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:

Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity

Nature Microbiology volume 1, Article number: 16164 (2016) Cite this article

Subjects

Abstract

Vaccination has achieved remarkable successes in the control of childhood viral diseases. To control emerging infections, however, vaccines will need to be delivered to older individuals who, unlike infants, probably have had prior infection or vaccination with related viruses and thus have cross-reactive antibodies against the vaccines. Whether and how these cross-reactive antibodies impact live attenuated vaccination efficacy is unclear. Using an open-label randomized trial design, we show that subjects with a specific range of cross-reactive antibody titres from a prior inactivated Japanese encephalitis vaccination enhanced yellow fever (YF) immunogenicity upon YF vaccination. Enhancing titres of cross-reactive antibodies prolonged YF vaccine viraemia, provoked greater pro-inflammatory responses, and induced adhesion molecules intrinsic to the activating Fc-receptor signalling pathway, namely immune semaphorins, facilitating immune cell interactions and trafficking. Our findings clinically demonstrate antibody-enhanced infection and suggest that vaccine efficacy could be improved by exploiting cross-reactive antibodies.

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

Figure 1: Clinical trial overview.
Figure 2: Cross-reactive antibodies enhance YF vaccine infection to produce prolonged viraemia and improved immunogenicity.
Figure 3: Cross-reactive antibodies differentially regulate the production of inflammatory lipids and metabolites during YF vaccination.
Figure 4: Cross-reactive antibodies upregulate immune semaphorins via activating FcγR ligation.
Figure 5: Cross-reactive antibodies increase DC activation, migration and semaphorin expression for improved antigen presentation during YF vaccination.

Similar content being viewed by others

References

  1. Pike, B. L. et al. The origin and prevention of pandemics. Clin. Infect. Dis. 50, 1636–1640 (2010).

    Article  Google Scholar 

  2. Fauci, A. S. & Morens, D. M. Zika virus in the Americas—yet another arbovirus threat. N. Engl. J. Med. 374, 601–604 (2016).

    Article  Google Scholar 

  3. WHO Ebola Response Team. Ebola virus disease in West Africa—the first 9 months of the epidemic and forward projections. N. Engl. J. Med. 371, 1481–1495 (2014).

    Article  Google Scholar 

  4. D'Argenio, D. A. & Wilson, C. B. A decade of vaccines: integrating immunology and vaccinology for rational vaccine design. Immunity 33, 437–440 (2010).

    Article  CAS  Google Scholar 

  5. Rappuoli, R., Mandl, C. W., Black, S. & De Gregorio, E. Vaccines for the twenty-first century society. Nat. Rev. Immunol. 11, 865–872 (2011).

    Article  CAS  Google Scholar 

  6. Henao-Restrepo, A. M. et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 386, 857–866 (2015).

    Article  CAS  Google Scholar 

  7. Buchbinder, S. P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).

    Article  CAS  Google Scholar 

  8. Davenport, F. M., Hennessy, A. V. & Francis, T. Jr Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J. Exp. Med. 98, 641–656 (1953).

    Article  CAS  Google Scholar 

  9. Hadinegoro, S. R. et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N. Engl. J. Med. 373, 1195–1206 (2015).

    Article  CAS  Google Scholar 

  10. Villar, L. et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N. Engl. J. Med. 372, 113–123 (2015).

    Article  Google Scholar 

  11. Capeding, M. R. et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 384, 1358–1365 (2014).

    Article  CAS  Google Scholar 

  12. Halstead, S. B., Mahalingam, S., Marovich, M. A., Ubol, S. & Mosser, D. M. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect. Dis. 10, 712–722 (2010).

    Article  CAS  Google Scholar 

  13. Chan, K. R. et al. Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue. Proc. Natl Acad. Sci. USA 111, 2722–2727 (2014).

