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:

Varicella vaccination: Evidence for frequent reactivation of the vaccine strain in healthy children

Nature Medicine volume 6, pages 451–454 (2000)Cite this article

Abstract

Wild-type varicella zoster virus (VZV) causes chickenpox, a common childhood illness characterized by fever and a vesicular rash1 and rare serious complications2. Wild-type VZV persists in a latent form in the sensory ganglia, and can re-activate to cause herpes zoster3. More than 10 million American children have received the live attenuated Oka strain VZV vaccine (OkaVZV) since its licensure in 1995. Pre-licensure clinical studies showed that mean serum anti-VZV levels among vaccinees continued to increase with time after vaccination. This was attributed to immunologic boosting caused by exposure to wild-type VZV in the community4,5. Here, we examine the alternative, that large-scale asymptomatic reactivation of OkaVZV might occur in vaccinees. We analyzed serum antibody levels and infection rates for 4 years of follow-up in 4,631 children immunized with OkaVZV. Anti-VZV titers decreased over time in high-responder subjects, but rose in vaccinees with low titers. Among subjects with low anti-VZV titers, the frequency of clinical infection and immunological boosting substantially exceeded the 13%-per-year rate of exposure to wild-type varicella. These findings indicate that OkaVZV persisted in vivo and reactivated as serum antibody titers decreased after vaccination. This has salient consequences for individuals immunized with OkaVZV.

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

Figure 1: Antibody titers were obtained from seronegative vaccinees 6 weeks after immunization and yearly thereafter.

Similar content being viewed by others

References

  1. Cohen, J.I., Brunell, P.A., Straus, S.E. & Krause, P.R. NIH conference: Recent advances in varicella-zoster virus infection. Ann. Intern. Med. 130, 922–932 (1999).

    Article  CAS  Google Scholar 

  2. Wharton, M. The epidemiology of varicella-zoster virus infections. Infect. Dis. Clin. North. Am. 10, 571–581 (1996).

    Article  CAS  Google Scholar 

  3. Straus, S.E. et al. Endonuclease analysis of viral DNA from varicella and subsequent zoster infections in the same patient. N. Engl. J. Med. 311, 1362–1364 (1984).

    Article  CAS  Google Scholar 

  4. Asano, Y., et al Experience and reason: Twenty-year follow-up of protective immunity of the Oka strain live varicella vaccine. Pediatrics 94, 524–526 (1994).

    CAS  PubMed  Google Scholar 

  5. Krause, P.R. & Klinman, D.M. Efficacy, immunogenicity, safety, and use of live attenuated chickenpox vaccine. J. Pediatr. 127, 518–525 (1995).

    Article  CAS  Google Scholar 

  6. Weibel, R.E., J, N.B. & Kuter, B.J. Live attenuated varicella vaccine: efficacy trial in healthy children. N. Engl. J. Med. 310, 1409– 1415 (1984).

    Article  CAS  Google Scholar 

  7. Kuter, B. et al. Oka/Merck varicella vaccine in healthy children: final report of a 2-year efficacy study and 7-year follow-up studies. Vaccine 9, 643–647 ( 1991).

    Article  CAS  Google Scholar 

  8. Choo, P.W., Donahue, J.G., Manson, J.E. & Platt, R. The epidemiology of varicella and its complications. J. Infect. Dis. 172, 706–712 ( 1995).

    Article  CAS  Google Scholar 

  9. Finger, R., Hughes, J., Meade, B., Pelletier, A. & Palmer, C. Age-specific incidence of chickenpox. Public Health Rep. 109, 750–755 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bernstein, H.H. et al. Clinical survey of natural varicella compared with breakthrough varicella after immunization with live attenuated Oka/Merck varicella vaccine . Pediatrics 92, 833–83 (1993).

    CAS  PubMed  Google Scholar 

  11. Varis, T. & Vesikari, T. Efficacy of high-titer live attenuated varicella vaccine in healthy young children. J. Infect. Di. 174, S330–4 (1996).

