Sculpting humoral immunity through dengue vaccination to enhance protective immunity
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 hemorr...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2012-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00334/full |
| _version_ | 1818582961867456512 |
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| author | Wayne eCrill Holly R Hughes Nicole B Trainor Brent S Davis Matt T Whitney Gwong-Jen J Chang |
| author_facet | Wayne eCrill Holly R Hughes Nicole B Trainor Brent S Davis Matt T Whitney Gwong-Jen J Chang |
| author_sort | Wayne eCrill |
| collection | DOAJ |
| description | 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 naïve 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. |
| first_indexed | 2024-12-16T07:57:42Z |
| format | Article |
| id | doaj.art-12e893a09d1b4a6689d84a3458efa5bc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T07:57:42Z |
| publishDate | 2012-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-12e893a09d1b4a6689d84a3458efa5bc2022-12-21T22:38:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242012-11-01310.3389/fimmu.2012.0033435589Sculpting humoral immunity through dengue vaccination to enhance protective immunityWayne eCrill0Holly R Hughes1Nicole B Trainor2Brent S Davis3Matt T Whitney4Gwong-Jen J Chang5US Centers for Disease Control and PreventionUS Centers for Disease Control and PreventionUS Centers for Disease Control and PreventionUS Centers for Disease Control and PreventionUS Centers for Disease Control and PreventionUS Centers for Disease Control and PreventionDengue 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 naïve 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.http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00334/fullAntibody-Dependent EnhancementDengueDengue Vaccinesvaccine safetyDNA VaccinesImmune Refocusing |
| spellingShingle | Wayne eCrill Holly R Hughes Nicole B Trainor Brent S Davis Matt T Whitney Gwong-Jen J Chang Sculpting humoral immunity through dengue vaccination to enhance protective immunity Frontiers in Immunology Antibody-Dependent Enhancement Dengue Dengue Vaccines vaccine safety DNA Vaccines Immune Refocusing |
| title | Sculpting humoral immunity through dengue vaccination to enhance protective immunity |
| title_full | Sculpting humoral immunity through dengue vaccination to enhance protective immunity |
| title_fullStr | Sculpting humoral immunity through dengue vaccination to enhance protective immunity |
| title_full_unstemmed | Sculpting humoral immunity through dengue vaccination to enhance protective immunity |
| title_short | Sculpting humoral immunity through dengue vaccination to enhance protective immunity |
| title_sort | sculpting humoral immunity through dengue vaccination to enhance protective immunity |
| topic | Antibody-Dependent Enhancement Dengue Dengue Vaccines vaccine safety DNA Vaccines Immune Refocusing |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00334/full |
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