Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Seeing the Forest Rather than a Few Trees Mark M. Davis 1,2,3 and Cristina M. Tato 2 1 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94304 2 Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California 94304 3 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94304 Correspondence: mmdavis@stanford.edu Preventing morbidity and mortality from infectious disease through the development and use of effective vaccines is one of medicine’s greatest achievements and greatest frustrations. We are struggling with improving vaccine efficacy for some of the most globally widespread diseases, such as malaria and tuberculosis. In an effort to gain an edge, systems biology approaches have begun to be employed to more broadly investigate the pathways leading to protective vaccine responses. As such, we are now at a critical juncture, needing to evaluate how fruitful these approaches have been. Herein we discuss the level of success achieved as compared to the original promise of systems methodologies, and conclude that while we have indeed begun to make clear inroads into understanding the immune response to vaccines, we still have much to learn and gain from the more comprehensive approach of systems-level analysis. GREAT DEBATES What are the most interesting topics likely to come up over dinner or drinks with your colleagues? Or, more importantly, what are the topics that don’t come up because they are a little too controversial? In Immune Memory and Vaccines: Great Debates, Editors Rafi Ahmed and Shane Crotty have put together a collection of articles on such ques- tions, written by thought leaders in these fields, with the freedom to talk about the issues as they see fit. This short, innovative format aims to bring a fresh perspective by encouraging authors to be opinionated, focus on what is most interesting and current, and avoid restating introductory material covered in many other reviews. The Editors posed 13 interesting questions critical for our understanding of vaccines and immune memory to a broad group of experts in the field. In each case, several different perspectives are provided. Note that while each author knew that there were additional scientists addressing the same question, they did not know who these authors were, which ensured the independence of the opinions and perspectives expressed in each article. Our hope is that readers enjoy these articles and that they trigger many more conversations on these important topics. Editors: Shane Crotty and Rafi Ahmed Additional Perspectives on Immune Memory and Vaccines: Great Debates available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028886 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a028886 1