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What does it mean to develop an HIV vaccine by rational design?

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Abstract

This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the inability of vaccinologists to develop an effective HIV vaccine. The strong goal-directed intentionality inherent in the concept of design together with excessive confidence in the power of rational thinking convinced investigators that the accumulated structural knowledge on HIV epitopes, derived from crystallographic studies of complexes of neutralizing antibodies bound to HIV Env epitopes, would allow them to rationally design complementary immunogens capable of inducing anti-HIV protective antibodies. This strategy failed because it was not appreciated that the structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not represent structures present in the free disordered molecules before they had interacted. In addition, reductionist thinking led investigators to accept that biology could be reduced to chemistry, and this made them neglect the fundamental difference between chemical antigenicity and biological immunogenicity. As a result, they did not investigate which inherent constituents of immune systems controlled the induction of protective antibodies and focused instead only on the steric complementarity that exists between bound epitopes and paratopes.

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References

  1. Kay L (2000) Who wrote the book of life: a history of the genetic code. Stanford University Press, Stanford

    Google Scholar 

  2. Ruse M (2002) Design as metaphor. Darwin and design: does evolution have a purpose? Harvard University Press, Cambridge, pp 271–288

    Google Scholar 

  3. Hanke D (2004). In: Cornwell J (ed) Explanations. Styles of Explanation in Science. Oxford University Press, Oxford, pp 143–155

    Google Scholar 

  4. Van Regenmortel MHV (2007) The rational design of biological complexity: a deceptive metaphor. Proteomics 7:965–975

    PubMed  Google Scholar 

  5. Van Regenmortel MHV (2019) Truth in science and in molecular recognition, post -truth in human affairs. J Mol Recognit 33(1):e2827. https://doi.org/10.1002/jmr2827

    Article  PubMed  Google Scholar 

  6. Bauer HH (1992) Scientific literacy and the myth of the scientific method. University of Illinois Press, Urbana

    Google Scholar 

  7. Gauch HG (2012) Scientific Method in Brief. University Press, Cambridge

    Google Scholar 

  8. McIntyre L (2019) The scientific attitude. The MIT Press, Cambridge

    Google Scholar 

  9. Van Regenmortel MHV (2016) Structure-based reverse vaccinology failed in the case of HIV because it disregarded accepted immunological theory. Int J Mol Sci 17:1591–1625

    PubMed Central  Google Scholar 

  10. Scherer EM, Leaman DP, Zwick MB, McMichael AJ, Burton DR (2010) Aromatic residues at the edge of the Ab combining site facilitate viral glycoprotein recognition through membrane interactions. Proc Natl Acad Sci USA 107:1529–1534

    CAS  PubMed  Google Scholar 

  11. Dupré J (1993) The disorder of things. Metaphysical foundations of the disunity of science. Harvard University Press, Cambridge

    Google Scholar 

  12. Berger R (1998) Understanding science: why causes are not enough. Philosos Sci 65:306–332

    Google Scholar 

  13. Magnani L (1999) Model-based creative abduction . In: Magnani L, Nersessian NJ, Thagard P (eds) Model-based reasoning in scientific discovery. Kluwer Academic/Plenum Publishers, New York, pp 219–238

    Google Scholar 

  14. Douven I (2017) Abduction. Stanford encyclopedia of philosophy. Center for the Study of Language and Information, Stanford University, Stanford

    Google Scholar 

  15. Simon H (1966) The sciences of the artificial, 3rd edn. MIT Press, Cambridge

    Google Scholar 

  16. Du Sautoy M (2016) What we cannot know. Harper Collins Publishers, New York, pp 36–73

    Google Scholar 

  17. Gannon F (2007) Too complex to understand? EMBO Rep 8:705

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Van Regenmortel MHV (2018) Development of a preventive HIV vaccine requires solving inverse problems which is not attainable by rational vaccine design. Front Immunol 8:2009

    PubMed  PubMed Central  Google Scholar 

  19. Laplane L, Mantovani P, Adolphe R, Chang H, Mantovani A, McFall-Ngai M, Rovelli C, Sober E, Pradeu T (2019) Why science needs philosophy. Proc Natl Acad Sci US 116:3948–3852

    CAS  Google Scholar 

  20. Crick FHC (1966) Of molecules and men. University of Washington Press, Seattle

    Google Scholar 

  21. Kurakin A (2010) Order without design. Theor Biol Med Model 7:12–22

    PubMed  PubMed Central  Google Scholar 

  22. Van Regenmortel MHV (2012) Basic research in HIV vaccinology is hampered by reductionist thinking. Front Immunol 3:194

    PubMed  PubMed Central  Google Scholar 

  23. Berzofsky JA (1985) Intrinsic and extrinsic factors in protein antigenic structure. Science 229:932–940

    CAS  PubMed  Google Scholar 

  24. Hilleman MR (1992) (1992) Impediments imponderables and alternatives in the attempt to develop an effective vaccine against AIDS. Vaccine 10:1053–1058

    CAS  PubMed  Google Scholar 

  25. Kong L, Sattentau QJ (2012) Antigenicity and immunogenicity in HIV-1 antibody-based vaccine design. J AIDS Clin Res https://doi.org/10.4172/2155-6113

  26. Burton DR, Ahmed R, Barouch DH, Butera ST, Crotty S, Godzik A, Godzik A, Kaufmann DE, McElrath MJ, Nussenzweig MC, Pulendran B et al (2012) A blueprint for HIV vaccine discovery. Cell Host Microbe 12:396–407

