Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

OPINION

Models of immune selection for multi-locus antigenic diversity of pathogens

Nature Reviews Immunology volume 19, pages 55–62 (2019)Cite this article

Subjects

Abstract

It is well accepted that pathogens can evade recognition and elimination by the host immune system by varying their antigenic targets. Thus, it has become a truism that host immunity is a major driver and determinant of the antigenic diversity of pathogens. However, it remains puzzling how host immunity selects for antigenic diversity at the level of the pathogen population, given that hosts have acquired immune responses to multiple antigens of most pathogens — sometimes through multiple effectors of both humoral and cellular immunity. In this Opinion article, we address this puzzle and the related question of why pathogens often have diversity at multiple antigenic loci. Here, we describe five hypotheses to explain the polymorphism of multiple antigens in a single pathogen species and highlight research relevant to our current models of thinking about multi-locus antigenic diversity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Hypothesis 1: non-overlapping antigenic repertoires.
Fig. 2: Hypothesis 2: additive effects of host immunity.
Fig. 3: Hypothesis 3: variation at one locus affects responses to other loci.

Similar content being viewed by others

References

  1. Abu-Raddad, L. J. & Ferguson, N. M. The impact of cross-immunity, mutation and stochastic extinction on pathogen diversity. Proc. Biol. Sci. 271, 2431–2438 (2004).

    PubMed  PubMed Central  Google Scholar 

  2. Abu-Raddad, L. J. & Ferguson, N. M. Characterizing the symmetric equilibrium of multi-strain host-pathogen systems in the presence of cross immunity. J. Math. Biol. 50, 531–558 (2005).

    CAS  PubMed  Google Scholar 

  3. Callaghan, M. J. et al. The effect of immune selection on the structure of the meningococcal opa protein repertoire. PLOS Pathog. 4, e1000020 (2008).

    PubMed  PubMed Central  Google Scholar 

  4. Ferguson, N., Anderson, R. & Gupta, S. The effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens. Proc. Natl Acad. Sci. USA 96, 790–794 (1999).

    CAS  PubMed  Google Scholar 

  5. Gog, J. R. & Swinton, J. A status-based approach to multiple strain dynamics. J. Math. Biol. 44, 169–184 (2002).

    CAS  PubMed  Google Scholar 

  6. Gog, J. R. & Grenfell, B. T. Dynamics and selection of many-strain pathogens. Proc. Natl Acad. Sci. USA 99, 17209–17214 (2002).

    CAS  PubMed  Google Scholar 

  7. Gomes, M. G., Medley, G. F. & Nokes, D. J. On the determinants of population structure in antigenically diverse pathogens. Proc. Biol. Sci. 269, 227–233 (2002).

    PubMed  PubMed Central  Google Scholar 

  8. Gupta, S., Ferguson, N. & Anderson, R. Chaos, persistence, and evolution of strain structure in antigenically diverse infectious agents. Science 280, 912–915 (1998).

    CAS  PubMed  Google Scholar 

  9. Lange, A. & Ferguson, N. M. Antigenic diversity, transmission mechanisms, and the evolution of pathogens. PLOS Comput. Biol. 5, e1000536 (2009).

    PubMed  PubMed Central  Google Scholar 

  10. Luo, S., Reed, M., Mattingly, J. C. & Koelle, K. The impact of host immune status on the within-host and population dynamics of antigenic immune escape. J. R. Soc. Interface 9, 2603–2613 (2012).

    PubMed  PubMed Central  Google Scholar 

  11. Penman, B. S., Ashby, B., Buckee, C. O. & Gupta, S. Pathogen selection drives nonoverlapping associations between HLA loci. Proc. Natl Acad. Sci. USA 110, 19645–19650 (2013).

    CAS  PubMed  Google Scholar 

  12. Recker, M. et al. Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature 429, 555–558 (2004).

    CAS  PubMed  Google Scholar 

  13. Recker, M., Pybus, O. G., Nee, S. & Gupta, S. The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types. Proc. Natl Acad. Sci. USA 104, 7711–7716 (2007).

