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1 March 2005

Volume 191, Number 5
The Journal of Infectious Diseases 2005;191:710–718
© 2005 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2005/19105-0009$15.00
DOI: 10.1086/427780
MAJOR ARTICLE

rDEN4Δ30, a Live Attenuated Dengue Virus Type 4 Vaccine Candidate, Is Safe, Immunogenic, and Highly Infectious in Healthy Adult Volunteers

Anna P. Durbin,1

Stephen S. Whitehead,2

Julie McArthur,1

John R. Perreault,1

Joseph E. Blaney, Jr.,2

Bhavin Thumar,1

Brian R. Murphy,2 and

Ruth A. Karron1

1Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, and 2Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Background.The live attenuated dengue virus type 4 (DEN‐4) vaccine candidate virus rDEN4Δ30 was previously found to be safe and immunogenic at a dose of 105 plaque‐forming units (pfu).

Methods.In a follow‐up placebo‐controlled phase 2 clinical trial, rDEN4Δ30 was administered as a single inoculation to 3 separate dose cohorts (103 pfu, 102 pfu, or 101 pfu), for further evaluation. Each dose cohort consisted of 20 vaccinees and 4 placebo recipients. Volunteers were monitored closely for adverse events, and serum was collected on study days 28 and 42 for determination of neutralizing antibody titer.

Results.The vaccine was well tolerated at all doses studied. The most common adverse events observed were a transient asymptomatic rash in >50% of vaccinees and a mild neutropenia in 20% of vaccinees. No vaccinee developed a dengue‐like illness. The vaccine was highly infectious and immunogenic, with 95%–100% of vaccinees in each dose cohort developing a 4‐fold increase in titers of serum neutralizing antibodies against DEN‐4.

Conclusions.The rDEN4Δ30 vaccine is safe and induced an antibody response that was broadly neutralizing against genotypically diverse DEN‐4 viruses. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation.

Received 27 July 2004; accepted 8 October 2004; electronically published 27 January 2005.

  • (See the editorial commentary by Edelman, on pages 647–9.)

Reprints or correspondence: Dr. Anna P. Durbin, Center for Immunization Research, Dept. of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 ().

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Annelies Wilder-Smith, Jacqueline L Deen. (2008) Dengue vaccines for travelers. Expert Review of Vaccines 7:5, 569-578
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Rebecca Ward, Andrew D Davidson. (2008) Reverse genetics and the study of dengue virus. Future Virology 3:3, 279-290
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Chih-Yun Lai, Hsien-Ping Hu, Chwan-Chuen King, Wei-Kung Wang. (2008) Incorporation of dengue virus replicon into virus-like particles by a cell line stably expressing precursor membrane and envelope proteins of dengue virus type 2. Journal of Biomedical Science 15:1, 15-27
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Stephen S. Whitehead, Joseph E. Blaney, Anna P. Durbin, Brian R. Murphy. (2007) Prospects for a dengue virus vaccine. Nature Reviews Microbiology 5:7, 518-528
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Robert Edelman. (2007) Dengue Vaccines Approach the Finish Line. Clinical Infectious Diseases 45:s1, S56-S60
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Joseph E. Blaney, Anna P. Durbin, Brian R. Murphy, Stephen S. Whitehead. (2006) Development of a Live Attenuated Dengue Virus Vaccine Using Reverse Genetics. Viral Immunology 19:1, 10-32
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Konstantin V Pugachev, Farshad Guirakhoo, Thomas P Monath. (2005) New developments in flavivirus vaccines with special attention to yellow fever. Current Opinion in Infectious Diseases 18:5, 387???394
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Robert Edelman. (2005) Dengue and Dengue Vaccines. The Journal of Infectious Diseases 191:5, 650-653
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  • Presented in part: American Society of Tropical Medicine and Hygiene Annual Meeting, Philadelphia, 3–6 December 2003 (abstract 379).

    Potential conflicts of interest: The rDEN4Δ30 vaccine candidate has been patented by the National Institute of Allergy and Infectious Diseases (NIAID), the institute with which B.R.M., S.S.W., and J.E.B. are affiliated. Through the execution of licensing agreements, the NIAID makes the rDEN4Δ30 vaccine candidate available to parties interested in its further development and commercialization.

    Financial support: National Institutes of Health (contract N01A115444).

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