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.

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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.

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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, Massachusetts 02139, USA

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

    • Soman N. Abraham

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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DOI

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

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