Structure-based immunogen design — leading the way to the new age of precision vaccines

Vaccines have been one of the most successful interventions in global health. However, traditional vaccine development has proven insufficient to deal with pathogens that elude the immune system through highly variable and non-functional epitopes. Emerging B cell technologies have yielded potent monoclonal antibodies targeting conserved epitopes, and their structural characterization has provided templates for rational immunogen design. Here, we review immunogen design strategies that leverage structural information to steer bulk immune responses towards the induction of precise antibody specificities targeting key antigenic sites. Immunogens designed to elicit well-defined antibody responses will become the basis of what we dubbed precision vaccines. Such immunogens have been used to tackle long-standing vaccine problems and have demonstrated their potential to seed the next-generation of vaccines.

[1]  Daniel W. Kulp,et al.  Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice , 2016, Science.

[2]  Dong Soo Yun,et al.  HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies , 2016, Immunity.

[3]  John P. Moore,et al.  Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers , 2017, Journal of Virology.

[4]  L. Stamatatos,et al.  Computational design of epitope-scaffolds allows induction of antibodies specific for a poorly immunogenic HIV vaccine epitope. , 2010, Structure.

[5]  J. McLellan,et al.  Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein , 2017, Nature Communications.

[6]  S. Harrison.  Viral membrane fusion , 2008, Nature Structural &Molecular Biology.

[7]  Joseph G. Jardine,et al.  HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen , 2016, Science.

[8]  B. Greenwood.  The contribution of vaccination to global health: past, present and future , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[9]  Cinque S. Soto,et al.  Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus , 2013, Science.

[10]  John P. Moore,et al.  Influences on Trimerization and Aggregation of Soluble, Cleaved HIV-1 SOSIP Envelope Glycoprotein , 2013, Journal of Virology.

[11]  David Nemazee,et al.  Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies , 2016, Cell.

[12]  Cinque S. Soto,et al.  Iterative structure-based improvement of a respiratory syncytial virus fusion glycoprotein vaccine , 2016, Nature Structural &Molecular Biology.

[13]  Matthew Angel,et al.  Defining B Cell Immunodominance to Viruses , 2017, Nature Immunology.

[14]  Mario Roederer,et al.  Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 , 2010, Science.

[15]  David Nemazee,et al.  Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen , 2015, Science.

[16]  F. Alt,et al.  Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires , 2016, Cell.

[17]  Gira Bhabha,et al.  Antibody Recognition of a Highly Conserved Influenza Virus Epitope , 2009, Science.

[18]  D. Baker,et al.  Elicitation of structure-specific antibodies by epitope scaffolds , 2010, Proceedings of the National Academy of Sciences.

[19]  Y. Kawaoka,et al.  Antibody‐dependent enhancement of viral infection: molecular mechanisms and in vivo implications , 2003, Reviews in medical virology.

[20]  David Baker,et al.  Proof of principle for epitope-focused vaccine design , 2014, Nature.

[21]  J. Mascola,et al.  Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection , 2015, Nature Medicine.

[22]  U. Baxa,et al.  Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env , 2015, Journal of Virology.

[23]  Prida Malasit,et al.  Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans , 2010, Science.

[24]  John P. Moore,et al.  Native‐like Env trimers as a platform for HIV‐1 vaccine design , 2017, Immunological reviews.

[25]  U. Baxa,et al.  Protection of calves by a prefusion-stabilized bovine RSV F vaccine , 2017, npj Vaccines.

[26]  Daniel W. Kulp,et al.  Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding , 2017, Nature Communications.

[27]  Y. Hamuro,et al.  Characterization of Pre-F-GCN4t, a Modified Human Respiratory Syncytial Virus Fusion Protein Stabilized in a Noncleaved Prefusion Conformation , 2017, Journal of Virology.

[28]  H. Schuitemaker,et al.  A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism , 2015, Nature Communications.

[29]  Barney S. Graham,et al.  Pre-fusion structure of a human coronavirus spike protein , 2016, Nature.

[30]  C. Palomo,et al.  Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention , 2012, Proceedings of the National Academy of Sciences.

[31]  B. Finlay,et al.  Anti-Immunology: Evasion of the Host Immune System by Bacterial and Viral Pathogens , 2006, Cell.

[32]  Ian A Wilson,et al.  The HIV‐1 envelope glycoprotein structure: nailing down a moving target , 2017, Immunological reviews.

[33]  Q. Sattentau,et al.  Stabilized HIV-1 envelope glycoprotein trimers for vaccine use , 2017, Current opinion in HIV and AIDS.

[34]  Tongqing Zhou,et al.  Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization , 2013, Cell.

[35]  P. Palese,et al.  Guiding the Immune Response against Influenza Virus Hemagglutinin toward the Conserved Stalk Domain by Hyperglycosylation of the Globular Head Domain , 2013, Journal of Virology.

[36]  R. Rappuoli,et al.  Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design , 2016, The Journal of experimental medicine.

[37]  L. Stamatatos,et al.  Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo , 2017, The Journal of experimental medicine.

[38]  G. Chuang,et al.  Prefusion F–specific antibodies determine the magnitude of RSV neutralizing activity in human sera , 2015, Science Translational Medicine.

[39]  Boguslaw Stec,et al.  Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses , 2009, Nature Structural &Molecular Biology.

[40]  P. Kwong,et al.  Structure of Respiratory Syncytial Virus Fusion Glycoprotein in the Postfusion Conformation Reveals Preservation of Neutralizing Epitopes , 2011, Journal of Virology.

[41]  J. Mascola,et al.  Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus , 2016, PloS one.

[42]  John P. Moore,et al.  Stabilization of the Soluble, Cleaved, Trimeric Form of the Envelope Glycoprotein Complex of Human Immunodeficiency Virus Type 1 , 2002, Journal of Virology.

[43]  Adrian Apetri,et al.  A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen , 2015, Science.

[44]  David Nemazee,et al.  Rational immunogen design to target specific germline B cell receptors , 2012, Retrovirology.

[45]  John P. Moore,et al.  Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes , 2015, Cell.

[46]  John P. Moore,et al.  Stabilization of the gp120 V3 loop through hydrophobic interactions reduces the immunodominant V3-directed non-neutralizing response to HIV-1 envelope trimers , 2017, The Journal of Biological Chemistry.

[47]  D. Baker,et al.  Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold , 2011, Science.

[48]  W. Schief,et al.  Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus. , 2011, Journal of molecular biology.

[49]  G. Nabel.  Designing tomorrow's vaccines. , 2013, The New England journal of medicine.

[50]  Young Do Kwon,et al.  Crystal structure , conformational fixation , and entry-related interactions of mature ligand-free HIV-1 Env , 2016 .

[51]  D. Baker,et al.  Heterologous Epitope-Scaffold Prime∶Boosting Immuno-Focuses B Cell Responses to the HIV-1 gp41 2F5 Neutralization Determinant , 2011, PloS one.

[52]  Barney S. Graham,et al.  Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen , 2017, Proceedings of the National Academy of Sciences.

[53]  D. Dimitrov,et al.  Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens , 2009, Biochemical and Biophysical Research Communications.