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.

  • Article
  • Published:

Effects of epistasis and recombination between vaccine-escape and virulence alleles on the dynamics of pathogen adaptation

Nature Ecology & Evolution volume 6, pages 786–793 (2022)Cite this article

Subjects

Abstract

Pathogen adaptation to public health interventions such as vaccination may take tortuous routes and involve multiple mutations at different locations in the pathogen genome, acting on distinct phenotypic traits. Yet how these multi-locus adaptations jointly evolve is poorly understood. Here we consider the joint evolution of two adaptations: pathogen escape from the vaccine-induced immune response and adjustments to pathogen virulence affecting transmission or clearance. We elucidate the role played by epistasis and recombination, with an emphasis on the different protective effects of vaccination. We show that vaccines blocking infection, reducing transmission and/or increasing clearance generate positive epistasis between the vaccine-escape and virulence alleles, favouring strains that carry both mutations, whereas vaccines reducing virulence mortality generate negative epistasis, favouring strains that carry either mutation but not both. High rates of recombination can affect these predictions. If epistasis is positive, frequent recombination can prevent the transient build-up of more virulent escape strains. If epistasis is negative, frequent recombination between loci can create an evolutionary bistability, favouring whichever adaptation is more accessible. Our work provides a timely alternative to the variant-centred perspective on pathogen adaptation and captures the effect of different types of vaccine on the interference between multiple adaptive mutations.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Schematic of the epidemiological model and the evolutionary model.
Fig. 2: Fitness landscape at the strain NA equilibrium.
Fig. 3: Negative epistasis and recombination can lead to evolutionary bistability.
Fig. 4: Positive epistasis and the evolution of virulence.

Similar content being viewed by others

Data availability

No data were used for this manuscript.

Code availability

All custom code used to generate the figures in the main text and Supplementary Information was written in MATLAB74 and is available as Supplementary Software.

References

  1. McLean, A. R. Vaccines and their impact on the control of disease. Br. Med. Bull. 54, 545–556 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Kennedy, D. A. & Read, A. F. Why does drug resistance readily evolve but vaccine resistance does not?. Proc. R. Soc. B 284, 20162562 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kennedy, D. A. & Read, A. F. Why the evolution of vaccine resistance is less of a concern than the evolution of drug resistance. Proc. Natl Acad. Sci. USA 115, 12878–12886 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McLean, A. R. Vaccination, evolution and changes in the efficacy of vaccines: a theoretical framework. Proc. R. Soc. B 261, 389–393 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Gupta, S., Ferguson, N. M. & Anderson, R. M. Vaccination and the population structure of antigenically diverse pathogens that exchange genetic material. Proc. R. Soc. B 264, 1435–1443 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lipsitch, M. Vaccination against colonizing bacteria with multiple serotypes. Proc. Natl Acad. Sci. USA 94, 6571–6576 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Restif, O. & Grenfell, B. T. Vaccination and the dynamics of immune evasion. J. R. Soc. Interface 4, 143–153 (2007).

    Article  PubMed  Google Scholar 

  8. van Boven, M., Mooi, F. R., Schellekens, J. F. P., de Melker, H. E. & Kretzschmar, M. Pathogen adaptation under imperfect vaccination: implications for pertussis. Proc. R. Soc. B 272, 1617–1624 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gandon, S., Mackinnon, M. J., Nee, S. & Read, A. F. Imperfect vaccines and the evolution of pathogen virulence. Nature 414, 751–756 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Gandon, S., Mackinnon, M., Nee, S. & Read, A. F. Imperfect vaccination: some epidemiological and evolutionary consequences. Proc. R. Soc. B 270, 1129–1136 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Andre, J. & Gandon, S. Vaccination, within-host dynamics, and virulence evolution. Evolution 60, 13–23 (2006).

    Article  PubMed  Google Scholar 

  12. Atkins, K. E. et al. Vaccination and reduced cohort duration can drive virulence evolution: Marek’s disease virus and industrialized agriculture. Evolution 67, 851–860 (2012).

    Article  PubMed  Google Scholar 

  13. Ganusov, V. V. & Antia, R. Imperfect vaccines and the evolution of pathogens causing acute infections in vertebrates. Evolution 60, 957–969 (2006).

    Article  PubMed  Google Scholar 

  14. Williams, P. D. & Day, T. Epidemiological and evolutionary consequences of targeted vaccination. Mol. Ecol. 17, 485–499 (2008).

    Article  PubMed  Google Scholar 

  15. Bernhauerová, V. Vaccine-driven evolution of parasite virulence and immune evasion in age-structured population: the case of pertussis. Theor. Ecol. 9, 431–442 (2016).

    Article  Google Scholar 

  16. Anderson, R. M. & May, R. M. Coevolution of hosts and parasites. Parasitology 85, 411–426 (1982).

    Article  PubMed  Google Scholar 

  17. Frank, S. A. Models of parasite virulence. Q. Rev. Biol. 71, 37–78 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Alizon, S., Hurford, A., Mideo, N. & van Baalen, M. Virulence evolution and the trade-off hypothesis: history, current state of affairs and the future. J. Evol. Biol. 22, 245–259 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Cressler, C. E., McLeod, D. V., Rozins, C., van den Hoogen, J. & Day, T. The adaptive evolution of virulence: a review of theoretical predictions and empirical tests. Parasitology 143, 915–930 (2016).

    Article  PubMed  Google Scholar 

  20. Witter, R. L. Increased virulence of Marek’s disease virus field isolates. Avian Dis. 41, 149–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Read, A. F. et al. Imperfect vaccination can enhance the transmission of highly virulent pathogens. PLoS Biol. 13, e1002198 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Read, A. F. & Mackinnon, M. J. in Evolution in Health and Disease (eds Stearns, S. C. & Koella, J. C.) Ch. 11 (Oxford Univ. Press, 2008).

  23. Mackinnon, M. J. & Read, A. F. Immunity promotes virulence evolution in a malaria model. PLoS Biol. 2, 1286–1292 (2004).

    Article  CAS  Google Scholar 

  24. Barclay, V. C. et al. The evoutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi. PLoS Biol. 10, e1001368 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mooi, F. R. et al. Bordetella pertussis strains with increased toxin production associated with pertussis resurgence. Emerg. Infect. Dis. 15, 1206–1213 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Grenfell, B. T. et al. Unifying the epidemiological and evolutionary dynamics of pathogens. Science 303, 327–323 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Saad-Roy, C. M. et al. Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes. Science 372, 363–370 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cobey, S., Larremore, D. B., Grad, Y. H. & Lipsitch, M. Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00544-9 (2021).

  29. Kouyos, R. D. et al. The path of least resistance: aggressive or moderate treatment? Proc. R. Soc. B 281, 20140566 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Acevedo, M. A., Dillemuth, F. P., Flick, A. J., Faldyn, M. J. & Elderd, B. D. Virulence-driven trade-offs in disease transmission: a meta-analysis. Evolution 73, 636–647 (2019).

    Article  PubMed  Google Scholar 

  31. Telenti, A. et al. After the pandemic: perspectives on the future trajectory of COVID-19. Nature 596, 495–504 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Slatkin, M. Linkage disequilibrium—understanding the evolutionary past and mapping the medical future. Nat. Rev. Genetics 9, 477–485 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Rice, S. H. Evolutionary Theory: Mathematical and Conceptual Foundations (Sinauer Associates, 2004).

  34. Day, T. & Gandon, S. The evolutionary epidemiology of multilocus drug resistance. Evolution 66, 1582–1597 (2012).

    Article  PubMed  Google Scholar 

  35. McLeod, D. V. & Gandon, S. Understanding the evolution of multiple drug resistance in structured populations. eLife 10, e65645 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Visser, J. A. G. M., Cooper, T. F. & Elena, S. F. The causes of epistasis. Proc. R. Soc. B 278, 3671–3624 (2011).

    Article  Google Scholar 

  37. Felsenstein, J. The effect of linkage on directional selection. Genetics 52, 349–363 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lewontin, R. C. & Kojima, K. The evolutionary dynamics of complex polymorphisms. Evolution 14, 458–472 (1960).

    Google Scholar 

  39. de Visser, J. A. G. M. & Elena, S. F. The evolution of sex: empirical insights into the roles of epistasis and drift. Nat. Rev. Genetics 8, 139–149 (2007).

    Article  PubMed  Google Scholar 

  40. Otto, S. P. & Barton, N. H. The evolution of recombination: removing the limits to natural selection. Genetics 147, 879–906 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fenner, F. J. The Florey lecture, 1983—biological control, as exemplified by smallpox eradication and myxomatosis. Proc. R. Soc. B 218, 259–285 (1983).

    CAS  Google Scholar 

  42. Muñoz-Alía, M. Á., Nace, R. A., Zhang, L. & Russell, S. J. Serotypic evolution of measles virus is constrained by multiple co-dominant B cell epitopes on its surface glycoproteins. Cell Rep. Med. 2, 100225 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kouyos, R. D., Fouchet, D. & Bonhoeffer, S. Recombination and drug resistance in HIV: population dynamics and stochasticity. Epidemics 1, 58–69 (2009).

    Article  PubMed  Google Scholar 

  44. Gandon, S. & Day, T. The evolutionary epidemiology of vaccination. J. R. Soc. Interface 4, 803–817 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Maynard Smith, J. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23–35 (1974).

    Article  Google Scholar 

  46. Harrison, T. J., Hopes, E. A., Oon, C. J., Zanetti, A. R. & Zuckerman, A. J. Independent emergence of a vaccine-induced escape mutant of hepatitis B virus. J. Hepatology 13, S105–S107 (1991).

    Article  CAS  Google Scholar 

  47. Mooi, F. R. et al. Polymorphism in the Bordetella pertussis virulence factors P.69/Pertactin and pertussis toxin in the Netherlands: temporal trends and evidence for vaccine-driven evolution. Infect. Immun. 66, 670–675 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gandon, S. & Day, T. Evidences of parasite evolution after vaccination. Vaccine 26, C4–C7 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Pica, N. & Palese, P. Toward a universal influenza virus vaccine: prospects and challenges. Annu. Rev. Med. 64, 189–202 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Subramanian, R., Graham, A. L., Grenfell, B. T. & Arinaminpathy, N. Universal or specific? A modeling-based comparison of broad-spectrum influenza vaccines against conventional, strain-matched vaccines. PLoS Comput. Biol. 12, e1005204 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Viboud, C. et al. Beyond clinical trials: evolutionary and epidemiological considerations for development of a universal influenza vaccine. PLoS Pathog. 16, e1008583 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Arinaminpathy, N. et al. Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza. Proc. Natl Acad. Sci. USA 109, 3173–3177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Saad-Roy, C. M., McDermott, A. B. & Grenfell, B. T. Dynamic perspectives on the search for a universal influenza vaccine. J. Infect. Dis. 219, S46–S56 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Arinaminpathy, N., Riley, S., Barclay, W. S., Saad-Roy, C. & Grenfell, B. Population implications of the deployment of novel universal vaccines against epidemic and pandemic influenza. J. R. Soc. Interface 17, 20190879 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ekiert, D. C. et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246–251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Epstein, S. L. & Price, G. E. Cross-protective immunity to influenza A viruses. Expert Rev. Vaccines 9, 1325–1341 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Yurkovetskiy, L. et al. Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Cell 183, 739–751.e8 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ozono, S. et al. SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. Nat. Commun. 12, 848 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jangra, S. et al. SARS-CoV-2 spike E484K mutation reduces antibody neutralisation. Lancet Microbe 2, E283–E284 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Greaney, A. J. et al. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. bioRxiv https://doi.org/10.1101/2021.03.17.435863 (2021).

