![]() ![]() Taken advantage of the modern – omics technologies a consortium among excellent academic and industrial partners was created in order to identify biomarkers that could be indicative of vaccine efficacy and, more important, safety. Still the eternal question regarding the vaccines induced immunity against pathogens remains to be answered. In fact, if the natural disease induces protection against re-infection by causing an inflammatory reaction that brings rubor, tumor, calor, dolor et functio laesa, what is the level of mild inflammation that a vaccine should induce to obtain protection without causing excessive side effects? The project Biomarkers For Enhanced Vaccine Safety ( BioVacSafe) was designed for addressing this key issue. Aldo Tagliabue EFPIA Coordinator ![]() ![]() Surrey’s Clinical Research Centre (CRC) Team The three clinical studies, employing five different vaccines plus placebo groups, will generate datasets on clinical, metabolic, immunological and gene expression responses as well as a biobank of samples. Apart from using different vaccines, each study follows the same protocol that will allow data to be combined into one dataset and biobank. Integrated systems biology analysis of the data and iterative access to the biobank will identify ‘putative biomarkers’ of inflammation, which will be confirmed or refuted in later, larger clinical trials in Gent. The different licensed vaccines are prototypical representatives of a class of vaccine used in a particular target population, and include: Varilrix, Stamaril, Engerix B, Fluad, and Agrippal. Stamaril, for example, represents a live vaccine given to a population of healthy adults that have no immunity to that disease (Yellow Fever), in the context of a live vaccine. Varilrix represents a live vaccine given to a population of healthy adults that are already immune to that disease (Chicken pox), in the context of a live booster vaccine. In each study, regular assessments are performed before and after vaccination, to record clinical events (recorded adverse events), physiological responses (heart rate, blood pressure), metabolic responses (metabolic gene expression), innate immune responses (e.g. cytokine levels), and adaptive immune responses (serum antibody and antigen-specific cellular responses). Surrey CRC’s extensive experience in running chronobiology studies, with intensive sampling across the 24 hour day under highly controlled conditions, affords a unique opportunity to study inflammatory responses to vaccines by collecting frequent blood samples for multiple analyses. Whereas previous studies of physiological responses to vaccines have generally obtained single blood samples on Days 0/1/3/7, our studies incorporate a much greater sampling frequency. During a 7-day residential in-patient stay, incorporating immunisation on the second day, there is extensive sampling both pre- and post-immunisation at 4-12 hour intervals, depending on the study day. In addition, single blood samples are obtained on days 7, 14, 21 and 28 during outpatient visits. The selection of the time and frequency of the different sample types, including serum, whole blood, plasma, RNA, PBMCs, CyTOF, etc, has required careful planning to ensure the optimal capture of the timecourse of the response being measured. In addition, to minimise events caused by factors other than the vaccine, procedures have been developed relating to catheter insertion, removal and monitoring. The CRC305C study utilises the flu vaccines Fluad and Agrippal. To eliminate flu infection as a possible confounding variable, Surrey CRC waited until the flu season finished in March/April 2013 before starting the study. With an expiry date of June 2013 for the Fluad vaccine, this meant there was just 2 months to enrol 48 subjects into the study. Because of the frequent blood sampling and the labour-intensive sample processing procedures involved, each group had a maximum of 8 subjects. Six groups were scheduled, plus one ‘straggler’ group in case it was not possible fill all 8 spaces in each group. An equal number of male and female subjects had to be enrolled. After the study started, with the clinical, medical, and recruitment teams working virtually non-stop, it was a nail-biting two months before we would find out if we could enrol all 48 subjects before the vaccine expired. On Friday 31st May, the last three subjects were dosed in the straggler group, just one day before the Fluad expiry date. With ‘last subject last visit’ for the Fluad and Agrippal study due at the end of June, the medical, clinical and recruitment teams have started to focus on recruitment for the Varilrix and Stamaril study (CRC305A), and to complete the Engerix B study (CRC305B), which started in February 2012. Sample shipment to the different laboratories has begun. The BioVacSafe partner ‘Max Planck Institute for Infection Biology’ will start to analyse the CRC305C whole blood samples for transcriptomics after the end of June, starting initially with 11 of the 30 sample timepoints per subject. It will take some time before the results of the sample analyses become available and we are able to finalise the protocols for the larger trials in Gent later in the BioVacSafe project. ![]() ![]() Foto | Wiebke Peitz | CharitéThe Charité Paediatric Infectious Diseases & Vaccines Team The Charité Paediatric Infectious Diseases & Vaccines Team (PI: Barbara Rath, MD PhD, contact: kinderinfekte@charite.de) was initiated in 2009. The multidisciplinary team aims to develop an innovative, comprehensive and personalized approach to the prevention and management of acute infectious diseases in infants and children. The communication with concerned parents and families plays a major role in the daily work of the Paediatric Infectious Diseases & Vaccines Team. Commonly, parents taking their children to an academic medical centre, seek not only medical care, but also evidence-based and detailed information about the safety of anti-infective medications and vaccines. ![]() Foto | Wiebke Peitz | CharitéIn the context of the BioVacSafe Work Package 5, co-lead by Charité as the academic partner, the level of data processing and standardisation is taken to the next level. The common goal of BioVacSafe Work Packages 5 and 6 is to achieve full compliance with data standards developed by BioVacSafe partner CDISC (www.cdisc.org), to achieve a maximum level of data interoperability and meta-analysability across different clinical sites in the Consortium. To this end, disease area standards and clinical scores will be developed to define the clinical background information required for the selection and classification of specific and unusual disease presentations for the targeted analysis of biomarkers following “natural” infectious disease. In BioVacSafe Work Packages 1, 3, and 4, the Charité cohorts serve as an unbiased, representative tertiary care system to determine the full spectrum of acute infectious disease presentations. This includes influenza and meningitis patients with severe underlying conditions as well as previously healthy subjects, ranging from 0-18 years of age and from outpatients in the ER to inpatients to those requiring intensive care. The Paediatric and Neonatal Units at Charité are situated in three different Charité campuses in Berlin: an upper-middle class suburb in the south, in the city center, as well as in an ethnically diverse working class neighbourhood in the north. The high level of data standardisation and consistency in the conduct of the Charité cohorts allow for the identification of extreme disease presentations on the background of a perennial hospital surveillance system as well as national sentinel surveillance at the Robert Koch Institute.Targeted biomarker assessments in carefully selected cases will help to set the “upper limits” of biomarker responses in the context of maximal immune system activation during natural infection. This will enable us to distinguish “show-stoppers” from trivial reactions, and contextualise profiles observed in BioVacSafe clinical vaccine trials in the context of natural disease. Foto | Wiebke Peitz | Charité ![]() ![]() ![]() click here to find the program 15th International Congress of Immunology, Milano, Italy 22- 27 August 2013. More information can be found here click here to find the program 7th Vaccine & ISV Congress, Sitges, Barcelona, Spain 27-29 October 2013. More information can be found here click here to find the program click here for registration Advancing Vaccines in the Genomics Era, Rio de Janeiro, Brazil, October 31-Nov 4, 2013. More information can be found here click here to find the program ![]() ![]() ![]() ![]() ![]() ![]() |