Pediatr Infect Dis J, 2004;23:99–109 Vol. 23, No. 2 Copyright © 2004 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. Safety and immunogenicity of a three dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-year-old Thai children ARUNEE SABCHAREON, MD, JEAN LANG, MD, PHD, PORNTHEP CHANTHAVANICH, MD, SUTEE YOKSAN, MD, PHD, REMI FORRAT, MD, PHANORSI ATTANATH, MSC, CHUKIATE SIRIVICHAYAKUL, MD, KRISANA PENGSAA, MD, CHANATHEP POJJAROEN-ANANT, MSC, LAURENT CHAMBONNEAU, MSC, JEAN-FRANCOIS SALUZZO, PHD AND NATTH BHAMARAPRAVATI, MD, DSC Objective. The safety and immunogenicity of tetravalent live-attenuated dengue vaccines af- ter a three dose vaccination series were evalu- ated in Thai children. Method. One hundred three healthy flavivirus- seronegative schoolchildren ages 5 to 12 years were randomized to receive either dengue vac- cine containing 3, 2, 1 and 2 log 10 of the 50% cell culture infective dose, respectively, of the live- attenuated dengue vaccine serotypes 1, 2, 3 and 4 per dose (F3212; n  40) or 3, 3, 1 and 3 log 10 of the 50% cell culture infective dose (F3313; n  42) or purified Vero cell rabies vaccine (control group; n  21) given in a two dose schedule (3 to 5 months apart). A third dose was administered 8 to 12 months after the second dose to 90 subjects. Safety and immunogenicity were evaluated within 28 days after each injection. Results. No serious adverse event related to the vaccines occurred. Most children experienced mild to moderate fever, rash, headache and my- algia occurring within 12 days after Dose 1 and generally lasting 3 days or less. One subject in Group F3212 had a 1-week dengue-like fever. Reactogenicity was minimal after Doses 2 and 3. Transient mild variations in liver enzymes and hematologic indices were noted mainly after Dose 1. After the third dose 89% of the subjects in Group F3212 seroconverted (neutralizing anti- body response, >10) to all four serotypes, and all children in Group F3313 seroconverted. Conclusion. This study demonstrates a moder- ate although improvable reactogenicity and high seroconversion rates against the four serotypes of dengue after a three dose schedule of tetrava- lent live-attenuated dengue vaccine in children. INTRODUCTION Dengue fever (DF), and especially the more severe dengue hemorrhagic fever (DHF), is a major global public health concern. Dengue infection is caused by dengue virus serotypes 1 to 4 (DEN 1– 4) of the Flavi- viridae family. DF and DHF have increased steadily in both incidence and distribution during the past 40 years. In 1996, 2500 to 3000 people were living in areas potentially at risk for dengue virus transmission. It is estimated that each year there are 20 million cases of dengue infection, resulting in 24 000 deaths. 1 Cur- rently dengue is endemic/epidemic in tropical areas including Asia, Africa, the Americas and some Pacific Islands. In high endemic areas DHF is typically con- fined to children younger than 15 years, with a mean age of 5 to 10 years. The only method currently avail- able to prevent dengue infections is the control of Aedes aegypti, the principal mosquito vector. This approach is expensive and most often unfeasible. No specific ther- apy is available to cure the illness. A safe, effective and accessible dengue vaccine is therefore required. 1, 2 Be- cause of the reported association of DHF with second- ary dengue virus infection, an ideal vaccine should induce immunity to all 4 serotypes. 3 Aventis Pasteur (Lyon, France) has produced Good Manufacturing Practices Phase I vaccine lots from the attenuated four candidate vaccine viruses developed by the Mahidol University group in Thailand. The Ma- hidol live-attenuated vaccines tested as monovalent, bivalent, trivalent and tetravalent vaccines in volun- Accepted for publication Oct. 29, 2003. From the Vaccine Trial Center, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (AS, PC, PA, CS, KP, CP); Research and Development Department, Aventis Pasteur, Lyon, France (JL, RF, LC, JFS); and Center for Vaccine Devel- opment, Institute of Sciences and Technology for Research and Development, Mahidol University, Salaya, Nakhonpathom, Thai- land (SY, NB). Key words: Dengue vaccine, pediatric trial, safety, immunoge- nicity. Address for reprints: Dr. Jean LANG, Research and Develop- ment Department, Aventis Pasteur, Campus Me ´rieux, 1541, avenue Marcel Me ´rieux, 69280 Marcy l’E ´ toile, France. Fax 00 33 4 37 37 31 80; E-mail Jean.Lang@aventis.com. 99