  62. Peck, K. M., Burch, C. L., Heise, M. T. & Baric, R. S. Coronavirus host range expansion and Middle East respiratory syndrome coronavirus emergence: biochemical mechanisms and evolutionary perspectives. Annu. Rev. Virol. 2, 95–117 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Jackson, B. et al. Generation and transmission of inter-lineage recombinants in the SARS-CoV-2 pandemic. Cell https://doi.org/10.1016/j.cell.2021.08.014 (2021).

  64. Turkahia, Y. Pandemic-scale phylogenomics reveals elevated recombination rates in the SARS-CoV-2 spike region. bioRxiv https://doi.org/10.1101/2021.08.04.455157 (2021).

  65. VanInsberghe, D., Neish, A. S., Lowen, A. C. & Koelle, K. Recombinant SARS-CoV-2 genomes circulated at low levels over the first year of the pandemic. Virus Evol. https://doi.org/10.1093/ve/veab059 (2021).

  66. Can we predict the limits of SARS-CoV-2 variants and their phenotypic consequences? (UK SAGE, 2021); https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1007566/S1335_Long_term_evolution_of_SARS-CoV-2.pdf

  67. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    Article  CAS  PubMed  Google Scholar 

  68. Dagan, N. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N. Engl. J. Med. 384, 1412–1423 (2021).

    Article  CAS  PubMed  Google Scholar 

  69. Regev-Yochay, G. et al. Decreased infectivity following BNT162b2 vaccination: a prospective cohort study in Israel. Lancet Reg. Health Eur. 7, 100150 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ke, R. et al. Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution. medRxiv https://doi.org/10.1101/2021.08.30.21262701 (2021).

  71. Thompson, M. G. et al. Prevention and attenuation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines. N. Engl. J. Med. 385, 320–329 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Baker, R. E. et al. The impact of COVID-19 nonpharmaceutical interventions on the future dynamics of endemic infections. Proc. Natl Acad. Sci. USA 117, 30547–30553 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gandon, S. & Lion, S. Targeted vaccination and the speed of SARS-CoV-2 adaptation. Proc. Natl Acad. Sci. USA 119, e2110666119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. MATLAB v. 9.6.0 (R2019a) (The MathWorks Inc., 2019).

Download references

Acknowledgements

This work was supported by a NSERC-CRSNG postdoctoral fellowship to D.V.M. S.G. acknowledges financial support from the CNRS and from Agence Nationale de la Recherche (ANR-17-CE35-0012).

Author information

Authors and Affiliations

  1. CEFE, CNRS, Univ Montpellier, EPHE, IRD, Montpellier, France

    David V. McLeod & Sylvain Gandon

  2. Institute of Ecology and Evolution, Universität Bern, Bern, Switzerland

    David V. McLeod

  3. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    David V. McLeod

Authors
  1. David V. McLeod
    View author publications

    Search author on:PubMed Google Scholar

  2. Sylvain Gandon
    View author publications

    Search author on:PubMed Google Scholar

Contributions

D.V.M. and S.G. formulated the research question, designed and analysed the model and wrote the manuscript.

Corresponding authors

Correspondence to David V. McLeod or Sylvain Gandon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Ecology & Evolution thanks Ana Bento and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Supplementary information

Supplementary Information

Supplementary Discussion 1–10 and Figs. 1–6.

Supplementary Software

All custom code to make figures featured in main text and supplementary information.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McLeod, D.V., Gandon, S. Effects of epistasis and recombination between vaccine-escape and virulence alleles on the dynamics of pathogen adaptation. Nat Ecol Evol 6, 786–793 (2022). https://doi.org/10.1038/s41559-022-01709-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41559-022-01709-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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