BioVacSafe – Newsletter January  2015 Issue number 5  Subscribe to this newsletterBioVacSafe Partners ProfileIn every biannual newsletter the profile of some  of BioVacSafe’s research partners is highlighted. In this edition you will meet the Utrecht University in Utrecht, The Netherlands and NOVARTIS VACCINES in Siena, Italy.    Utrecht UniversityThe Biovacsafe immunology group of Utrecht University, led by Willem van Eden, is part of the graduate school Infectious Diseases and Immunology and located in the Utrecht Science Park ‘de Uithof’. Utrecht University has the largest conglomerate of Life Sciences institutions in the Netherlands. In addition Utrecht is the only Dutch University having a faculty of Veterinary Medicine, which is located next to the academic medical center (UMCU). This situation is ideal for interactions between the human and veterinary biomedical groups. For vaccine research the activities are combine in the One Health program. This means that the existing emphasis on vaccine technologies as needed for veterinary vaccines helps to introduce innovative technologies in human vaccines. An example of the advantage of research and development in veterinary vaccines is the possibility of performing challenge experiments. The research in the group of Broere, van der Zee and van Eden has a focus on the immunomodulation of autoimmune inflammatory diseases. For this reason the safety issues around vaccines and autoimmunity is the area of their specific expertise. An example of their activities is the development of an immunotherapeutic vaccine against rheumatic inflammatory diseases. Chronic non-communicable diseases are a major cause of death and disability and have replaced infectious diseases as the major medical burden of society in large parts of the world. Given the physiological complexity of most chronic inflammatory conditions risk factor based solutions are scarce and therefore prevention or treatment through vaccination can be a daring and attractive alternative.Prof. Willem van Eden and the BIOVACSAFE Immunology groupThe problem of chronic inflammatory diseases and  of the low grade inflammation of metabolic syndromes is faulty regulation of the inflammatory process. Thus, the rational goal of intervention in diseases of unregulated inflammatory activation is to reinstate physiological regulation. Heat shock proteins offer chances for an antigen specific vaccination approach targeted towards a specialized subpopulation of regulatory T cells in the adaptive immune response.Immunization with heat shock proteins (HSP) has led to disease suppression in inflammatory diseases such as arthritis, inflammatory bowel diseases and diabetes type I. This has been observed in experimental models and in clinical trials in humans (van Eden et al. 2005; 2013). The mechanistic pathways through which HSP immunizations control inflammation stem from the enhanced cellular expression of these stress proteins in the inflammatory sites evoked by inflammatory mediators such as cytokines. Recently autophagy was uncovered as a mechanism of cells to cope with stress. Given its central role in so-called chaperone mediated autophagy (CMA), HSP70 was shown to be a major source of endogenous peptides for MHC class II presentation by cells under stress (Dengjel et al. 2005). As a result, HSP70 peptides are abundant in the MHC II binding pockets and are part of a default peptide repertoire that is available for cognate interactions with CD4+ Tregs, especially in inflamed tissues (van Eden et al. 2013; Herwijnen et al. 2012).  As a consequence of these findings HSP70 has become a major target in the development of an immunomodulatory vaccine against chronic inflammation. Utrecht Science Park  NOVARTIS VACCINESNovartis Vaccines (NV) has the mission to develop vaccines against infectious diseases that affect people at various ages, from childhood till old age. This is achieved through a strong commitment in research and development that operates via both internal discovery and applied research and through collaborative work with academic groups internationally recognized in the field of vaccines. For these reasons, NV has constantly played an active role in the EU-sponsored consortia and more recently in the private-public partnerships established by IMI JU. BIOVACSAFE is a key example of this collaborative work with the academic world. Safety is of paramount importance for vaccines. The development of novel vaccines, of novel vaccine adjuvants, of novel delivery systems, etc needs a drastic shift from the traditional empirical, observational approach, to a more mechanistic approach aimed at defining biomarkers that would enable the prediction of potential safety issues and of potential benefits at early stages of vaccine development. The tremendous progress experienced in the past few years in the fields of immunology, molecular biology, systems biology etc can now allow this approach.  