    Article  CAS  Google Scholar 

  14. Boonnak, K., Dambach, K. M., Donofrio, G. C., Tassaneetrithep, B. & Marovich, M. A. Cell type specificity and host genetic polymorphisms influence antibody-dependent enhancement of dengue virus infection. J. Virol. 85, 1671–1683 (2011).

    Article  CAS  Google Scholar 

  15. Campi-Azevedo, A. C. et al. Subdoses of 17DD yellow fever vaccine elicit equivalent virological/immunological kinetics timeline. BMC Infect. Dis. 14, 391 (2014).

    Article  Google Scholar 

  16. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

  17. Gaucher, D. et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J. Exp. Med. 205, 3119–3131 (2008).

    Article  CAS  Google Scholar 

  18. Querec, T. D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat. Immunol. 10, 116–125 (2009).

    Article  CAS  Google Scholar 

  19. McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. & Smith, K. G. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).

    Article  CAS  Google Scholar 

  20. Acuto, O. & Michel, F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat. Rev. Immunol. 3, 939–951 (2003).

    Article  CAS  Google Scholar 

  21. Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12, 180–190 (2012).

    Article  CAS  Google Scholar 

  22. Suzuki, K., Kumanogoh, A. & Kikutani, H. Semaphorins and their receptors in immune cell interactions. Nat. Immunol. 9, 17–23 (2008).

    Article  CAS  Google Scholar 

  23. Takamatsu, H. & Kumanogoh, A. Diverse roles for semaphorin-plexin signaling in the immune system. Trends Immunol. 33, 127–135 (2012).

    Article  CAS  Google Scholar 

  24. Kolodkin, A. L., Matthes, D. J. & Goodman, C. S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75, 1389–1399 (1993).

    Article  CAS  Google Scholar 

  25. Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).

    Article  CAS  Google Scholar 

  26. Suzuki, K. et al. Semaphorin 7A initiates T-cell-mediated inflammatory responses through α1β1 integrin. Nature 446, 680–684 (2007).

    Article  CAS  Google Scholar 

  27. van Rijn, A. et al. Semaphorin 7A promotes chemokine-driven dendritic cell migration. J. Immunol. 196, 459–468 (2016).

    Article  CAS  Google Scholar 

  28. Daynes, R. A., Dowell, T. & Araneo, B. A. Platelet-derived growth factor is a potent biologic response modifier of T cells. J. Exp. Med. 174, 1323–1333 (1991).

    Article  CAS  Google Scholar 

  29. Gavalas, N. G. et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br. J. Cancer 107, 1869–1875 (2012).

    Article  CAS  Google Scholar 

  30. Ziogas, A. C. et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int. J. Cancer 130, 857–864 (2012).

    Article  CAS  Google Scholar 

  31. Liu, Y. et al. Regulated expression of FcgammaR in human dendritic cells controls cross-presentation of antigen-antibody complexes. J. Immunol. 177, 8440–8447 (2006).

    Article  CAS  Google Scholar 

  32. Guzman, M. G. et al. Dengue hemorrhagic fever in Cuba, 1981: a retrospective seroepidemiologic study. Am. J. Trop. Med. Hyg. 42, 179–184 (1990).

    Article  CAS  Google Scholar 

  33. de Alwis, R. et al. Dengue viruses are enhanced by distinct populations of serotype cross-reactive antibodies in human immune sera. PLoS Pathogens 10, e1004386 (2014).

    Article  Google Scholar 

  34. Halstead, S. B. & O'Rourke, E. J. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med. 146, 201–217 (1977).

    Article  CAS  Google Scholar 

  35. Olkowski, S. et al. Reduced risk of disease during postsecondary dengue virus infections. J. Infect. Dis. 208, 1026–1033 (2013).

    Article  Google Scholar 

  36. Thanachartwet, V. et al. Identification of clinical factors associated with severe dengue among Thai adults: a prospective study. BMC Infect. Dis. 15, 420 (2015).

    Article  Google Scholar 

  37. Ben Mkaddem, S. et al. Shifting FcγRIIA-ITAM from activation to inhibitory conFig.uration ameliorates arthritis. J. Clin. Invest. 124, 3945–3959 (2014).

