Yellow Fever Vaccine (YFV) is one of the most successful vaccines ever made, with a protective efficacy of over 90% and an excellent safety record. Like most licensed vaccines, however, surprisingly little is known about the biological mechanisms that underpin its success. Several groups of scientists are now attempting to address this knowledge gap using a relatively new approach called systems biology; rather than distilling down to single factors in the traditional reductionist mold, systems biology involves trying to make sense of large suites of complex data by identifying patterns and using mathematical techniques to sort out true effects from irrelevant variation (or “noise”). Databases are also consulted in order to help explain results; in the case of gene expression changes, for example, databases can shed light on connections between genes based on previously documented signaling pathways.
Two recently published papers describe the first results obtained with this strategy, using data derived from several small human trials in which YFV was administered to healthy volunteers. While the data are extremely complex, the researchers identify specific, reproducible changes in gene expression that occur after immunization and associate with the development of robust immune responses to YFV. In the paper from the laboratory of Bali Pulendran at Emory University, it is shown that certain changes can predict the CD8 T cell and antibody response to vaccination with a high degree of accuracy. These studies represent the first attempts to marry systems biology to vaccinology, and hopefully augur the beginning of a long and productive relationship between the two disciplines.
The Journal of Experimental Medicine
Published online December 1, 2008
Denis Gaucher1,2,3, René Therrien1,2,3, Nadia Kettaf1,2,3, Bastian R. Angermann1,2, Geneviève Boucher1, Abdelali Filali-Mouhim1, Janice M. Moser4, Riyaz S. Mehta4, Donald R. Drake, III4, Erika Castro5,6, Rama Akondy7, Aline Rinfret8,9, Bader Yassine-Diab1,2,3, Elias A. Said1,2,3, Younes Chouikh1,2,3, Mark J. Cameron10, Robert Clum10, David Kelvin10, Roland Somogyi11, Larry D. Greller11, Robert S. Balderas12, Peter Wilkinson1, Giuseppe Pantaleo5, Jim Tartaglia13, Elias K. Haddad1,2,3,14, and Rafick-Pierre Sékaly1,2,3,14
1 Laboratoire d'immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM) Saint-Luc, Montréal, Québec, H2X 1P1, Canada
2 Laboratoire d'immunologie, Département de microbiologie et d'immunologie, 3 INSERM U743, CR-CHUM, Université de Montréal, Québec H2X 1P1, Canada
4 VaxDesign Corporation, Orlando, FL 32826
5 Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland
6 Travel Medicine and Vaccination Unit, Policlinique Médicale Universitaire, 1011 Lausanne, Switzerland
7 Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322
8 Canadian Network for Vaccines and Immunotherapeutics, Montréal, Québec, H3X 2H9, Canada
9 Biologics and Genetic Therapies Directorate, Health Canada, Tunney's Pasture, Ottawa, Ontario, K1A 0K9, Canada
10 Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
11 Biosystemix, Ltd., Sydenham, Ontario K0H 2T0, Canada
12 BD Biosciences, San Diego, CA 92121
13 Aventis Pasteur, Ltd., Toronto, Ontario, M2R 3T4, Canada
14 Department of Microbiology and Immunology, McGill University, Montréal, Québec, H3A 2B4, Canada
Correlates of immune-mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of 40 volunteers followed for up to 1 yr after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity, including complement, the inflammasome, and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (modular immune in vitro construct [MIMIC] system), by the coordinated up-regulation of transcripts for specific transcription factors, including STAT1, IRF7, and ETS2, which are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional, and persistent immune response that integrates all effector cells of the immune system.
Published online: 23 November 2008 | doi:10.1038/ni.1688
Troy D Querec1,8, Rama S Akondy1,8, Eva K Lee2, Weiping Cao1, Helder I Nakaya1, Dirk Teuwen3, Ali Pirani4, Kim Gernert4, Jiusheng Deng1, Bruz Marzolf5, Kathleen Kennedy5, Haiyan Wu5, Soumaya Bennouna1, Herold Oluoch1, Joseph Miller1, Ricardo Z Vencio5, Mark Mulligan1,6, Alan Aderem5, Rafi Ahmed1 & Bali Pulendran1,7
1. Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
2. Center for Operations Research in Medicine & Healthcare, School of Industrial & Systems Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
3. Sanofi Pasteur, 2 avenue Pont Pasteur, Lyon Cedex 07, France.
4. BimCore, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
5. Institute for Systems Biology, 1441 North 34th Street, Seattle, Washington 98103-8904, USA.
6. The Hope Clinic, 603 Church Street, Decatur, Georgia 30030, USA.
7. Department of Pathology & Laboratory Medicine, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, USA.
8. These authors contributed equally to this work.
A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4—an orchestrator of the integrated stress response—that correlated with and predicted YF-17D CD8+ T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
Nature Immunology 10, 14 - 16 (2009)
News and Views
Paul G Thomas1 & Peter C Doherty2
1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
2. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA, and the Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
A systems biology approach provides correlates of successful vaccination, which allows a new method for measuring early vaccine efficiency and suggests hypotheses for the mechanisms that underlie immunogenicity.