    CAS  PubMed  Google Scholar 

  14. Watkins, E. R., Grad, Y. H., Gupta, S. & Buckee, C. O. Contrasting within- and between-host immune selection shapes Neisseria Opa repertoires. Sci. Rep. 4, 6554 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. in Immunobiology (ed. Gibbs, S.) (Garland Science, New York, 2001).

  16. DeFranco, A. L., Locksley, R. M. & Robertson, M. in Immunity: the Immune Response in Infectious and Inflammatory Disease (Oxford Univ. Press, 2007).

  17. Gupta, S. & Maiden, M. C. J. Exploring the evolution of diversity in pathogen populations. Trends Microbiol. 9, 181–185 (2001).

    CAS  PubMed  Google Scholar 

  18. Lipsitch, M. & O’Hagan, J. J. Patterns of antigenic diversity and the mechanisms that maintain them. J. R. Soc. Interface 4, 787–802 (2007).

    PubMed  PubMed Central  Google Scholar 

  19. Mandl, J. N. et al. Reservoir host immune responses to emerging zoonotic viruses. Cell 160, 20–35 (2015).

    CAS  PubMed  Google Scholar 

  20. Lipsitch, M. et al. Viral factors in influenza pandemic risk assessment. eLife 5, e18491 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. Das, S. R. et al. Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy. Proc. Natl Acad. Sci. USA 108, E1417–E1422 (2011).

    CAS  PubMed  Google Scholar 

  22. Friedrich, T. C. et al. Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nat. Med. 10, 275–281 (2004).

    CAS  PubMed  Google Scholar 

  23. Troyer, R. M. et al. Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. PLOS Pathog. 5, e1000365 (2009).

    PubMed  PubMed Central  Google Scholar 

  24. Kosik, I. et al. Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs. PLOS Pathog. 14, e1006796 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Lyons, D. M. & Lauring, A. S. Mutation and epistasis in influenza virus evolution. Viruses 10, 407 (2018).

    PubMed Central  Google Scholar 

  26. zur Wiesch, P. A., Kouyos, R., Engelstädter, J., Regoes, R. R. & Bonhoeffer, S. Population biological principles of drug-resistance evolution in infectious diseases. Lancet Infect. Dis. 11, 236–247 (2011).

    PubMed  Google Scholar 

  27. Consortium, R. E. X. Heterogeneity of selection and the evolution of resistance. Trends Ecol. Evol. 28, 110–118 (2013).

    Google Scholar 

  28. Gillespie, S. H. Evolution of drug resistance in Mycobacterium tuberculosis: clinical and molecular perspective. Antimicrob. Agents Chemother. 46, 267–274 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dye, C. Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis. Nat. Rev. Microbiol. 7, 81–87 (2009).

    CAS  PubMed  Google Scholar 

  30. Ehrlich, P. Address in pathology on chemotherapeutics: scientific principles, methods, and results. Lancet 182, 445–451 (1913).

    Google Scholar 

  31. Kennedy, D. A. & Read, A. F. Why does drug resistance readily evolve but vaccine resistance does not? Proc. Biol. Sci. 284, 20162562 (2017).

    PubMed  PubMed Central  Google Scholar 

  32. Koelle, K., Cobey, S., Grenfell, B. & Pascual, M. Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans. Science 314, 1898–1903 (2006).

    CAS  PubMed  Google Scholar 

  33. Zinder, D., Bedford, T., Gupta, S. & Pascual, M. The roles of competition and mutation in shaping antigenic and genetic diversity in influenza. PLOS Pathog. 9, e1003104 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cobey, S. & Lipsitch, M. Niche and neutral effects of acquired immunity permit coexistence of pneumococcal serotypes. Science 335, 1376–1380 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Buckee, C. O. et al. Role of selection in the emergence of lineages and the evolution of virulence in Neisseria meningitidis. Proc. Natl Acad. Sci. USA 105, 15082–15087 (2008).

    CAS  PubMed  Google Scholar 

  36. Buckee, C. O., Gupta, S., Kriz, P., Maiden, M. C. & Jolley, K. A. Long-term evolution of antigen repertoires among carried meningococci. Proc. Biol. Sci. 277, 1635–1641 (2010).

    PubMed  PubMed Central  Google Scholar 

  37. Hausdorff, W. P., Feikin, D. R. & Klugman, K. P. Epidemiological differences among pneumococcal serotypes. Lancet Infect. Dis. 5, 83–93 (2005).

    PubMed  Google Scholar 

  38. Li, Y. et al. Distinct effects on diversifying selection by two mechanisms of immunity against Streptococcus pneumoniae. PLOS Pathog. 8, e1002989 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ndung’u, T. & Weiss, R. A. On HIV diversity. AIDS 26, 1255–1260 (2012).

    PubMed  Google Scholar 

  40. Korber, B., Hraber, P., Wagh, K. & Hahn, B. H. Polyvalent vaccine approaches to combat HIV-1 diversity. Immunol. Rev. 275, 230–244 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gupta, S. et al. The maintenance of strain structure in populations of recombining infectious agents. Nat. Med. 2, 437–442 (1996).

    CAS  PubMed  Google Scholar 

  42. Croucher, N. J. et al. Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening. Proc. Natl Acad. Sci. USA 114, E357–E366 (2017).

    CAS  PubMed  Google Scholar 

  43. Buckee, C., Recker, M., Watkins, E. R. & Gupta, S. Role of stochastic processes in maintaining discrete strain structure in antigenically diverse pathogen populations. Proc. Natl Acad. Sci. USA 108, 15504–15509 (2011).

    CAS  PubMed  Google Scholar 

  44. Azarian, T. et al. Association of pneumococcal protein antigen serology with age and antigenic profile of colonizing Isolates. J. Infect. Dis. 215, 713–722 (2017).

    CAS  PubMed  Google Scholar 

  45. Weinberger, D. M. et al. Epidemiologic evidence for serotype-specific acquired immunity to pneumococcal carriage. J. Infect. Dis. 197, 1511–1518 (2008).

    PubMed  Google Scholar 

  46. Turner, P. et al. A longitudinal study of Streptococcus pneumoniae carriage in a cohort of infants and their mothers on the Thailand-Myanmar border. PLOS ONE 7, e38271 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hensley, S. E. et al. Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Science 326, 734–736 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gamblin, S. J. & Skehel, J. J. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J. Biol. Chem. 285, 28403–28409 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Plotkin, J. B., Dushoff, J. & Levin, S. A. Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. Proc. Natl Acad. Sci. USA 99, 6263–6268 (2002).

    CAS  PubMed  Google Scholar 

  50. Wilson, I. A. & Cox, N. J. Structural basis of immune recognition of influenza virus hemagglutinin. Annu. Rev. Immunol. 8, 737–771 (1990).

    CAS  PubMed  Google Scholar 

  51. Yewdell, J. W., Webster, R. G. & Gerhard, W. U. Antigenic variation in three distinct determinants of an influenza type A haemagglutinin molecule. Nature 279, 246–248 (1979).

    CAS  PubMed  Google Scholar 

  52. Benton, D. J., Martin, S. R., Wharton, S. A. & McCauley, J. W. Biophysical measurement of the balance of influenza A hemagglutinin and neuraminidase activities. J. Biol. Chem. 290, 6516–6521 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Maiden, M. C. et al. Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity. J. Infect. Dis. 197, 737–743 (2008).

    PubMed  Google Scholar 

  54. Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J. & Davis, M. M. Virus-specific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–383 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Correia-Neves, M., Waltzinger, C., Mathis, D. & Benoist, C. The shaping of the T cell repertoire. Immunity 14, 21–32 (2001).

    CAS  PubMed  Google Scholar 

  56. von Boehmer, H. Shaping the T cell repertoire. J. Immunol. 175, 7067–7068 (2005).

    Google Scholar 

  57. Bevan, M. J. The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J. Exp. Med. 142, 1349–1364 (1975).

    CAS  PubMed  Google Scholar 

  58. Lyashchenko, K. et al. Heterogeneous antibody responses in tuberculosis. Infect. Immun. 66, 3936–3940 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Weidt, G., Utermohlen, O., Heukeshoven, J., Lehmann-Grube, F. & Deppert, W. Relationship among immunodominance of single CD8 T cell epitopes, virus load, and kinetics of primary antiviral CTL response. J. Immunol. 160, 2923–2931 (1998).

    CAS  PubMed  Google Scholar 

  60. Yewdell, J. W. & Bennink, J. R. Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu. Rev. Immunol. 17, 51–88 (1999).

    CAS  PubMed  Google Scholar 

  61. Burrows, S. R., Khanna, R., Burrows, J. M. & Moss, D. J. An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease. J. Exp. Med. 179, 1155–1161 (1994).

    CAS  PubMed  Google Scholar 

  62. Burrows, S. R. et al. T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen. J. Exp. Med. 182, 1703–1715 (1995).

    CAS  PubMed  Google Scholar 

  63. Moir, S. et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J. Exp. Med. 205, 1797–1805 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Corti, D. et al. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J. Clin. Invest. 120, 1663–1673 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Avnir, Y. et al. Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLOS Pathog. 10, e1004103 (2014).

    PubMed  PubMed Central  Google Scholar 

  66. Wu, X. et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333, 1593–1602 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Weng, N. P. Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24, 495–499 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Goronzy, J. J. & Weyand, C. M. Immune aging and autoimmunity. Cell. Mol. Life Sci. 69, 1615–1623 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Shaw, A. C., Joshi, S., Greenwood, H., Panda, A. & Lord, J. M. Aging of the innate immune system. Curr. Opin. Immunol. 22, 507–513 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Moreno, A. T. et al. Cross-reactivity of antipneumococcal surface protein C (PspC) antibodies with different strains and evaluation of inhibition of human complement factor H and secretory IgA binding via PspC. Clin. Vaccine Immunol. 19, 499–507 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Iannelli, F., Oggioni, M. R. & Pozzi, G. Allelic variation in the highly polymorphic locus pspC of Streptococcus pneumoniae. Gene 284, 63–71 (2002).

    CAS  PubMed  Google Scholar 

  72. Brooks-Walter, A., Briles, D. E. & Hollingstead, S. K. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein, PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect. Immun. 67, 6533–6542 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Georgieva, M., Kagedan, L., Lu, Y. J., Thompson, C. M. & Lipsitch, M. Antigenic variation in Streptococcus pneumoniae PspC. promotes immune escape in the presence of variant-specific immunity. mBio 9, e00264–18 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Hyams, C. et al. Streptococcus pneumoniae capsular serotype invasiveness correlates with the degree of factor H binding and opsonization with C3b/iC3b. Infect. Immun. 81, 354–363 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Yuste, J. et al. The effects of PspC on complement-mediated immunity to Streptococcus pneumoniae vary with strain background and capsular serotype. Infect. Immun. 78, 283–292 (2010).

    CAS  PubMed  Google Scholar 

  76. Li, Y. et al. Single hemagglutinin mutations that alter both antigenicity and receptor binding avidity influence influenza virus antigenic clustering. J. Virol. 87, 9904–9910 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Comas, I. et al. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat. Genet. 42, 498–503 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Coscolla, M. et al. M. tuberculosis T cell epitope analysis reveals paucity of antigenic variation and identifies rare variable TB antigens. Cell Host Microbe 18, 538–548 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Reichler, M. R. et al. Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA 287, 991–995 (2002).

    PubMed  Google Scholar 

  80. Griffin, D. E. The immune response in measles: virus control, clearance and protective immunity. Viruses 8, 282 (2016).

    PubMed Central  Google Scholar 

  81. Birrer, M. J., Udem, S., Nathenson, S. & Bloom, B. R. Antigenic variants of measles virus. Nature 293, 67–69 (1981).

    CAS  PubMed  Google Scholar 

  82. Frank, S. A. & Bush, R. M. Barriers to antigenic escape by pathogens: trade-off between reproductive rate and antigenic mutability. BMC Evol. Biol. 7, 229 (2007).

    PubMed  PubMed Central  Google Scholar 

  83. Kadioglu, A., Weiser, J. N., Paton, J. C. & Andrew, P. W. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat. Rev. Microbiol. 6, 288–301 (2008).

    CAS  PubMed  Google Scholar 

  84. Serruto, D., Rappuoli, R., Scarselli, M., Gros, P. & van Strijp, J. A. Molecular mechanisms of complement evasion: learning from staphylococci and meningococci. Nat. Rev. Microbiol. 8, 393–399 (2010).

