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Evaluation of Interferences between Dengue Vaccine Serotypes in a Monkey Model

Interferences between different antigens in the same vaccine formulation have been reported for some vaccines (e.g., polio vaccines, live attenuated dengue vaccine candidates). We examined interferences between the four serotypes of ChimeriVax dengue vaccines (CYDs) in a monkey model when present within a tetravalent formulation in equal concentrations (TV-5555). Immunoassays of vaccinated non-human primates showed that serotype 4 (DEN-4), and to a lesser extent, DEN-1 were dominant in terms of neutralizing antibody levels. Parameters that affected the interferences were identified, including 1) the simultaneous administration of two complementary bivalent vaccines at separate anatomical sites drained by different lymph nodes; 2) the sequential administration of two complementary bivalent vaccines; 3) the establishment of heterologous flavivirus pre-immunity before subsequent tetravalent immunization; 4) the adaptation of formulations by decreasing the dose of the immunodominant serotype; and 5) the administration of a 1-year booster. The applicability of these data to human responses is discussed.

Received May 13, 2008. Accepted for publication August 26, 2008.

Acknowledgments: The authors thank Gee Marsh and Simon Jones for critical help in the preparation of the manuscript; Franck Raynal, Celine Vaure, and the animal facility team for excellent care and expertise; and Jeffrey Almond and Emanuelle Trannoy for constant support and helpful discussions.

Disclosure: The authors are employed by Sanofi Pasteur. This statement is made in the interest of full disclosure and not because the authors consider this a conflict of interest.

^* Address correspondence to Bruno Guy, Sanofi Pasteur, 69280 Marcy l’Etoile, France. E-mail: bruno.guy{at}sanofipasteur.com

Authors’ addresses: Bruno Guy, Veronique Barban, Nathalie Mantel, Marion Aguirre, Sandrine Gulia, Jeremy Pontvianne, Therese-Marie Jourdier, Laurence Ramirez, Veronique Gregoire, Christophe Charnay, Nicolas Burdin, Rafaele Dumas, and Jean Lang, Sanofi Pasteur, 69280 Marcy l’Etoile, France.