several studies have identified an association between PandemrixTM, an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under-diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies

Red Queen Dynamics with Non-Standard Fitness Interactions

Antagonistic coevolution between hosts and parasites can involve rapid fluctuations of genotype frequencies that are known as Red Queen dynamics. Under such dynamics, recombination in the hosts may be advantageous because genetic shuffling can quickly produce disproportionately fit offspring (the Red Queen hypothesis). Previous models investigating these dynamics have assumed rather simple models of genetic interactions between hosts and parasites. Here, we assess the robustness of earlier theoretical predictions about the Red Queen with respect to the underlying host-parasite interactions. To this end, we created large numbers of random interaction matrices, analysed the resulting dynamics through simulation, and ascertained whether recombination was favoured or disfavoured. We observed Red Queen dynamics in many of our simulations provided the interaction matrices exhibited sufficient ‘antagonicity’. In agreement with previous studies, strong selection on either hosts or parasites favours selection for increased recombination. However, fast changes in the sign of linkage disequilibrium or epistasis were only infrequently observed and do not appear to be a necessary condition for the Red Queen hypothesis to work. Indeed, recombination was often favoured even though the linkage disequilibrium remained of constant sign throughout the simulations. We conclude that Red Queen-type dynamics involving persistent fluctuations in host and parasite genotype frequencies appear to not be an artefact of specific assumptions about host-parasite fitness interactions, but emerge readily with the general interactions studied here. Our results also indicate that although recombination is often favoured, some of the factors previously thought to be important in this process such as linkage disequilibrium fluctuations need to be reassessed when fitness interactions between hosts and parasites are complex

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: A multinational self-controlled case series in Europe

Background: The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk

Mapping the Organization of Axis of Motion Selective Features in Human Area MT Using High-Field fMRI

Functional magnetic resonance imaging (fMRI) at high magnetic fields has made it possible to investigate the columnar organization of the human brain in vivo with high degrees of accuracy and sensitivity. Until now, these results have been limited to the organization principles of early visual cortex (V1). While the middle temporal area (MT) has been the first identified extra-striate visual area shown to exhibit a columnar organization in monkeys, evidence of MT's columnar response properties and topographic layout in humans has remained elusive. Research using various approaches suggests similar response properties as in monkeys but failed to provide direct evidence for direction or axis of motion selectivity in human area MT. By combining state of the art pulse sequence design, high spatial resolution in all three dimensions (0.8 mm isotropic), optimized coil design, ultrahigh field magnets (7 Tesla) and novel high resolution cortical grid sampling analysis tools, we provide the first direct evidence for large-scale axis of motion selective feature organization in human area MT closely matching predictions from topographic columnar-level simulations

Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines – Multi-country assessment

Background: In 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines. Methods: We used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009. Results: No changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03. Conclusions: Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study

Pediatric drug safety signal detection: a new drug-event reference set for performance testing of data-mining methods and systems

BACKGROUND: Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)-Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug-event associations is required. OBJECTIVE: The aim of this study was to develop a pediatric-specific reference set of positive and negative drug-event associations. METHODS: Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0-18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug-event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug's Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. RESULTS: Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. CONCLUSION: We propose a drug-event reference set that can be used to compare different signal detection methods in the pediatric population

Evaluation of a multinational, multilingual vaccine debate on Twitter.

BACKGROUND: Public confidence in an immunization programme is a pivotal determinant of the programme's success. The mining of social media is increasingly employed to provide insight into the public's sentiment. This research further explores the value of monitoring social media to understand public sentiment about an international vaccination programme. OBJECTIVE: To gain insight into international public discussion on the paediatric pentavalent vaccine (DTP-HepB-Hib) programme by analysing Twitter messages. METHODS: Using a multilingual search, we retrospectively collected all public Twitter messages mentioning the DTP-HepB-Hib vaccine from July 2006 until May 2015. We analysed message characteristics by frequency of referencing other websites, type of websites, and geographic focus of the discussion. In addition, a sample of messages was manually annotated for positive or negative message tone. RESULTS: We retrieved 5771 messages. Only 3.1% of the messages were reactions to other messages, and 86.6% referred to websites, mostly news sites (70.7%), other social media (9.8%), and health-information sites (9.5%). Country mentions were identified in 70.4% of the messages, of which India (35.4%), Indonesia (18.3%), and Vietnam (13.9%) were the most prevalent. In the annotated sample, 63% of the messages showed a positive or neutral sentiment about DTP-HepB-Hib. Peaks in negative and positive messages could be related to country-specific programme events. CONCLUSIONS: Public messages about DTP-HepB-Hib were characterized by little interaction between tweeters, and by frequent referencing of websites and other information links. Twitter messages can indirectly reflect the public's opinion about major events in the debates about the DTP-HepB-Hib vaccine

Recombination accelerates adaptation on a large-scale empirical fitness landscape in HIV-1

Recombination has the potential to facilitate adaptation. In spite of the substantial body of theory on the impact of recombination on the evolutionary dynamics of adapting populations, empirical evidence to test these theories is still scarce. We examined the effect of recombination on adaptation on a large-scale empirical fitness landscape in HIV-1 based on in vitro fitness measurements. Our results indicate that recombination substantially increases the rate of adaptation under a wide range of parameter values for population size, mutation rate and recombination rate. The accelerating effect of recombination is stronger for intermediate mutation rates but increases in a monotonic way with the recombination rates and population sizes that we examined. We also found that both fitness effects of individual mutations and epistatic fitness interactions cause recombination to accelerate adaptation. The estimated epistasis in the adapting populations is significantly negative. Our results highlight the importance of recombination in the evolution of HIV-I

Safety of pandemic H1N1 vaccines in children and adolescents

During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children. We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines. As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines - particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally