Strategies to guide the antibody affinity maturation process.

Antibodies with protective activity are critical for vaccine efficacy. Affinity maturation increases antibody activity through multiple rounds of somatic hypermutation and selection in the germinal center. Identification of HIV-1 specific and influenza-specific antibody developmental pathways, as well as characterization of B cell and virus co-evolution in patients, has informed our understanding of antibody development. In order to counteract HIV-1 and influenza viral diversity, broadly neutralizing antibodies precisely target specific sites of vulnerability and require high levels of affinity maturation. We present immunization strategies that attempt to recapitulate these natural processes and guide the affinity maturation process.

[1]  J. Whittle,et al.  Structural and genetic basis for development of broadly neutralizing influenza antibodies , 2012, Nature.

[2]  Thomas B Kepler,et al.  B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study , 2012, Nature Biotechnology.

[3]  Chaim A. Schramm,et al.  Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies , 2014, Nature.

[4]  L. Morris,et al.  Viral Escape from HIV-1 Neutralizing Antibodies Drives Increased Plasma Neutralization Breadth through Sequential Recognition of Multiple Epitopes and Immunotypes , 2013, PLoS pathogens.

[5]  John P. Moore,et al.  Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer , 2013, Science.

[6]  Florian Krammer,et al.  Influenza virus hemagglutinin stalk-based antibodies and vaccines. , 2013, Current opinion in virology.

[7]  Michael Meyer-Hermann,et al.  Germinal Center Dynamics Revealed by Multiphoton Microscopy with a Photoactivatable Fluorescent Reporter , 2010, Cell.

[8]  Feng Gao,et al.  Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies , 2014, Cell.

[9]  Mehran Kardar,et al.  Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies , 2015, Cell.

[10]  Peter D. Kwong,et al.  Structure and Mechanistic Analysis of the Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5 in Complex with Its gp41 Epitope , 2004, Journal of Virology.

[11]  John P. Moore,et al.  A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene , 2015, Journal of Virology.

[12]  L. BenMohamed,et al.  Boosting immunity to small tumor-associated carbohydrates with bacteriophage qβ capsids. , 2013, ACS chemical biology.

[13]  Gwo-Yu Chuang,et al.  Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-120 interface , 2014, Nature.

[14]  J. Mascola,et al.  Outer Domain of HIV-1 gp120: Antigenic Optimization, Structural Malleability, and Crystal Structure with Antibody VRC-PG04 , 2012, Journal of Virology.

[15]  J. Binley,et al.  Targeting HIV-1 Envelope Glycoprotein Trimers to B Cells by Using APRIL Improves Antibody Responses , 2011, Journal of Virology.

[16]  Xuesong Yu,et al.  Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection , 2008, Journal of Virology.

[17]  T. Kepler,et al.  Two Distinct Broadly Neutralizing Antibody Specificities of Different Clonal Lineages in a Single HIV-1-Infected Donor: Implications for Vaccine Design , 2012, Journal of Virology.

[18]  J. Mascola,et al.  Structural Basis for HIV-1 Neutralization by 2F5-Like Antibodies m66 and m66.6 , 2013, Journal of Virology.

[19]  R. Zinkernagel,et al.  The influence of antigen organization on B cell responsiveness. , 1993, Science.

[20]  Ron Diskin,et al.  Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding , 2011, Science.

[21]  J. Binley,et al.  A comparative immunogenicity study of HIV-1 virus-like particles bearing various forms of envelope proteins, particles bearing no envelope and soluble monomeric gp120. , 2007, Virology.

[22]  John P. Moore,et al.  A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies , 2013, PLoS pathogens.

[23]  R. Sanders,et al.  Immunosilencing a Highly Immunogenic Protein Trimerization Domain* , 2015, The Journal of Biological Chemistry.

[24]  J. Gern,et al.  Antibody Landscapes After Influenza Virus Infection or Vaccination , 2015, Pediatrics.

[25]  James E. Crowe,et al.  A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin , 2013, Nature Structural &Molecular Biology.

[26]  Baoshan Zhang,et al.  Broad and potent neutralization of HIV-1 by a gp41-specific human antibody , 2012, Nature.

[27]  D. Burton,et al.  Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope , 2014, Journal of Virology.

[28]  Mark Mulligan,et al.  Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells , 2012, Proceedings of the National Academy of Sciences.

[29]  R. Brink,et al.  Affinity‐based selection and the germinal center response , 2012, Immunological reviews.

[30]  N. Haigwood,et al.  Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially. , 2012, Vaccine.

[31]  James C Paulson,et al.  Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. , 2014, Immunity.

[32]  John P. Moore,et al.  Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation , 2013, Proceedings of the National Academy of Sciences.

[33]  David C Montefiori,et al.  The role of antibodies in HIV vaccines. , 2010, Annual review of immunology.

[34]  Renate Kunert,et al.  Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41. , 2005, Immunity.

[35]  J. Sodroski,et al.  Highly Stable Trimers Formed by Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Fused with the Trimeric Motif of T4 Bacteriophage Fibritin , 2002, Journal of Virology.

[36]  J. McKeating,et al.  Truncated gp120 envelope glycoprotein of human immunodeficiency virus 1 elicits a broadly reactive neutralizing immune response. , 2002, The Journal of general virology.

[37]  John Steel,et al.  Cross-neutralization of influenza A viruses mediated by a single antibody loop , 2012, Nature.

[38]  Ron Diskin,et al.  Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120 , 2012, Proceedings of the National Academy of Sciences.

[39]  Tongqing Zhou,et al.  Structure and immune recognition of trimeric prefusion HIV-1 Env , 2014, Nature.

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

[41]  Jerome H. Kim,et al.  Lessons from the RV144 Thai phase III HIV-1 vaccine trial and the search for correlates of protection. , 2015, Annual review of medicine.

[42]  J. Mascola,et al.  Single-Cell and Deep Sequencing of IgG-Switched Macaque B Cells Reveal a Diverse Ig Repertoire following Immunization , 2014, The Journal of Immunology.

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

[44]  Jim Euchner.  Design , 2014, Catalysis from A to Z.

[45]  L. Stamatatos,et al.  Diverse Recombinant HIV-1 Envs Fail To Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D , 2013, Journal of Virology.

[46]  B. Haynes,et al.  HIV‐1 neutralizing antibodies: understanding nature's pathways , 2013, Immunological reviews.

[47]  Patrick C. Wilson,et al.  Rapid cloning of high-affinity human monoclonal antibodies against influenza virus , 2008, Nature.

[48]  J. Yewdell,et al.  The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype) , 1982, Cell.

[49]  Chaim A. Schramm,et al.  Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus , 2013, Nature.

[50]  John P. Moore,et al.  Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer , 2013, Science.

[51]  Mario Roederer,et al.  Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing , 2011, Science.

[52]  Thomas B. Kepler,et al.  Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains , 2014, Proceedings of the National Academy of Sciences.

[53]  Young Do Kwon,et al.  Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies. , 2013, Immunity.

[54]  Anurag Sethi,et al.  Viral Escape from Neutralizing Antibodies in Early Subtype A HIV-1 Infection Drives an Increase in Autologous Neutralization Breadth , 2013, PLoS pathogens.

[55]  Michael S. Seaman,et al.  Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies , 2012, Proceedings of the National Academy of Sciences.

[56]  Qian Wang,et al.  Adaptations of nanoscale viruses and other protein cages for medical applications. , 2006, Nanomedicine : nanotechnology, biology, and medicine.

[57]  D. J. Stevens,et al.  The Structure and Receptor Binding Properties of the 1918 Influenza Hemagglutinin , 2004, Science.

[58]  Richard T. Wyatt,et al.  Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site , 2012, Journal of Virology.

[59]  P. Pitisuttithum.  HIV-1 prophylactic vaccine trials in Thailand. , 2005, Current HIV research.

[60]  Pham Phung,et al.  Broad neutralization coverage of HIV by multiple highly potent antibodies , 2011, Nature.

[61]  A. Takada,et al.  Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity , 2012, Proceedings of the National Academy of Sciences.

[62]  Dennis R. Burton,et al.  Toward a more accurate view of human B-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding , 2014, Scientific Reports.

[63]  Young Do Kwon,et al.  Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 , 2011, Nature.

[64]  John P. Moore,et al.  Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env , 2015, Nature Communications.

[65]  R. Hai,et al.  Chimeric Hemagglutinin Influenza Virus Vaccine Constructs Elicit Broadly Protective Stalk-Specific Antibodies , 2013, Journal of Virology.

[66]  L. Stamatatos,et al.  Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies , 2013, The Journal of experimental medicine.

[67]  D. Calado,et al.  Germinal Centers , 2017, Methods in Molecular Biology.

[68]  M. Mulligan,et al.  Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. , 2011, The Journal of infectious diseases.

[69]  Klaus Rajewsky,et al.  Intraclonal generation of antibody mutants in germinal centres , 1991, Nature.

[70]  Jessica B. Graham.  Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial , 2012 .

[71]  Tongqing Zhou,et al.  Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 , 2010, Science.

[72]  K. Uberla,et al.  Targeting and activation of antigen-specific B-cells by calcium phosphate nanoparticles loaded with protein antigen. , 2014, Biomaterials.

[73]  Gwo-Yu Chuang,et al.  Antibodies VRC01 and 10E8 Neutralize HIV-1 with High Breadth and Potency Even with Ig-Framework Regions Substantially Reverted to Germline , 2014, The Journal of Immunology.

[74]  N. Haigwood,et al.  Sequential Immunization with a Subtype B HIV-1 Envelope Quasispecies Partially Mimics the In Vivo Development of Neutralizing Antibodies , 2011, Journal of Virology.

[75]  L. Stamatatos,et al.  Changes in the Immunogenic Properties of Soluble gp140 Human Immunodeficiency Virus Envelope Constructs upon Partial Deletion of the Second Hypervariable Region , 2003, Journal of Virology.