    Article  CAS  Google Scholar 

  38. Aloulou, M. et al. IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses. Blood 119, 3084–3096 (2012).

    Article  CAS  Google Scholar 

  39. Chan, K. R. et al. Ligation of Fc γ receptor IIB inhibits antibody-dependent enhancement of dengue virus infection. Proc. Natl Acad. Sci. USA 108, 12479–12484 (2011).

    Article  CAS  Google Scholar 

  40. Lennartz, M. R. & Brown, E. J. Arachidonic acid is essential for IgG Fc receptor-mediated phagocytosis by human monocytes. J. Immunol. 147, 621–626 (1991).

    CAS  PubMed  Google Scholar 

  41. Stachowska, E. et al. Conjugated linoleic acids can change phagocytosis of human monocytes/macrophages by reduction in Cox-2 expression. Lipids 42, 707–716 (2007).

    Article  CAS  Google Scholar 

  42. Middleton, M. K., Rubinstein, T. & Pure, E. Cellular and molecular mechanisms of the selective regulation of IL-12 production by 12/15-lipoxygenase. J. Immunol. 176, 265–274 (2006).

    Article  CAS  Google Scholar 

  43. Calder, P. C. & Grimble, R. F. Polyunsaturated fatty acids, inflammation and immunity. Eur. J. Clin. Nutr. 56(Suppl. 3), S14–S19 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Casanova, J. L. & Abel, L. The genetic theory of infectious diseases: a brief history and selected illustrations. Annu. Rev. Genom. Hum. Genet. 14, 215–243 (2013).

    Article  CAS  Google Scholar 

  46. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

    Article  CAS  Google Scholar 

  47. Goh, K. C. et al. Molecular determinants of plaque size as an indicator of dengue virus attenuation. Sci. Rep. 6, 26100 (2016).

    Article  CAS  Google Scholar 

  48. Jafari, H. et al. Polio eradication. Efficacy of inactivated poliovirus vaccine in India. Science 345, 922–925 (2014).

    Article  CAS  Google Scholar 

  49. Bass, J. W. et al. Booster vaccination with further live attenuated measles vaccine. JAMA 235, 31–34 (1976).

    Article  CAS  Google Scholar 

  50. Low, J. G. et al. The role of pre-existing cross-reactive antibodies in determining the efficacy of vaccination in humans: study protocol for a randomized controlled trial. Trials 16, 147 (2015).

    Article  Google Scholar 

  51. Domingo, C. et al. Advanced yellow fever virus genome detection in point-of-care facilities and reference laboratories. J. Clin. Microbiol. 50, 4054–4060 (2012).

    Article  Google Scholar 

  52. Cui, L. et al. Serum metabolome and lipidome changes in adult patients with primary dengue infection. PLoS Negl. Trop. Dis. 7, e2373 (2013).

    Article  Google Scholar 

  53. Hanson, B. J. et al. Passive immunoprophylaxis and therapy with humanized monoclonal antibody specific for influenza A H5 hemagglutinin in mice. Respir. Res. 7, 126 (2006).

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank C. Chua for technical assistance and also thank the research coordinators and nurses, G.K.Y. Li, E.Y.L. Lim and A.K.L. Shum. The authors thank E. Ong for her constructive review of this work. This work is supported by the Translational Clinical Research Programme of the Biomedical Research Council of Singapore. Y.B.C. was supported by the National Research Foundation, Singapore, under its Clinician Scientist Award (award no. NMRC/CSA/039/2012) administered by the Singapore Ministry of Health's National Medical Research Council.