    CAS  PubMed  Google Scholar 

  85. Stanisic, D. I., Barry, A. E. & Good, M. F. Escaping the immune system: how the malaria parasite makes vaccine development a challenge. Trends Parasitol. 29, 612–622 (2013).

    CAS  PubMed  Google Scholar 

  86. Malley, R. et al. CD4 T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc. Natl Acad. Sci. USA 102, 4848–4853 (2005).

    CAS  PubMed  Google Scholar 

  87. Yassine, H. M. et al. Use of hemagglutinin stem probes demonstrate prevalence of broadly reactive group 1 influenza antibodies in human sera. Sci. Rep. 8, 8628 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. Xu, G. J. et al. Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Science 348, aaa0698 (2015).

    PubMed  PubMed Central  Google Scholar 

  89. Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).

    CAS  PubMed  Google Scholar 

  90. Deng, K. et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517, 381–385 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Asquith, B., Edwards, C. T., Lipsitch, M. & McLean, A. R. Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo. PLOS Biol. 4, e90 (2006).

    PubMed  PubMed Central  Google Scholar 

  92. Cnops, J., Magez, S. & De Trez, C. Escape mechanisms of African trypanosomes: why trypanosomosis is keeping us awake. Parasitology 142, 417–427 (2015).

    PubMed  Google Scholar 

  93. Peck, A. & Mellins, E. D. Precarious balance: Th17 cells in host defense. Infect. Immun. 78, 32–38 (2010).

    CAS  PubMed  Google Scholar 

  94. Trzcinski, K. et al. Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells. Infect. Immun. 76, 2678–2684 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Li, Y., Thompson, C. M., Trzcinski, K. & Lipsitch, M. Within-host selection is limited by an effective population of Streptococcus pneumoniae during nasopharyngeal colonization. Infect. Immun. 81, 4534–4543 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bonhoeffer, S. & Nowak, M. A. Intra-host versus inter-host selection: viral strategies of immune function impairment. Proc. Natl Acad. Sci. USA 91, 8062–8066 (1994).

    CAS  PubMed  Google Scholar 

  97. Frank, S. A. in Immunology and Evolution of Infectious Disease (Princeton Univ. Press, 2002).

  98. Sette, A. & Sundaran, R. in Immunodominance - The Choice of the Immune System (ed. Frelinger, J. A.) 55–71 (Wiley-VCH Verlag GmbH & Co, Weinheim, 2006).

  99. Sadegh-Nasseri, S. & Kim, A. Selection of immunodominant epitopes during antigen processing is hierarchical. Mol. Immunol. https://doi.org/10.1016/j.molimm.2018.08.011 (2018).

    Article  PubMed  Google Scholar 

  100. Angeletti, D. & Yewdell, J. W. Understanding and manipulating viral immunity: antibody immunodominance enters center stage. Trends Immunol. 39, 549–561 (2018).

    CAS  PubMed  Google Scholar 

  101. Giuliani, M. et al. Human protective response induced by meningococcus B vaccine is mediated by the synergy of multiple bactericidal epitopes. Sci. Rep. 8, 3700 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors’ work was supported by award R01AI048935 from the US National Institutes of Health.

Reviewer information

Nature Reviews Immunology thanks J. Ernst, R. Rappuoli and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Author notes

  1. Maria Georgieva

    Present address: Department of Physiology, University of Lausanne, Lausanne, Switzerland

Authors and Affiliations

  1. Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Maria Georgieva, Caroline O. Buckee & Marc Lipsitch

  2. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Marc Lipsitch

Authors
  1. Maria Georgieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline O. Buckee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Lipsitch
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Maria Georgieva.

Ethics declarations

Competing interests

M.L. has received consulting income and/or honoraria from Affinivax, Antigen Discovery, Merck and Pfizer and has received institutional grant funding from Pfizer. The other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Georgieva, M., Buckee, C.O. & Lipsitch, M. Models of immune selection for multi-locus antigenic diversity of pathogens. Nat Rev Immunol 19, 55–62 (2019). https://doi.org/10.1038/s41577-018-0092-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-018-0092-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology