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Original Research ARTICLE

Front. Immunol., 08 November 2012 | http://dx.doi.org/10.3389/fimmu.2012.00334

Sculpting humoral immunity through dengue vaccination to enhance protective immunity

Wayne D. Crill*, Holly R. Hughes, Nicole B. Trainor, Brent S. Davis, Matt T. Whitney and Gwong-Jen J. Chang*
  • Arboviral Diseases Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Service, Fort Collins, CO, USA

Dengue viruses (DENV) are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF). Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1) DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT) with this cross-reactivity reduced (CRR) vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naїve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine-induced immune responses.

Keywords: dengue, dengue vaccines, DNA vaccines, immune refocusing, vaccine safety, antibody-dependent enhancement, original antigenic sin, dengue hemorrhagic fever

Citation: Crill WD, Hughes HR, Trainor NB, Davis BS, Whitney MT and Chang G-JJ (2012) Sculpting humoral immunity through dengue vaccination to enhance protective immunity. Front. Immun. 3:334. doi: 10.3389/fimmu.2012.00334

Received: 31 August 2012; Accepted: 20 October 2012;
Published online: 08 November 2012.

Edited by:

Ken J. Ishii, National Institute of Biomedical Innovation, Japan

Reviewed by:

Alice Nyakeriga, Texas Tech University, USA
Qibin Leng, Institut Pasteur of Shanghai, Chinese Academy of Sciences, China

Copyright: © 2012 Crill, Hughes, Trainor, Davis, Whitney and Chang. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Wayne D. Crill and Gwong-Jen J. Chang, Arboviral Diseases Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Service, P. O. Box 2087, 3156 Rampart Rd., Fort Collins, CO 80521, USA. e-mail: wcrill@cdc.gov; gxc7@cdc.gov

Present address: Holly R. Hughes, Florida Department of Health, Tampa, FL, USA.