Author information

Authors and Affiliations

  1. Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857,

    Kuan Rong Chan, Xiaohui Wang, Wilfried A. A. Saron, Esther Shuyi Gan, Hwee Cheng Tan, Summer Li-Xin Zhang, Soman N. Abraham, Ashley L. St John & Eng Eong Ooi

  2. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597,

    Darren Z. L. Mok & Eng Eong Ooi

  3. Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research & Technology (SMART), Singapore 138602,

    Yie Hou Lee, Cui Liang, Steven R. Tannenbaum & Eng Eong Ooi

  4. KK Research Centre, KK Women's and Children's Hospital, Singapore 229899,

    Yie Hou Lee

  5. Department of Infectious Diseases, Singapore General Hospital, Singapore 169856,

    Limin Wijaya & Jenny G. H. Low

  6. Centre for Computational Biology, Duke-NUS Medical School, Singapore 169857,

    Sujoy Ghosh

  7. Center for Quantitative Medicine, Duke-NUS Medical School, Singapore 169857,

    Yin Bun Cheung

  8. Department for International Health, University of Tampere, 33100, Finland

    Yin Bun Cheung

  9. Department of Biological Engineering and Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Steven R. Tannenbaum

  10. Department of Immunology and the Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Soman N. Abraham

Authors
  1. Kuan Rong Chan
    View author publications

    Search author on:PubMed Google Scholar

  2. Xiaohui Wang
    View author publications

    Search author on:PubMed Google Scholar

  3. Wilfried A. A. Saron
    View author publications

    Search author on:PubMed Google Scholar

  4. Esther Shuyi Gan
    View author publications

    Search author on:PubMed Google Scholar

  5. Hwee Cheng Tan
    View author publications

    Search author on:PubMed Google Scholar

  6. Darren Z. L. Mok
    View author publications

    Search author on:PubMed Google Scholar

  7. Summer Li-Xin Zhang
    View author publications

    Search author on:PubMed Google Scholar

  8. Yie Hou Lee
    View author publications

    Search author on:PubMed Google Scholar

  9. Cui Liang
    View author publications

    Search author on:PubMed Google Scholar

  10. Limin Wijaya
    View author publications

    Search author on:PubMed Google Scholar

  11. Sujoy Ghosh
    View author publications

    Search author on:PubMed Google Scholar

  12. Yin Bun Cheung
    View author publications

    Search author on:PubMed Google Scholar

  13. Steven R. Tannenbaum
    View author publications

    Search author on:PubMed Google Scholar

  14. Soman N. Abraham
    View author publications

    Search author on:PubMed Google Scholar

  15. Ashley L. St John
    View author publications

    Search author on:PubMed Google Scholar

  16. Jenny G. H. Low
    View author publications

    Search author on:PubMed Google Scholar

  17. Eng Eong Ooi
    View author publications

    Search author on:PubMed Google Scholar

Contributions

K.R.C., J.G.H.L., S.N.A. and E.E.O. conceptualized and designed the study. J.G.H.L., L.W. and X.W. enrolled the subjects of the trial. K.R.C., H.C.T., X.W., E.S.G. and D.Z.L.M. performed the biochemical and in vitro experiments. C.L. and Y.H.L. performed the lipid and cytokine profiling. K.R.C., E.S.G. and S.G. performed the transcriptomic analysis. S.L.-X.Z. generated and characterized the primary dendritic cells. W.A.A.S. and A.L.S. designed and performed the mouse experiments. Y.B.C. designed the clinical trial and performed the data analysis methods and interpretation. K.R.C., J.G.H.L., Y.H.L., S.R.T., Y.B.C., A.L.S., S.N.A. and E.E.O. analysed the data. K.R.C. and E.E.O. wrote the first version of the manuscript. K.R.C., J.G.H.L., Y.H.L., Y.B.C., A.L.S., S.N.A. and E.E.O. reviewed and revised the manuscript.

Corresponding authors

Correspondence to Jenny G. H. Low or Eng Eong Ooi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Figures 1–7, Supplementary Tables 1–6 (PDF 4697 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chan, K., Wang, X., Saron, W. et al. Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity. Nat Microbiol 1, 16164 (2016). https://doi.org/10.1038/nmicrobiol.2016.164

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/nmicrobiol.2016.164

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