Giuseppe Del Giudice and the BIOVACSAFE immunology groupWithin the frame of BIOVACSAFE NV is involved in the activities aimed at defining potential biomarkers of vaccine safety and, possibly, of efficacy. The major (although not exclusive) focus is on biomarkers of safety of influenza vaccines, both conventional non-adjuvanted vaccines and those adjuvanted with MF59, a vaccine adjuvant developed at NV and licensed for use in humans with seasonal influenza vaccine in the elderly since 1997, and more recently with avian and with pandemic vaccines at all ages (1). The very large database existing for MF59-adjuvanted influenza vaccine witnesses the excellent safety profile of this vaccine. Work carried out at NV had already deciphered some of the early events triggered by MF59 in the muscle and in the draining lymph nodes in mice (2), and of various cellular parameters in humans predicting effective antibody responses at later time points (3). However, little is still known on the existence of potential early biomarkers detectable in the peripheral blood of vaccinees receiving the vaccine with or without the adjuvant.The acquisition of this information in humans has been made possible thanks to the clinical trial CRC305_C carried out within BIOVACSAFE at the University of Surrey in which healthy adults received the non-adjuvanted influenza vaccine, the MF59-adjuvanted vaccine, or placebo. Many blood samples were taken periodically during the first week following the vaccination. Innate immunity was analysed by standard immunological methods and by gene microarray.The investigation of the parameters of innate immunity at early time points induced by non-adjuvanted and MF59-adjuvanted influenza vaccine as compared to placebo on whole blood and PBMC samples was carried out at NV using CyTOF and FACS, respectively. These methodologies allow the identification of cellular populations and subpopulations thanks to specific surface markers, and in many instances also of their functional activity via the intracellular staining for various soluble factors secreted by these cell populations. If by flow cytometry one can evaluate up to about 15 parameters on the same cell, CyTOF (which combines cytometry with mass spectrometry) allows a multiparametric approach being able to determine more than 50-60 parameters concomitantly on each cell.Using these methodologies, work carried out at NV evidenced a rapid increase (day 1) in the frequency of classical monocytes in response to vaccination with the MF59-adjuvanted vaccine, but not in response to the non-adjuvanted vaccine nor after placebo. These monocytes exhibited an up-regulation of CD64 (FcRI) and CD40 activation markers on their surface. Neutrophils also expanded on day 1, but no evidence of activation was observed.An integrated analysis of these data together with those obtained by gene profiling, with the clinical data and with the biochemical data is now in progress involving scientist from NV, from the Max Planck Institute in Berlin and from the University of Surrey.Early biomarkers predicting efficacy of vaccines are also highly desirable along the path of vaccine development. In the same BIOVACSAFE clinical study NV is currently investigating antigen-specific antibody, plasmablast, and CD4+ T-cell responses induced by non-adjuvanted and MF59-adjuvanted influenza vaccine as compared to placebo. In particular, the interest is to see how early induction of antigen-specific CD4+ T follicular helper cells (Tfh) may predict the production at later time points of protective levels of antibodies inhibiting the virus strain-specific hemagglutination, which are known to correlate with protection against influenza.  Upcoming events:Upcoming interesting conferences are:  World Vaccine Congress 7-9 April 2015, Walter E. Washington Convention Center, Washington D.C., USA. More information can be found here 2015 Annual Conference on Vaccine Research April 13-15, 2015, Bethesda, MD, USA. More information can be found hereModern Vaccines Adjuvants & Delivery Systems MVADS 2015  18 – 20 May 2015, Leiden University, The Netherlands.  More information can be found hereESF-EMBO Symposium. Symbiomes: systems biology of host-microbiome interactions 5-10 June 2015. Pultusk, Poland.  