    Article  Google Scholar 

  12. Luby, J., Ramirez-Ronda, C., Rinner, S., Hull, A. & Vergne-Marini, P. Alongitudinal study of varicella-zoster virus infections in renal transplant recipients. J. Infect. Dis. 135, 659–663 ( 1977).

    Article  CAS  Google Scholar 

  13. Arvin, A., Koropchak, C. & Wittek, A. Immunologic Evidence of re-infection with varicella-zoster virus. J. Infect. Dis. 148, 200– 205 (1983).

    Article  CAS  Google Scholar 

  14. Tomita, H., Tanaka, M., Kukimoto, N. & Ikeda, M. An ELISA study on varicella-zoster virus infection in acute peripheral facial palsy. Acta Otolaryngol. (Stockh.) 446, 10– 16 (1988).

    CAS  Google Scholar 

  15. Scheiermann, N. & Gesemann, M. Anti-HBs antibody kinetics - A 4 year follow-up after hepatitis B vaccination. Zentralbl. Bakteriol. 278, 120–126 (1993).

    Article  CAS  Google Scholar 

  16. Hope-Simpson, R.E. The nature of herpes zoster: a long-term study and a new hypothesis. Proc. R. Soc. Lond. 58, 9–20 (1965).

    CAS  Google Scholar 

  17. Ljungman, P. et al. Clinical and subclinical reactivation of varicella-zoster virus in immunocompromised patients. J. Infect. Dis. 153, 840–847 (1986).

    Article  CAS  Google Scholar 

  18. Wilson, A., Sharp, M., Koropchak, C.M., Ting, S.F. & Arvin, A.M. Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J. Infect. Dis. 165, 119–26 (1992).

    Article  CAS  Google Scholar 

  19. Merck & Co. in Physician's Desk Reference 52nd edn. 1762–1765 (Medical Economics, Montvale, New Jersey, 1998).

  20. Brunell, P.A., Taylor, J., Geiser, C.F., Frierson, L. & Lydick, E. Risk of herpes zoster in children with leukemia: varicella vaccine compared with history of chickenpox. Pediatrics 77, 53–65 (1986).

    CAS  PubMed  Google Scholar 

  21. Hardy, I., Gershon, A.A., Steinberg, S.P. & LaRussa, P. The incidence of zoster after immunization with live attenuated varicella vaccine. N. Engl. J. Med. 325, 1545– 1550 (1991).

    Article  CAS  Google Scholar 

  22. Wasmuth, E.H. & Miller, W.J. Sensitive ELISA for antibody to varicella-zoster virus using purified VZV glycoprotein antigen. J. Med. Virol. 32, 189–193 (1990).

    Article  CAS  Google Scholar 

  23. Keller, P.M., Lonergan, K., Neff, B.J., Morton, D.A. & Ellis, R.W. Purification of individual varicella-zoster virus (VZV) glycoproteins gpI, gpII, and gpIII and their use in ELISA for detection of V ZV glycoprotein-specific antibodies. J. Virol. Meth. 14, 177–188 (1986).

    Article  CAS  Google Scholar 

  24. Colton, T. in Statistics in Medicine 153–159 (Little, Brown, Boston, 1974).

    Google Scholar 

Download references

Acknowledgements

We thank P., Patriarca, A., Rosenberg, F., Steinberg and W., Egan for their critical review of this manuscript. We also thank M. Gesemann for providing raw data from a 4-year follow-up of recipients of hepatitis B vaccine. The assertions herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the Food and Drug Administration.

Author information

Authors and Affiliations

  1. Laboratory of DNA Viruses,

    Philip R. Krause

  2. Division of Viral Products Center for Biologics Evaluation and Research, Section of Retroviral Research, Food and Drug Administration, Bethesda, 20892, Maryland, USA

    Dennis M. Klinman

Authors
  1. Philip R. Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dennis M. Klinman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip R. Krause.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krause, P., Klinman, D. Varicella vaccination: Evidence for frequent reactivation of the vaccine strain in healthy children. Nat Med 6, 451–454 (2000). https://doi.org/10.1038/74715

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/74715

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