1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Medicine
  4. Volume 70, 2019
  5. Article

Annual Review of Medicine

Volume 70, 2019

Structure-Based Vaccine Antigen Design

Abstract

Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.

Keyword(s): coronavirus, electron microscopy, immunization, influenza, nanoparticle display, platform technology, respiratory syncytial virus, vaccine development, X-ray crystallography
Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-121217-094234
2019-01-27
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/med/70/1/annurev-med-121217-094234.html?itemId=/content/journals/10.1146/annurev-med-121217-094234&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Schmaljohn AL 2013. Protective antiviral antibodies that lack neutralizing activity: precedents and evolution of concepts. Curr. HIV Res. 11:345–53
     [Google Scholar]
  2. 2.  Ackerman ME, Alter G 2013. Opportunities to exploit non-neutralizing HIV-specific antibody activity. Curr. HIV Res. 11:365–77
     [Google Scholar]
  3. 3.  Sullivan NJ, Hensley L, Asiedu C et al. 2011. CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat. Med. 17:1128–31
     [Google Scholar]
  4. 4.  McMichael AJ, Koff WC 2014. Vaccines that stimulate T cell immunity to HIV-1: the next step. Nat. Immunol. 15:319–22
     [Google Scholar]
  5. 5.  Kong L, Lee JH, Doores KJ et al. 2013. Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120. Nat. Struct. Mol. Biol. 20:796–803
     [Google Scholar]
  6. 6.  Georgiev IS, Gordon Joyce M, Zhou T et al. 2013. Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site. Curr. Opin. HIV AIDS 8:382–92
     [Google Scholar]
  7. 7.  Kallewaard NL, Corti D, Collins PJ et al. 2016. Structure and function analysis of an antibody recognizing all influenza A subtypes. Cell 166:596–608
     [Google Scholar]
  8. 8.  Corti D, Voss J, Gamblin SJ et al. 2011. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333:850–56
     [Google Scholar]
  9. 9.  McLellan JS, Pancera M, Carrico C et al. 2011. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480:336–43
     [Google Scholar]
  10. 10.  Lee PS, Arnell AJ, Wilson IA 2015. Structure of the apo anti-influenza CH65 Fab. Acta Crystallogr. F Struct. Biol. Commun. 71:145–48
     [Google Scholar]
  11. 11.  Cunningham AL, Lal H, Kovac M et al. 2016. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N. Engl. J. Med. 375:1019–32
     [Google Scholar]
  12. 12.  Kim HW, Canchola JG, Brandt CD et al. 1969. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89:422–34
     [Google Scholar]
  13. 13.  Kapikian AZ, Mitchell RH, Chanock RM et al. 1969. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am. J. Epidemiol. 89:405–21
     [Google Scholar]
  14. 14.  Fulginiti VA, Eller JJ, Sieber OF et al. 1969. Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am. J. Epidemiol. 89:435–48
     [Google Scholar]
  15. 15.  Chin J, Magoffin RL, Shearer LA et al. 1969. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am. J. Epidemiol. 89:449–63
     [Google Scholar]
  16. 16.  Murphy BR, Alling DW, Snyder MH et al. 1986. Effect of age and preexisting antibody on serum antibody response of infants and children to the F and G glycoproteins during respiratory syncytial virus infection. J. Clin. Microbiol. 24:894–98
     [Google Scholar]
  17. 17.  Murphy BR, Walsh EE 1988. Formalin-inactivated respiratory syncytial virus vaccine induces antibodies to the fusion glycoprotein that are deficient in fusion-inhibiting activity. J. Clin. Microbiol. 26:1595–97
     [Google Scholar]
  18. 18.  Killikelly AM, Kanekiyo M, Graham BS 2016. Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus. Sci. Rep. 6:34108
     [Google Scholar]
  19. 19.  Graham BS 2013. Advances in antiviral vaccine development. Immunol. Rev. 255:230–42
     [Google Scholar]
  20. 20.  Rappuoli R 2000. Reverse vaccinology. Curr. Opin. Microbiol. 3:445–50
     [Google Scholar]
  21. 21.  Burton DR 2002. Antibodies, viruses and vaccines. Nat. Rev. Immunol. 2:706–13
     [Google Scholar]
  22. 22.  Verlinde CL, Merritt EA, Van den Akker F et al. 1994. Protein crystallography and infectious diseases. Protein Sci 3:1670–86
     [Google Scholar]