More information can be found here9th European Congress on Tropical Medicine and International Health 6 – 10 September 2015, Basel, Switzerland. More information can be found hereInfluenza Vaccines for the World 6 – 9 October 2015, Albufeira, Portugal. More information can be found here Recent Pubblications:A list of recent publications related to BioVacSafe project:  Rappuoli R, Pizza M, Del Giudice G, De Gregorio E: Vaccines, new opportunities for a new society. Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12288-93. doi: 10.1073/pnas.140298111. http://www.ncbi.nlm.nih.gov/pubmed/25136130Maertzdorf J, Kaufmann SH, Weiner J 3rd. Toward a unified biosignature for tuberculosis.Cold Spring Harb Perspect Med. 2014 Oct 23. pii: a018531. doi: 10.1101/cshperspect.a018531. http://www.ncbi.nlm.nih.gov/pubmed/25342061Andersen P and Kaufmann S.H.E. Novel vaccination strategies against tuberculosis.. doi:10.1101/cshperspect.a018523.4(6): a018523 http://perspectivesinmedicine.cshlp.org/conten/4/6/a018523.full#content-blockKaufmann S.H.E , Mc Elrath MJ, Lewis DJM, Del Giudice G: Challenges and responses in human vaccine development. Curr. Opin. Immunol 2014; 28:18-26. http://www.sciencedirect.com/science/article/pii/S0952791514000107Dorhoi A., Iannaccone M., Maertzdorf J., Nouailles G., Weiner J. 3rd, Kaufmann S.H.E.: Reverse translation in tuberculosis: neutrophils provide clues for understanding development of active disease. Frontiers in Immunol 2014; 5(36): 1-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913996/Kaufmann, S.H.E : Tuberculosis vaccine development at a divide. Curr Opin Pulm Med 2014, 20:294–300. http://www.ncbi.nlm.nih.gov/pubmed/24626237Kaufmann, S.H.E.,Lange C., Rao M., Balaji K.N., Lotze M., Schito M., Zumla A.I., Maeurer M.: Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir Med 2014; 2: 301–20. http://www.sciencedirect.com/science/article/pii/S2213260014700335Weiner J. 3rd & Kaufmann S.H.E: Recent advances towards tuberculosis control: vaccines and Biomarkers. J Intern Med, 2014, 275; 467–480. http://www.ncbi.nlm.nih.gov/pubmed/24635488Dutruel C, Thole J, Geels M, Mollenkopf HJ, Ottenhoff T, Guzman CA, Fletcher HA, Leroy O, Kaufmann SH:TRANSVAC workshop on standardisation and harmonisation of analytical platforms for HIV, TB and malaria vaccines: ‘How can big data help?’. Vaccine. 2014 Jun 17. pii: S0264-410X(14)00803-2 http://www.ncbi.nlm.nih.gov/pubmed/24950356Maurer W, Seeber L, Rundblad G, Kochhar S, Trusko B, Kisler B, Kush R, Rath B; Vienna Vaccine Safety Initiative: Standardization and Simplification of Vaccination Records. Expert Review of Vaccines 2014, Apr;13(4):545-59. http://www.ncbi.nlm.nih.gov/pubmed/24597495Weiner J 3rd, Maertzdorf J, Kaufmann SH: The dual role of biomarkers for understanding basic principles and devising novel intervention strategies in tuberculosis. Ann N Y Acad Sci. 2013; 1283: 22-29. http://www.ncbi.nlm.nih.gov/pubmed/23181737Guenounou S, Bosquet N, Dembek CJ, Le Grand R, Cosma A: OMIP-016: Characterization of Antigen-Responsive Macaque and Human T –cells. Cytometry PART A 2013; 83A: 182-184. http://onlinelibrary.wiley.com/doi/10.1002/cyto.a.22233/abstractKaufmann, S: Tuberculosis vaccines: Time to think about the next generation. Seminars in Immunology, 2013; 25: 172-181. http://www.sciencedirect.com/science/article/pii/S1044532313000225A. R. Everitt, S. Clare, J. U. McDonald,, L.Kane, K.Harcourt, M. Ahras, A. Lall, C.Hale, A. Rodgers, D. B. Young, A. Haque, O. Billker, J. S. Tregoning, G. Dougan, P. Kellam:Defining the range of pathogens susceptible to ifitm3 restriction using a knockout mouse mode. Plos one 2013; 8: 1- 12. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0080723Kaufmann, S.H.E., A. Dorhoi: Inflammation in tuberculosis: interactions, imbalances and interventions. (Special issue: Host pathogens). Curr. Opin. Immunol. 2013; 25: 441–449. http://www.sciencedirect.com/science/article/pii/S0952791513000757Maertzdorf J, Weiner J 3rd, Kaufmann SH: Enabling biomarkers for tuberculosis control. Int J Tuberc Lung Dis. 2012;16(9):1140-8. http://www.ncbi.nlm.nih.gov/pubmed/22871324Kaufmann, S: Tuberculosis vaccine development: strength lies in tenacity. Trends in Immunol. 2012; 33 (7):373-379. http://www.ncbi.nlm.nih.gov/pubmed/22560865BioVacSafe contacts:info@biovacsafe.eu – http://www.biovacsafe.eu – Facebook – Twitter – Linkedin This project is supported by the grant n° 115308 from the Innovative Medicines Initiative JU, a joint undertaking between the European Union and the EFPIA companies’ in kind contribution.