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kunik V, Ofran Y (2013) The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops. Protein Eng Des Sel 26:599–609

    CAS  PubMed  Google Scholar 

  28. Eisen HN, Chakraborty AK (2010) Evolving concepts of specificity in immune reactions. Proc Natl Acad Sci USA 107:22373–22380

    CAS  PubMed  Google Scholar 

  29. Eisen HN (2001) Specificity and degeneracy: Yin and Yang in the immune system. Ann Rev Immunol 19:1–21

    CAS  Google Scholar 

  30. Van Regenmortel MHV (2014) Specificity, polyspecificity and heterospecificity of antigen-antibody recognition. J Mol Recognit 27:627–639

    PubMed  Google Scholar 

  31. Douek DC, Kwong PD, Nabel GJ (2006) The rational design of an AIDS vaccine. Cell 124:677–681

    CAS  PubMed  Google Scholar 

  32. Bramwell VW, Perrie Y (2005) The rational design of vaccines. Drug Discov Today 10:1527–1534

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Burton DR (2010) Scaffolding to build a rational vaccine design strategy. Proc Natl Acad Sci USA 107:17859–17860

    CAS  PubMed  Google Scholar 

  34. Walker LM, Burton DR (2010) Rational antibody-based HIV-1 vaccine design: current approaches and future directions. Curr Opin Immunol 22:358–366

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Van Regenmortel MHV (2015) Why does the molecular structure of broadly neutralizing monoclonal antibodies isolated from individuals infected with HIV-1 not inform the rational design of an HIV-1 vaccine? AIMS Public Health 2:183–193

    PubMed  PubMed Central  Google Scholar 

  36. Hans D, Young PR, Fairlie DP (2006) Current status of short synthetic peptides as vaccines. Med Chem 2:627–646

    CAS  PubMed  Google Scholar 

  37. Burton DR (2002) Antibodies, viruses and vaccines. Nat Rev Immunol 2:706–713

    CAS  PubMed  Google Scholar 

  38. Rappuoli R (2001) Reverse vaccinology, a genome-based approach to vaccine development. Vaccine 19:2688–2691

    CAS  PubMed  Google Scholar 

  39. Rappuoli R, Bagnoli F (2011) Vaccine design: innovative approaches and novel strategies. Caister Academic Press, Norfolk

    Google Scholar 

  40. Burton DR (2017) What are the most powerful immunogen design strategies? Reverse vaccinology 2.0 shows great promise. Cold Spring Harbor Perspect Biol 9:a030262

    Google Scholar 

  41. Neurath AR, Rubin BA (1971) Viral Structural components as immunogens of prophylactic value. In: Monographs in Virology, Basel: Karger.

  42. Van Regenmortel MHV (1992) The conformational specificity of viral epitopes. FEMS Microbiol Lett 100:483–466

    PubMed  Google Scholar 

  43. Xiao X, Chen W, FenG Y, Zhu Z, Prabakaran P, Wang Y, Zhang MY, Longo NS, Dimitrov DS (2009) Germline -like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycopropteins: implications for evasion of immune responses and design of vaccine immunogens. Biochem Biophys Res Commun 390:404–409

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Dimitrov DS (2010) Therapeutic antibodies, vaccines and antibodyomes. MAbs 2:347–356

    PubMed  PubMed Central  Google Scholar 

  45. Mascola JR, Haynes BF (2013) HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol Rev 254:225–244

    PubMed  PubMed Central  Google Scholar 

  46. Doria-Rose NA, Joyce MG (2015) Strategies to guide the antibody maturation process. Curr Opin Virol 11:137–147

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Umotoy J, Bagaya BS, Joyce C, Schiffner T, Menis S et al (2019) Rapid and focused maturation of a VRC01-class HIV broadly neutralizing antibody lineage involves both binding and accommodation of the N276-glycan. Immunity 51:141–154

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Greenspan NS (2014) Design challenges for HIV-1 vaccines based on humoral immunity. Front Immunol 5:335

    PubMed  PubMed Central  Google Scholar 

  49. Esparza J (2013) A brief history of the global effort to develop an HIV vaccine. Vaccine 31:3502–3518

    PubMed  Google Scholar 

  50. Esparza J (2015) A new scientific paradigm may be needed to finally develop an HIV vaccine. Front Immunol 6:124

    PubMed  PubMed Central  Google Scholar 

  51. Goh GK, Dunker AK, Uversky VN (2015) Shell disorder, immune evasion and transmission behaviors among human and animal retroviruses. Mol Biost 11:437–447

    Google Scholar 

  52. Goh GK, Dunker AK, Foster JA, Uversky VN (2019) HIV vaccine mystery and viral shell disorder. Biomolecules 9:178

    CAS  PubMed Central  Google Scholar 

  53. Nakaya HI, Pulendran B (2012) Systems vaccinology: its promise and challenge for HIV vaccine development. Curr Opin HIV AIDS 7:24–31

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Pulendran B (2014) Systems vaccinology: probing’s humanity’s diverse immune systems with vaccines. Proc Natl Acad Sci USA 111:12300–12306

    CAS  PubMed  Google Scholar 

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  1. Medical University of Vienna, Vienna, Austria

    Marc H. V. van Regenmortel

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  1. Marc H. V. van Regenmortel
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Correspondence to Marc H. V. van Regenmortel.

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van Regenmortel, M.H.V. What does it mean to develop an HIV vaccine by rational design?. Arch Virol 166, 27–33 (2021). https://doi.org/10.1007/s00705-020-04884-0

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