[76]  Qing Zhu,et al.  Rapid development of broadly influenza neutralizing antibodies through redundant mutations , 2014, Nature.

[77]  D. Burke,et al.  Substitutions Near the Receptor Binding Site Determine Major Antigenic Change During Influenza Virus Evolution , 2013, Science.

[78]  S. Zolla-Pazner,et al.  Brief Definitive Report , 2022 .

[79]  J. Mascola,et al.  HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies , 2015, Journal of Virology.

[80]  S. Reed,et al.  Key roles of adjuvants in modern vaccines , 2013, Nature Medicine.

[81]  J. Baeten,et al.  Breadth of Neutralizing Antibody Response to Human Immunodeficiency Virus Type 1 Is Affected by Factors Early in Infection but Does Not Influence Disease Progression , 2009, Journal of Virology.

[82]  Rolf Kaiser,et al.  HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice , 2013, Proceedings of the National Academy of Sciences.

[83]  B. Moss,et al.  CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge , 2014, Journal of Virology.

[84]  J. Binley,et al.  HIV-1 Virus-Like Particles Bearing Pure Env Trimers Expose Neutralizing Epitopes but Occlude Nonneutralizing Epitopes , 2012, Journal of Virology.

[85]  L. Stamatatos,et al.  Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies , 2014, Science.

[86]  L. Morris,et al.  Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection , 2014, Current opinion in HIV and AIDS.

[87]  N. Haigwood,et al.  Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits , 2014, Journal of Virology.

[88]  Jerome H. Kim,et al.  Infant HIV type 1 gp120 vaccination elicits robust and durable anti-V1V2 immunoglobulin G responses and only rare envelope-specific immunoglobulin A responses. , 2014, The Journal of infectious diseases.

[89]  Surender Khurana,et al.  Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin , 2011, Proceedings of the National Academy of Sciences.

[90]  W. Cao,et al.  Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity , 2014, Journal of Virology.

[91]  A S Perelson,et al.  Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts. , 1997, Journal of immunology.

[92]  C. Berek,et al.  Somatic mutations in antibodies expressed by germinal centre B cells early after primary immunization. , 1990, International immunology.

[93]  Lynn Morris,et al.  Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape , 2012, Nature Medicine.

[94]  Richard T. Wyatt,et al.  Breadth of Human Immunodeficiency Virus-Specific Neutralizing Activity in Sera: Clustering Analysis and Association with Clinical Variables , 2009, Journal of Virology.

[95]  K. Subbarao,et al.  Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. , 2010, The Journal of clinical investigation.

[96]  Yan Liu,et al.  A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield , 2011, Science.

[97]  Richard T. Wyatt,et al.  Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals , 2009, Nature.

[98]  T. Kepler,et al.  Analysis of a Clonal Lineage of HIV-1 Envelope V2/V3 Conformational Epitope-Specific Broadly Neutralizing Antibodies and Their Inferred Unmutated Common Ancestors , 2011, Journal of Virology.

[99]  Gary J. Nabel,et al.  Vaccine-Induced IgG Antibodies to V1V2 Regions of Multiple HIV-1 Subtypes Correlate with Decreased Risk of HIV-1 Infection , 2014, PloS one.

[100]  J. Ravetch,et al.  Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant , 2011, The Journal of Immunology.

[101]  Pham Phung,et al.  Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target , 2009, Science.

[102]  Gregory M. Frank,et al.  Flow Cytometry Reveals that H5N1 Vaccination Elicits Cross-Reactive Stem-Directed Antibodies from Multiple Ig Heavy-Chain Lineages , 2014, Journal of Virology.

[103]  L. Pena,et al.  Deceptive imprinting and immune refocusing in vaccine design. , 2008, Vaccine.

[104]  A. Holmberg,et al.  A Unique Role of the Cholera Toxin A1-DD Adjuvant for Long-Term Plasma and Memory B Cell Development , 2011, The Journal of Immunology.

[105]  H. Hammad,et al.  Mechanism of action of clinically approved adjuvants. , 2009, Current opinion in immunology.

[106]  Michel C. Nussenzweig,et al.  Clonal selection in the germinal centre by regulated proliferation and hypermutation , 2014, Nature.

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

[108]  R. Varadarajan,et al.  Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection , 2014, Proceedings of the National Academy of Sciences.

[109]  John P. Moore,et al.  Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex , 2014, Proceedings of the National Academy of Sciences.

[110]  P. Palese,et al.  Toward a universal influenza virus vaccine: prospects and challenges. , 2013, Annual Review of Medicine.

[111]  Vasso Apostolopoulos,et al.  Pathogen recognition and development of particulate vaccines: does size matter? , 2006, Methods.

[112]  I. Wilson,et al.  Structural basis of immune recognition of influenza virus hemagglutinin. , 1990, Annual review of immunology.

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

[114]  J. Whittle,et al.  Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies , 2013, Nature.

[115]  T. Kepler,et al.  Isolation of a Human Anti-HIV gp41 Membrane Proximal Region Neutralizing Antibody by Antigen-Specific Single B Cell Sorting , 2011, PloS one.