  23. 23.  Dormitzer PR, Ulmer JB, Rappuoli R 2008. Structure-based antigen design: a strategy for next generation vaccines. Trends Biotechnol 26:659–67
     [Google Scholar]
  24. 24.  Dormitzer PR, Grandi G, Rappuoli R 2012. Structural vaccinology starts to deliver. Nat. Rev. Microbiol. 10:807–13
     [Google Scholar]
  25. 25.  Rappuoli R, Bottomley MJ, D'Oro U et al. 2016. Reverse vaccinology 2.0: human immunology instructs vaccine antigen design. J. Exp. Med. 213:469–81
     [Google Scholar]
  26. 26.  Blount RE Jr., Morris JA, Savage RE 1956. Recovery of cytopathogenic agent from chimpanzees with coryza. Proc. Soc. Exp. Biol. Med. 92:544–49
     [Google Scholar]
  27. 27.  Chanock R, Finberg L 1957. Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). II. Epidemiologic aspects of infection in infants and young children. Am. J. Hyg. 66:291–300
     [Google Scholar]
  28. 28.  Chanock R, Roizman B, Myers R 1957. Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). I. Isolation, properties and characterization. Am. J. Hyg. 66:281–90
     [Google Scholar]
  29. 29.  Hall CB, Weinberg GA, Iwane MK et al. 2009. The burden of respiratory syncytial virus infection in young children. N. Engl. J. Med. 360:588–98
     [Google Scholar]
  30. 30.  Graham BS, Anderson LJ 2013. Challenges and opportunities for respiratory syncytial virus vaccines. Curr. Top Microbiol. Immunol. 372:391–404
     [Google Scholar]
  31. 31.  Walsh EE, Falsey AR 2012. Respiratory syncytial virus infection in adult populations. Infect. Disord. Drug Targets 12:98–102
     [Google Scholar]
  32. 32.  Falsey AR, McElhaney JE, Beran J et al. 2014. Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness. J. Infect. Dis. 209:1873–81
     [Google Scholar]
  33. 33.  Glezen WP, Taber LH, Frank AL et al. 1986. Risk of primary infection and reinfection with respiratory syncytial virus. Am. J. Dis. Child 140:543–46
     [Google Scholar]
  34. 34.  Lo MS, Brazas RM, Holtzman MJ 2005. Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J. Virol. 79:9315–19
     [Google Scholar]
  35. 35.  Barik S 2013. Respiratory syncytial virus mechanisms to interfere with type 1 interferons. Curr. Top. Microbiol. Immunol. 372:173–91
     [Google Scholar]
  36. 36.  Johnson TR, Johnson JE, Roberts SR et al. 1998. Priming with secreted glycoprotein G of respiratory syncytial virus (RSV) augments interleukin-5 production and tissue eosinophilia after RSV challenge. J. Virol. 72:2871–80
     [Google Scholar]
  37. 37.  Johnson TR, McLellan JS, Graham BS 2012. Respiratory syncytial virus glycoprotein G interacts with DC-SIGN and L-SIGN to activate ERK1 and ERK2. J. Virol. 86:1339–47
     [Google Scholar]
  38. 38.  Tripp RA, Jones LP, Haynes LM et al. 2001. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nat. Immunol. 2:732–38
     [Google Scholar]
  39. 39.  McLellan JS, Chen M, Leung S et al. 2013. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 340:1113–17
     [Google Scholar]
  40. 40.  Gilman MS, Castellanos CA, Chen M et al. 2016. Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors. Sci. Immunol. 1:eaaj1879
     [Google Scholar]
  41. 41.  Mousa JJ, Kose N, Matta P et al. 2017. A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein. Nat. Microbiol. 2:16271
     [Google Scholar]
  42. 42.  Goodwin E, Gilman MSA, Wrapp D et al. 2018. Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation. Immunity 48:339–49
     [Google Scholar]
  43. 43.  McLellan JS, Chen M, Joyce MG et al. 2013. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342:592–98
     [Google Scholar]
  44. 44.  Stewart-Jones GB, Thomas PV, Chen M et al. 2015. A cysteine zipper stabilizes a pre-fusion F glycoprotein vaccine for respiratory syncytial virus. PLOS ONE 10:e0128779
     [Google Scholar]
  45. 45.  Joyce MG, Zhang B, Ou L et al. 2016. Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV. Nat. Struct. Mol. Biol. 23:811–20
     [Google Scholar]
  46. 46.  Krarup A, Truan D, Furmanova-Hollenstein P et al. 2015. A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism. Nat. Commun. 6:8143
     [Google Scholar]
  47. 47.  Ngwuta JO, Chen M, Modjarrad K et al. 2015. Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci. Transl. Med. 7:309ra162
     [Google Scholar]
  48. 48.  Liang B, Surman S, Amaro-Carambot E et al. 2015. Enhanced neutralizing antibody response induced by respiratory syncytial virus prefusion F protein expressed by a vaccine candidate. J. Virol. 89:9499–510
     [Google Scholar]
  49. 49.  Liu X, Liang B, Ngwuta J et al. 2017. Attenuated human parainfluenza virus type 1 expressing the respiratory syncytial virus (RSV) fusion (F) glycoprotein from an added gene: effects of prefusion stabilization and packaging of RSV F. J. Virol. 91:e01101–17
     [Google Scholar]
  50. 50.  Stobart CC, Rostad CA, Ke Z et al. 2016. A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation. Nat. Commun. 7:13916
     [Google Scholar]
  51. 51.  Cullen LM, Blanco JC, Morrison TG 2015. Cotton rat immune responses to virus-like particles containing the pre-fusion form of respiratory syncytial virus fusion protein. J. Transl. Med. 13:350
     [Google Scholar]
  52. 52.  Widjojoatmodjo MN, Bogaert L, Meek B et al. 2015. Recombinant low-seroprevalent adenoviral vectors Ad26 and Ad35 expressing the respiratory syncytial virus (RSV) fusion protein induce protective immunity against RSV infection in cotton rats. Vaccine 33:5406–14
     [Google Scholar]
  53. 53.  Battles MB, Mas V, Olmedillas E et al. 2017. Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein. Nat. Commun. 8:1528
     [Google Scholar]
  54. 54.  Buchholz UJ, Bukreyev A, Yang L et al. 2004. Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity. PNAS 101:9804–9
     [Google Scholar]
  55. 55.  Kirchdoerfer RN, Cottrell CA, Wang N et al. 2016. Pre-fusion structure of a human coronavirus spike protein. Nature 531:118–21
     [Google Scholar]
  56. 56.  Walls AC, Tortorici MA, Bosch BJ et al. 2016. Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer. Nature 531:114–17
     [Google Scholar]
  57. 57.  Walls AC, Tortorici MA, Frenz B et al. 2016. Glycan shield and epitope masking of a coronavirus spike protein observed by cryo-electron microscopy. Nat. Struct. Mol. Biol. 23:899–905
     [Google Scholar]
  58. 58.  Yuan Y, Cao D, Zhang Y et al. 2017. Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains. Nat. Commun. 8:15092
     [Google Scholar]
  59. 59.  Pallesen J, Wang N, Corbett KS et al. 2017. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. PNAS 114:E7348–57
     [Google Scholar]
  60. 60.  Burton DR, Ahmed R, Barouch DH et al. 2012. A blueprint for HIV vaccine discovery. Cell Host Microbe 12:396–407
     [Google Scholar]
  61. 61.  Binley JM, Sanders RW, Clas B et al. 2000. A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J. Virol. 74:627–43
     [Google Scholar]
  62. 62.  Sanders RW, Vesanen M, Schuelke N et al. 2002. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J. Virol. 76:8875–89
     [Google Scholar]
  63. 63.  Klasse PJ, Depetris RS, Pejchal R et al. 2013. Influences on trimerization and aggregation of soluble, cleaved HIV-1 SOSIP envelope glycoprotein. J. Virol. 87:9873–85
     [Google Scholar]
  64. 64.  Sanders RW, Derking R, Cupo A et al. 2013. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLOS Pathog 9:e1003618
     [Google Scholar]
  65. 65.  Lyumkis D, Julien JP, de Val N et al. 2013. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342:1484–90
     [Google Scholar]
  66. 66.  Julien JP, Cupo A, Sok D et al. 2013. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342:1477–83
     [Google Scholar]
  67. 67.  Lopez JA, Andreu D, Carreno C et al. 1993. Conformational constraints of conserved neutralizing epitopes from a major antigenic area of human respiratory syncytial virus fusion glycoprotein. J. Gen. Virol. 74:Pt. 122567–77
     [Google Scholar]
  68. 68.  Ofek G, Guenaga FJ, Schief WR et al. 2010. Elicitation of structure-specific antibodies by epitope scaffolds. PNAS 107:17880–87
     [Google Scholar]
  69. 69.  McLellan JS, Chen M, Kim A et al. 2010. Structural basis of respiratory syncytial virus neutralization by motavizumab. Nat. Struct. Mol. Biol. 17:248–50
     [Google Scholar]
  70. 70.  McLellan JS, Correia BE, Chen M et al. 2011. Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus. J. Mol. Biol. 409:853–66
     [Google Scholar]
  71. 71.  Correia BE, Bates JT, Loomis RJ et al. 2014. Proof of principle for epitope-focused vaccine design. Nature 507:201–6
     [Google Scholar]
  72. 72.  Hollingshead S, Jongerius I, Exley RM et al. 2018. Structure-based design of chimeric antigens for multivalent protein vaccines. Nat. Commun. 9:1051
     [Google Scholar]
  73. 73.  Herve PL, Deloizy C, Descamps D et al. 2017. RSV N-nanorings fused to palivizumab-targeted neutralizing epitope as a nanoparticle RSV vaccine. Nanomedicine 13:411–20
     [Google Scholar]
  74. 74.  Chackerian B, Durfee MR, Schiller JT 2008. Virus-like display of a neo-self antigen reverses B cell anergy in a B cell receptor transgenic mouse model. J. Immunol. 180:5816–25
     [Google Scholar]
  75. 75.  Schiller JT, Lowy DR 2012. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat. Rev. Microbiol. 10:681–92
     [Google Scholar]
  76. 76.  Chang LJ, Dowd KA, Mendoza FH et al. 2014. Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial. Lancet 384:2046–52
     [Google Scholar]
  77. 77.  Dowd KA, Mukherjee S, Kuhn RJ et al. 2014. Combined effects of the structural heterogeneity and dynamics of flaviviruses on antibody recognition. J. Virol. 88:11726–37
     [Google Scholar]
  78. 78.  Pierson TC, Diamond MS 2012. Degrees of maturity: the complex structure and biology of flaviviruses. Curr. Opin. Virol. 2:168–75
     [Google Scholar]
  79. 79.  Swanstrom JA, Plante JA, Plante KS et al. 2016. Dengue virus envelope dimer epitope monoclonal antibodies isolated from dengue patients are protective against Zika virus. MBio 7:e01123–16
     [Google Scholar]
  80. 80.  de Alwis R, Smith SA, Olivarez NP et al. 2012. Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. PNAS 109:7439–44
     [Google Scholar]
  81. 81.  Rey FA, Heinz FX, Mandl C et al. 1995. The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution. Nature 375:291–98
     [Google Scholar]
  82. 82.  Kuhn RJ, Zhang W, Rossmann MG et al. 2002. Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108:717–25
     [Google Scholar]
  83. 83.  Kotecha A, Seago J, Scott K et al. 2015. Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design. Nat. Struct. Mol. Biol. 22:788–94
     [Google Scholar]
  84. 84.  Scott KA, Kotecha A, Seago J et al. 2017. SAT2 foot-and-mouth disease virus structurally modified for increased thermostability. J. Virol. 91:e02312–16
     [Google Scholar]
  85. 85.  Yassine HM, Boyington JC, McTamney PM et al. 2015. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med. 21:1065–70
     [Google Scholar]
  86. 86.  Kanekiyo M, Wei CJ, Yassine HM et al. 2013. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499:102–6
     [Google Scholar]
  87. 87.  Georgiev IS, Joyce MG, Chen RE et al. 2018. Two-component ferritin nanoparticles for multimerization of diverse trimeric antigens. ACS Infect. Dis. 4:788–96
     [Google Scholar]
  88. 88.  Jardine J, Julien JP, Menis S et al. 2013. Rational HIV immunogen design to target specific germline B cell receptors. Science 340:711–16
     [Google Scholar]
  89. 89.  Burkhard P, Lanar DE 2015. Malaria vaccine based on self-assembling protein nanoparticles. Expert Rev. Vaccines 14:1525–27
     [Google Scholar]
  90. 90.  King NP, Sheffler W, Sawaya MR et al. 2012. Computational design of self-assembling protein nanomaterials with atomic level accuracy. Science 336:1171–74
     [Google Scholar]
  91. 91.  King NP, Bale JB, Sheffler W et al. 2014. Accurate design of co-assembling multi-component protein nanomaterials. Nature 510:103–8
     [Google Scholar]
  92. 92.  Wu X, Zhou T, Zhu J et al. 2011. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333:1593–602
     [Google Scholar]
  93. 93.  Joyce MG, Wheatley AK, Thomas PV et al. 2016. Vaccine-induced antibodies that neutralize group 1 and group 2 influenza A viruses. Cell 166:609–23
     [Google Scholar]
/content/journals/10.1146/annurev-med-121217-094234
Loading
Structure-Based Vaccine Antigen Design
Annual Review of Medicine 70, 91 (2019); https://doi.org/10.1146/annurev-med-121217-094234
/content/journals/10.1146/annurev-med-121217-094234
/content/journals/10.1146/annurev-med-121217-094234
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error