ORIGINAL STUDIES Live-attenuated Tetravalent Dengue Vaccine in Dengue-naïve Children, Adolescents, and Adults in Mexico City Randomized Controlled Phase 1 Trial of Safety and Immunogenicity Jorge Poo, MD,* Francisco Galan, MD,† Remi Forrat, MD,‡ Betzana Zambrano, MD,§ Jean Lang, MD,‡ and Gustavo H. Dayan, MD¶ Background: Preliminary results in healthy, young US adults showed that a tetravalent, live-attenuated dengue vaccine (TDV) was safe and immu- nogenic, but no data are available in children. Methods: In a multicenter, randomized, controlled, observer-blinded study in the city of Mexico, children aged 2 to 5, 6 to 11, and 12 to 17 years (36 children per age group), and adults (n = 18) aged 45 years received the following: 3 injections of TDV at months 0, 3.5, and 12 (TDV-TDV-TDV), or 1 injection of yellow fever vaccine (YF) at month 0, and 2 injections of TDV at months 3.5 and 12 (YF-TDV-TDV). Adverse events and biologic safety (biochemistry and hematology) were documented. Plaque reduction neutralization test (PRNT 50 ) antibody titers against the TDV parental viruses were measured 28 days after vaccination. Seropositivity was defined as antibody titers 10 1/dil. Results: No vaccine-related serious adverse events, other significant clin- ical adverse events, or clinically significant trends in biologic safety were observed. Reactogenicity did not increase with successive TDV injections, and mild-to-moderate injection site pain, headache, myalgia, and malaise were most commonly reported (14%– 40% after each vaccination). After 3 TDV vaccinations, the seropositivity rate against each dengue serotype was in the range 77% to 92%, compared with 85% to 94% after completion of the YF-TDV-TDV regimen. Of the 2- to 11-year-old participants, 95% were seropositive against 3 serotypes after 3 vaccinations. Conclusions: A 3-dose TDV regimen had a favorable safety profile in children and adults and elicited neutralizing antibody responses against all 4 serotypes. These findings support the continued development of this vaccine. Key Words: dengue vaccines, vaccines, attenuated, clinical trial, phase I, children (Pediatr Infect Dis J 2011;30: e9 – e17) D engue disease is caused by dengue virus serotypes 1 to 4 of the genus Flavivirus that are usually transmitted by Aedes aegypti mosquitoes. 1 Dengue can produce a spectrum of clinical illnesses ranging from a nonspecific viral syndrome to severe, fatal hemorrhagic disease. 2,3 Dengue fever is characterized by fever, headache, myalgia, arthralgia, prostration, rash, and lymphadenop- athy. Recovery is usually complete in 7 to 10 days. Dengue hemorrhagic fever (DHF) is a severe clinical manifestation that can lead to hypovolemia and hypotension (dengue shock syn- drome, DSS), often complicated by severe internal bleeding. Hos- pitals experienced in volume replacement report DHF/DSS case fatality rates of 1% to 5%. 4 Dengue disease is now re-emerging, and many regions have gone from being epidemic to hyperepi- demic, with all 4 serotypes prevalent at once. 5,6 In Latin America, the number of dengue cases has dramat- ically increased in the last 3 decades with a total of 1 million cases reported in the 1980s, 2.7 million in the 1990s, and more than 4.7 million cases reported for the period between 2000 and 2007. 7 Between 2000 and 2007, the number of DHF cases and deaths has similarly increased to attain almost 112,000 DHF cases (an inci- dence rate of 1.7 DHF cases per 100,000 persons) and 1391 deaths. 7 In Mexico alone, 31,000 dengue cases, 6000 DHF/DSS cases, and 24 deaths were reported in 2008. 8 Currently, there is no licensed vaccine nor specific treatment against dengue. Preventive measures such as mosquito control and personal protection are limited in efficacy, difficult to enforce, and expensive. A safe and effective vaccine against the 4 dengue serotypes is needed. A tetravalent dengue vaccine (TDV) has been developed using 4 live-attenuated chimeric viruses, each express- ing the main antigens against which humoral immune responses are directed (the premembrane and envelope proteins) of 1 of the 4 dengue serotypes. Each of the 4 vaccine viruses was produced by inserting dengue premembrane and envelope protein coding se- quences in place of the corresponding sequences of the attenuated yellow fever vaccine virus strain, YF 17D. 9,10 Preliminary phase 1 results in adults have shown that the vaccine has potential for further development. 11,12 The next step is the evaluation of vaccine safety and immunogenicity in various populations, especially children. In this article, we primarily describe the safety and immunogenicity of TDV in children and adults living in a nonendemic area. MATERIALS AND METHODS Trial Design and Participants We randomized 126 participants 2:1 to receive either (i) 3 injections of TDV at months 0, 3.5, and 12, or (ii) 1 injection of licensed yellow fever (YF) control vaccine at month 0 followed by 2 TDV injections at months 3.5 and 12, in a phase I, multicenter, controlled, study that was observer-blinded for the month 0 injec- tion. With a step-down design and as a safety precaution, we recruited participants from 4 age cohorts: first 18 adults (18 – 45 years), then 36 adolescents (12–17 years), 36 children (6 –11 years), and finally 36 young children (2–5 years). An independent Accepted for publication September 22, 2010. All authors declare no other conflicts of interest. From the *Pharma Research Unit (Cif-Biotec), Medica Sur Hospital and Clinical Foundation (CIF BIOTEC) Medicasur Hospital, Mexico DF, Mex- ico; †Pharma Research Unit (Cif-Biotec), Hospital Valle de Chalco, Insti- tute of Health of the State of Mexico (ISEM), Solidaridad, Mexico; ‡Research and Development Department, Sanofi Pasteur, Marcy l’Etoile, France; §Research and Development Department, Sanofi Pasteur, Montevideo, Uruguay; and ¶Research and Development Department, Sanofi Pasteur, Swift- water, PA. Supported by Sanofi Pasteur. R.F., B.Z., J.L., and G.D. are employed by the study sponsor, Sanofi Pasteur. Address for correspondence: Gustavo Dayan, MD, Sanofi Pasteur, 1 Discovery Drive, Swiftwater, PA 18370. E-mail: Gustavo.dayan@sanofipasteur.com. Copyright © 2010 by Lippincott Williams & Wilkins ISSN: 0891-3668/11/3001-0009 DOI: 10.1097/INF.0b013e3181fe05af The Pediatric Infectious Disease Journal • Volume 30, Number 1, January 2011 www.pidj.com | e9