Why Children Receiving GSK‘s Pandemic Flu Vaccine are at an almost Tenfold Increased Risk of Narcolepsy
The Pandemrix investigation in Finland continues: understanding the results.
In February 2011 Finland‘s National Institute for Health and Welfare (NIHW) presented an interim report suggesting that children administered GlaxoSmithKline‘s Pandemrix® vaccine against the H1N1 pandemic flu were nine-times more likely to suffer from the sleeping disorder narcolepsy within 8 months of inoculation, compared with those who did not receive the jab.
Although results are yet to be confirmed, the preliminary research, which was conducted by the Finnish national narcolepsy committee, illustrates a nearly tenfold increase in narcolepsy cases among 60 children and adolescents aged 4 to 19 years, who had received the vaccine during 2009 and 2010. Of those who fell ill, 52 had received Pandemrix.
Hanna Nohynek, the NIHW‘s vaccine safety officer stated: “The baseline risk for narcolepsy in children aged between 4 and 19 was less than 1 per 100,000 and the study found that among those who had the Pandemrix vaccine the risk rose to 8.1 per 100,000”.
“The National Institute considers it probable that the Pandemrix vaccine was a contributing factor to this observed increase, and has called for further investigation of other cofactors that may be associated with the increased risk”, the WHO claimed. “They consider it most likely that the Pandemrix vaccine increased the risk of narcolepsy in a joint effect in those genetically disposed with some other, still unknown, genetic and/or environmental factor”.
Whilst researchers at the NIHW attribute the rise in narcolepsy to this combined effect of Pandemrix and other factors, the British drug maker GSK claim it is too soon to draw any conclusions in an emailed statement: “This (Finnish) investigation is independent of a broader ongoing European Medicines Agency (EMA) investigation initiated in 2010. GSK is reviewing the report and believes it would be premature to draw any conclusions on a potential association between Pandemrix and narcolepsy until this European investigation has been completed”.
Meanwhile in Finland, the genetics behind the increase in narcolepsy is being investigated by the Finnish National Narcolepsy Task Force. Their final report is planned to be released on the 31 August 2011 after further investigations into the epidemiologic, immunologic and genetic causes for the onset of narcolepsy postvaccination are conducted.
To date, the HLA-DQB1*0602 genotype has been implicated in the increased risk of narcolepsy following inoculation. Patrick Zuber, WHO‘s top vaccine safety official highlights: “approximately 30% of Finnish people have this particular genotype, compared with 15% in the rest of Europe”.
Meanwhile, an EMA spokeswoman recently stated that the safety review was continuing. “There is really not enough data at this point in time to determine anything, For the time being, the benefit–risk balance of Pandemrix remains positive”.
In accordance with GSK statistics, over 31 million doses of Pandemrix have been administered worldwide in 47 countries. Since 31 January 2011, a total of 162 cases of narcolepsy have been reported, with 70% of those cases originating from Finland and Sweden.
Source: Statement from the National Institute for Health and Welfare of Finland of 1 February 2011 www.euro.who.int/en/what-we-do/health-topics/disease-prevention/vaccines-and-immunization/news/news/2011/02/panderix-vaccine-and-increased-risk-of-narcolepsy
The Bubble of Genomics Research needs Deflating
Policy experts have urged for a more realistic approach to genomics research, with more rational expectations regarding genomic medicine, which they state have created a ‘bubble‘ that needs deflating before it puts the field‘s long-term benefits at risk.
The policy experts air their concerns in the February 18 issue of Science. One of the four authors, Dr James Evans, Clinical Professor at the University of North Carolina (NC, USA) explains the rationale for publishing the perspective article: “Our commentary was an attempt to bring some balance to the hopes and claims that swirl around the issue of genomic medicine. It is a cautionary essay that tries to extol the real and formidable potential of genomic medicine but also attempts to counter what we see as exaggerated claims”.
The fears of the experts are grounded in the belief that if we are uncritical and naive in our enthusiasm for these exciting technologies, “we risk both diversion of precious resources and premature implementation which could hurt patients – as well as a backlash which will hurt our field”.
Speculating on the implications of this viewpoint on the field of pharmacogenomics, Dr Evans states: “We point out that pharmacogenomics in certain, targeted applications, will be a likely near-term success of genomics. Drugs that have a narrow therapeutic window and are used for severe indications we suspect will be quite amenable to pharmacogenomic approaches. On the other hand, it seems naive to think that pharmacogenomics will revolutionize the use of all (or even most) agents”.
On how he sees the field of genomics developing in the next 10 years, the Bryson Distinguished Professor of Genetics and Medicine went on to remark: “I think the biggest benefit will be from the gradual accumulation of basic insights which will undoubtedly stem from the application of genomics”.
