BACKGROUND: Live, multivalent vaccines have historically exhibited interference in humans; live dengue virus (DENV) vaccines have proven no exception. METHODS: To characterize interactions between DENV serotypes in a tetravalent live-attenuated virus vaccine candidate, we analyzed data from a factorial clinical trial in which all combinations of high- and low-dose DENV serotypes were combined in 16 live-attenuated tetravalent vaccine formulations (N = 64) and administered to flavivirus-naive adult volunteers. Regression models considered the outcomes of reactogenicity and seroconversion, controlling for all serotype doses simultaneously. Additionally, results were compared against earlier evaluations of the same viruses administered as monovalent formulations. RESULTS: DENV-1 was immunologically dominant in both monovalent and tetravalent formulations. In tetravalent formulations, DENV-1 and DENV-2 antagonized each other, with a high dose of one decreasing seroconversion to the other. However, high-dose DENV-1 significantly increased seroconversion against 3 or more serotypes, increasing seroconversion to DENV-1, DENV-3, and DENV-4. The highest reactogenicity occurred when DENV-1 was at high dose and all others were low; reactogenicity decreased with the incorporation of other high-dose serotypes. CONCLUSIONS: Interference and facilitation occurred between serotypes in the live vaccine candidate evaluated. These analyses suggest that it may be possible to exploit facilitation to increase overall seroconversion.
BACKGROUND: Live, multivalent vaccines have historically exhibited interference in humans; live dengue virus (DENV) vaccines have proven no exception. METHODS: To characterize interactions between DENV serotypes in a tetravalent live-attenuated virus vaccine candidate, we analyzed data from a factorial clinical trial in which all combinations of high- and low-dose DENV serotypes were combined in 16 live-attenuated tetravalent vaccine formulations (N = 64) and administered to flavivirus-naive adult volunteers. Regression models considered the outcomes of reactogenicity and seroconversion, controlling for all serotype doses simultaneously. Additionally, results were compared against earlier evaluations of the same viruses administered as monovalent formulations. RESULTS:DENV-1 was immunologically dominant in both monovalent and tetravalent formulations. In tetravalent formulations, DENV-1 and DENV-2 antagonized each other, with a high dose of one decreasing seroconversion to the other. However, high-dose DENV-1 significantly increased seroconversion against 3 or more serotypes, increasing seroconversion to DENV-1, DENV-3, and DENV-4. The highest reactogenicity occurred when DENV-1 was at high dose and all others were low; reactogenicity decreased with the incorporation of other high-dose serotypes. CONCLUSIONS: Interference and facilitation occurred between serotypes in the live vaccine candidate evaluated. These analyses suggest that it may be possible to exploit facilitation to increase overall seroconversion.
Authors: J Brian Kimble; Delphine C Malherbe; Michelle Meyer; Bronwyn M Gunn; Marcus M Karim; Philipp A Ilinykh; Mathieu Iampietro; Khaled S Mohamed; Surendra Negi; Pavlo Gilchuk; Kai Huang; Yuri I Wolf; Werner Braun; James E Crowe; Galit Alter; Alexander Bukreyev Journal: J Virol Date: 2019-02-05 Impact factor: 5.103
Authors: R W Kaminski; M Wu; K R Turbyfill; K Clarkson; B Tai; A L Bourgeois; L L Van De Verg; R I Walker; E V Oaks Journal: Clin Vaccine Immunol Date: 2014-01-08
Authors: Anna P Durbin; Beth D Kirkpatrick; Kristen K Pierce; Daniel Elwood; Catherine J Larsson; Janet C Lindow; Cecilia Tibery; Beulah P Sabundayo; Donna Shaffer; Kawsar R Talaat; Noreen A Hynes; Kimberli Wanionek; Marya P Carmolli; Catherine J Luke; Brian R Murphy; Kanta Subbarao; Stephen S Whitehead Journal: J Infect Dis Date: 2013-01-17 Impact factor: 5.226
Authors: Sandra Olkowski; Brett M Forshey; Amy C Morrison; Claudio Rocha; Stalin Vilcarromero; Eric S Halsey; Tadeusz J Kochel; Thomas W Scott; Steven T Stoddard Journal: J Infect Dis Date: 2013-06-17 Impact factor: 5.226
Authors: Jorge E Osorio; Ivan D Velez; Cynthia Thomson; Liliana Lopez; Alejandra Jimenez; Aurelia A Haller; Shawn Silengo; Jaclyn Scott; Karen L Boroughs; Janae L Stovall; Betty E Luy; John Arguello; Mark E Beatty; Joseph Santangelo; Gilad S Gordon; Claire Y-H Huang; Dan T Stinchcomb Journal: Lancet Infect Dis Date: 2014-07-23 Impact factor: 25.071
Authors: Janet C Lindow; Anna P Durbin; Stephen S Whitehead; Kristen K Pierce; Marya P Carmolli; Beth D Kirkpatrick Journal: Vaccine Date: 2013-06-02 Impact factor: 3.641
Authors: Stephen J Thomas; Kenneth H Eckels; Isabelle Carletti; Rafael De La Barrera; Francis Dessy; Stefan Fernandez; Robert Putnak; Jean-Francois Toussaint; Wellington Sun; Kristen Bauer; Robert V Gibbons; Bruce L Innis Journal: Am J Trop Med Hyg Date: 2012-12-03 Impact factor: 2.345