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Safety and Immunogenicity of a Tetravalent Live-attenuated Dengue Vaccine in Flavivirus Naive Children

A live-attenuated tetravalent dengue virus (DENV) vaccine candidate has been well tolerated and immunogenic in healthy, US flavivirus naive adult volunteers. We conducted a pilot, safety, and immunogenicity trial of the vaccine candidate in healthy Thai children (6–7 years of age) to prepare for its eventual evaluation in Thai infants. In an uncontrolled, open clinical trial, the investigational vaccine was administered on study Days 0 and 180 to seven volunteers residing in Bangkok without neutralizing antibodies to DENV1–4 or to Japanese encephalitis virus (JEV). Clinical and laboratory safety assessments were completed during the 30 days after each vaccine dose, and immunogenicity was determined at Day 30. In this study, the vaccine was well tolerated with no serious adverse events or alert laboratory values. One volunteer experienced fever (38.2°C, < 2 days) and associated DENV4 vaccine viremia 7 days after Dose 2. One month after Dose 2, six volunteers in the per-protocol analysis exhibited a tetravalent neutralizing antibody response with DENV1–4 geometric mean titers of 55, 475, 350, and 171, respectively. Ten weeks (~75 days) after Dose 2, five of the six volunteers continued to exhibit a tetravalent neutralizing antibody profile; one volunteer’s DENV4 PRNT₅₀ titer fell below the assay cut-off (29 < 10); (clinicaltrials.gov NCT00384670).

Received June 28, 2007. Accepted for publication December 15, 2007.

Acknowledgments: The authors thank the volunteers, their parents, and the medical staff of the Department of Pediatrics at Phramongkutklao Hospital (Bangkok, Thailand) for valuable participation in this study. Chanchai Aree provided study coordination and Drs Rudiwilai Samakoses and Angkool Kerdpanich provided medical support. The support of the teachers and administrators of the Wat Samian Naree primary school (Bangkok, Thailand) was invaluable. The authors thank the technical, quality control, and logistics staff of the Department of Virology, Armed Forces Research Institute of Medical Sciences (Bangkok, Thailand) Department of Virology and the Pilot Bioproduction Facility, Walter Reed Army Institute of Research (Silver Spring, MD) for performing laboratory assays to support the study and coordination of study activities. The authors thank Dr Suchitra Nimmannitya, who was the study’s medical monitor, and the following members of the study’s Independent Data Monitoring Committee: Drs Prayura Kunasol (chairperson), Nadhirat Sangkawibha, Pricha Singharaj, Kamnuan Ungchusak, and Pote Aimpun. Priya Pavithran and Dr Roselynn Tien (GSK) assisted in writing this report. The authors acknowledge the leadership of the United States Army Medical Materiel Development Activity, Dengue Product Manager Charles E. English, PhD, and GlaxoSmithKline dengue vaccine project managers Drs. Beth-Ann Coller and Yves Lobet.

Financial support: This work was funded by the United States Army Medical Research and Materiel Command (Fort Detrick, Frederick, MD) and GlaxoSmithKline Biologicals (Rixensart, Belgium).

Disclosure: Some of the authors are employed by the GlaxoSmithKline Group of Companies or are listed as inventors on the patent. This statement is made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the official views of the United States Army, Royal Thai Army, or the US Department of Defense.

^* Address correspondence to Stephen J. Thomas, USAMC-AFRIMS, APO AP, 96546, Thailand. E-mail: stephen.thomas{at}afrims.org

Authors’ addresses: Sriluck Simasathien, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand, Telephone: 662-6448971, Fax: 662-6444135, E-mail: ssriluck{at}hotmail.com. Stephen J. Thomas, USAMC-AFRIMS, APO AP, 96546, Thailand, Telephone: 662-644-5644, E-mail: stephen.thomas{at}afrims.org. Veerachai Watanaveeradej, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand, Telephone: 66-2-644-8971, Fax: 66-2-644-4135, E-mail: veerachaiw{at}yahoo.com. Ananda Nisalak, Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, Telephone: 662-644-5644, Fax: 662-644-4760, E-mail: ananda.nisalak{at}afrims.org. Célia Barberousse, GlaxoSmithKline Biologicals, Rixensart, Belgium, Telephone: 32-2-656-65-96, E-mail: celia.barberousse{at}gsk.com. Bruce L. Innis, GlaxoSmithKline, King of Prussia, PA, Telephone: 610-787-3105, Fax: 610-787-7057, E-mail: bruce.2.innis{at}gsk.com. Wellington Sun, Dengue Branch Division of Vector-borne Infectious Diseases Centers for Disease Control and Prevention, 1324 Calle Canada, San Juan, Puerto Rico 00920, Telephone: 787-706-2399, Fax: 787-706-2496, E-mail: WSun{at}cdc.gov or wks4{at}cdc.gov. J. Robert Putnak, Division of Viral Diseases, Walter Reed Army Institute of Research, Silver Spring, MD 20910, Telephone: 301-319-9426, Fax: 301-319-9661, E-mail: robert.putnak{at}amedd.army.mil. Kenneth H. Eckels, Division of Regulated Activities, Pilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, MD 20910, Telephone: 301-319-9233, E-mail: kenneth.eckels{at}amedd.army.mil. Yanee Hutagalung, Glaxo-SmithKline, Bangkok, Thailand, Telephone: 662-659-3060, Fax: 662-659-3147, E-mail: yanee.hutagalung{at}gsk.com. Robert V. Gibbons, Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, Telephone: 662-644-5644, Fax: 662-644-4760, E-mail: Robert.gibbons{at}afrims.org. Chunlin Zhang, Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, Telephone: 301-619-7891, Fax: 301-619-2416, E-mail: chunlin.zhang{at}amedd.army.mil. Rafael De La Barrera, Division of Regulated Activities, Pilot Bioproduction Facility, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, Telephone: 301-319-9052, Fax: 301-319-9180, E-mail: rafael.delabarrera{at}na.amedd.army.mil. Richard G. Jarman, Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, Telephone: 662-644-5644, Fax: 662-644-4760, E-mail: Richard.jarman{at}afrims.org. Wipa Chawachalasai, Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, Telephone: 662-644-5644, Fax: 662-644-4760, E-mail: Wipac{at}afrims.org. Mammen P. Mammen Jr., Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, Telephone: 301-619-2069, Fax: 301-619-2304, E-mail: mammen.mammen{at}amedd.army.mil.