In a closing statement, the North Carolina researcher concluded: “All concerned (scientists, doctors, the press) need to be thoughtful and responsible when we try to anticipate how basic advances will play out. We have to understand that the nature of science is incremental – and that‘s okay! We shouldn‘t always demand or expect breakthroughs”.
Source: Evans JP, Meslin EM, Marteau TM, Caulfield T: Deflating the genomic bubble. Science 331(6019), 861–862 (2011).
A New Candidate for Clopidogrel Pharmacogenomics
The antiplatelet drug clopidogrel is widely used to prevent atherothrombotic events, but its clinical efficacy demonstrates a high interindividual variability that has been attributed to genetic factors, for which the crucial causal factors remain unknown. A recent study published in Nature Medicine indicates that a main proportion of the variability is explained by a polymorphism in the paraoxonase-1 (PON1) gene. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.
“There is a large dispute about the genetic factors”, remarked Dirk Taubert, who led the German study. “CYP2C19 is currently the favored factor, but in our study we found no involvement of that factor”.
Researchers at the University of Cologne, Germany, found that PON1 was responsible for the metabolic bioactivation of clopidogrel. Homozygous carriers of the PON1 192Q polymorphism had a lower paraoxonase plasma activity, produced lower levels of the active clopidogrel metabolite and had a higher incidence of stent thrombosis compared with homozygous carriers of the 192R polymorphism.
Remarkably, this SNP was found to account for 72.5% of interindividual variance in response. This is in comparison to previous estimates of 12% for CYP2C19. In addition, this study cohort demonstrated no signal for CYP2C19 unlike previous large studies.
Asked how the results of the study should be carried forward, Dr Taubert commented: “Although our results are encouraging, it is not feasible to draw definite clinical conclusions at this stage of investigation. In order to assess the diagnostic relevance of PON1 for clopidogrel therapy we need the results from large prospective randomized controlled trials”.
Source: Bouman HJ, Schömig E, van Werkum JW et al.: Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat. Med. (17) 110–116 (2011).
Spanish Researchers Discover Cancer-Associated Gene Predicts Response to Erlotinib Treatment in EGFR-Mutant Lung Cancer Patients
The European Multidisciplinary Conference in Thoracic Oncology (EMCTO) in February 2011 proved a worthy stage to report new findings identifying astrocye elevated gene 1 (AEG-1) as a strong predictor of treatment outcome in certain lung cancer patients.
The conference, which was held in Lugano, Switzerland, saw the results of a non-small-cell lung cancer study comprising 55 patients presented by researchers from the Spanish Lung Cancer Group (SLCG) by the Founder and Chair of the Group and lead researcher Dr Rafael Rosell.
Remarking on the knowledge gap the study aimed to fill, Dr Rosell stated: “Currently we have no predictors for the duration of response to EGFR drugs in non-small-cell lung cancer patients with EGFR mutation. The median progression-free survival time for these patients ranges from 10 to 14 months, but there is a subgroup of patients with very short response while others have long lasting benefit”.
The SLCG scientists worked in collaboration with Pangaea Biotech (Barcelona, Spain), the first pharmacogenetic laboratory in Spain to receive accreditation, and employed technology from the privately held life sciences company NanoString (WA, USA) to investigate the expression of which genes indicated a lasting response to erlotinib treatment.
NanoString is a multiplex mRNA assay combined with digital technology that can detect the expression of targeted genes with high levels of precision and sensitivity, all in a single reaction. This technology was used to investigate the expression levels of 48 genes in patients with EGFR-mutant non-small-cell lung cancer receiving erlotinib treatment. The expression of AEG-1 was found to be the strongest indicator of progression-free survival. Patients with low AEG-1 expression demonstrated progression-free survival of 27 months whereas those with high expression showed only 12 months.
On the potential of these results and the possibility of enhancing patient information gleaned from AEG-1 expression by combining it with measurements of the expression of BRCA-1, Rosell comments: “Combining these two measurements could have very important clinical implications since defining a low-risk subgroup of patients can accurately predict situations when the simple administration of an oral EGFR drug could have an extremely durable effect, of more than 2 years”.
Going on to consider the impact this could have on patients, the researcher continues: “This could give confidence to the patient, their family and doctors, and eliminate the traditional anxiety of waiting for periodical CT scan reassessments”.
The results of the biomarker tests would also have positive implications for those in the high-risk group, as both patients and oncologists would be prepared for early progression and alternative treatment strategies could be formulated.
This study highlights the growing importance of personalized medicine in cancer, with the results demonstrating that biomarkers have the potential to affect the management of treatment, such as frequency of follow-up, and not just the initial treatment selection.
Source: O‘Byrne K, Rosell R, Baas P et al.: 5IN – ESMO non-small-cell lung cancer (NSCLC) consensus on pathology and molecular testing. Presented at: The European Multidisciplinary Conference in Thoracic Oncology (EMCTO). Lugano, Switzerland, 24–26 February 2011.