Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press What Are the Most Powerful Immunogen Design Vaccine Strategies? Reverse Vaccinology 2.0 Shows Great Promise Dennis R. Burton Department of Immunology and Microbial Science, Center for HIV/AIDS Vaccine Immunology and Immunogen Design, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037; and Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02129 Correspondence: [email protected] Functional antibodies, i.e., those with antipathogen activity in in vitro assays, are generally the best correlate of vaccine protection. Mimics of natural infection, including live attenu- ated and killed pathogens, which induce such antibodies in vivo, have generated highly successful vaccines. However, pathogens that induce functional antibodies at lower levels or more sporadically have been more refractory to vaccine design. Such pathogens are being tackled by more systematic approaches involving identifying functional antibodies, templat- ing immunogens from the antibodies, and then evaluating the immunogens iteratively. I believe this is a powerful new approach to vaccine design as discussed below. 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 # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a030262 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a030262 1 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press D.R. Burton WHAT ARE AND HOW DO VACCINES require an overwhelming rapid antibody re- WORK? sponse and B-cell memory may play a greater role. The notion of “functional antibody” is key description of the most powerful immuno- in thinking about immunogen design strategies. Agen design vaccine strategies would clearly For viruses, functionality is often associated benefit from understanding how vaccines might with an in vitro neutralization assay in which work for each individual pathogen. Google de- antibodies inhibit productive viral entry to fines a vaccine as “a substance used to stimulate target cells. Many pathogens have evolved the production of antibodies and provide im- mechanisms to evade antibody recognition munity against one or several diseases, prepared and immunogen design must seek to deal with from the causative agent of a disease, its prod- these mechanisms and elicit potent functional ucts, or a synthetic substitute, treated to act as antibodies. an antigen without inducing the disease.” The definition is lacking in that it is likely that cel- IMMUNOGEN DESIGN lular immune responses induced by immuniza- tion contribute, at least in some cases, to vaccine Antibodies evolve through mutation and selec- protection. The most successful vaccine strate- tion to recognize molecular shapes. In princi- gies for the future will unravel the relative con- ple, immunogen design problems boil down to tributions of humoral and cellular immunity to creating the appropriate molecular shapes. The protection for each pathogen and incorporate stunning successes achieved with whole organ- this knowledge into vaccine design. Neverthe- ism vaccines such as live attenuated and killed less, a good case can be made that for many pathogens are because of the effective presenta- vaccines the antibody response is crucial, and tion, to the humoral immune system, of the very antibody induction is the focus here. same molecular shapes that are found on the The provision of antibody-based immunity surface of the virulent pathogen. These patho- requires memory, which can be conceived in gens are typically “evasion lite” in that there is two forms, both generated following contact little evidence that molecular features have with antigen: circulating specific high-affinity evolved to evade immune recognition. The life antibody produced by long-lived plasma cells cycle of the pathogen may not require any such in the bone marrow and circulating memory B evasion (e.g., measles or polio viruses). Other cells expressing surface antibody receptors for pathogens such as HIV,influenza virus, and ma- antigen so that such cells can expand and dif- laria have life cycles that require survival at some ferentiate to produce specific high-affinity anti- point in an antibody-rich milieu. These patho- body on new antigen contact. Circulating anti- gens tend to be “evasion strong” in that they body has the great advantage that it can act have evolved a multitude of mechanisms that immediately against an invading pathogen. result in the elicitation of suboptimal antibody B-cell memory will require a longer time to responses with respect to long-term protection become effective, although plasmablasts gener- against circulating forms of the pathogen. Eva- ated by reactivated memory B cells could poten- sion can occur by different mechanisms, many tially provide protective levels of antibody in a of which involve the molecular nature of the matter of a few days after pathogen contact. pathogen surface. Examples include extreme se- Nevertheless, in many scenarios, the most pow- quence variation of the surface proteins (HIV, erful design strategies will seek to induce influenza virus, and malaria) and dense glycan sustained high levels of circulating functional coating (HIV and hepatitis C virus [HCV]). antibody. A clear-cut example here is HIV, in Powerful immunogen design strategies for these which the prevention of the establishment of pathogens require wholly different and much latency likely requires circulating antibody rath- more precise approaches for the elicitation of er than stimulation of B-cell memory. In other antibodies to the pathogen surface than have instances, the prevention of disease may not typically been applied. Classical vaccine ap- 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a030262 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Reverse Vaccinology 2.0 and Immunogen Design proaches have not worked to date and are un- approach described as reverse vaccinology 2.0 likely to do so in the future. (Fig. 1) (Burton 2002; Rappuoli et al. 2016). (Reverse vaccinology 1.0 is an approach based on bioinformatics and animal immunization STRATEGIES FOR IMMUNOGEN DESIGN: and challenge to determine the antigens most GETTING THE RIGHT SHAPES appropriate for inclusion in a vaccine. The The first problem for immunogen design is to approach led directly to the meningitis B vac- generate molecular shapes that will elicit func- cine.) It is no coincidence that the upsurge of tional antibodies. How to do this? Here, natural recent interest in rational vaccine design has infection can provide valuable leads. In virtual- followed the ability to isolate relatively rare ly all infections, a proportion of individuals, but potent functional antibodies from human sometimes quite small, will make highly potent infections (Burton et al. 2012). With the appro- functional antibody responses. Monoclonal an- priate monoclonal antibodies in hand, high- tibodies can be isolated from these individuals resolution structures from crystallography and and used to guide vaccine design in a reversal of cryoelectron microscopy(cryoEM) of antibody- the normal flow of vaccines to antibodies in an pathogen surface molecules can reveal impor- Mice Humanized mice Human mAb Ferrets Monkeys isolation In vitro Cotton Ab functional rats Protective human mAbs assay In vivo Ab protective activity Seropositive individuals Ag through infection or vaccination Protective epitope Structural studies of Abs in complex with target antigen on pathogen Mice Humanized mice Iteration Vaccine Rabbits Monkeys candidates Guinea pigs Structure-based immunogen design Animal evaluation Figure 1. Reverse vaccinology 2.0. Typically memory B cells or plasmablasts from seropositive individuals with high serum functional titers are used as a source of human monoclonal antibodies (mAbs) that are isolated by direct functional screening or antigen selection approaches. The mAbs are investigated for in vivo protective activity in