[논문]Distinct Humoral and Cellular Immunity Induced by Alternating Prime-boost Vaccination Using Plasmid DNA and Live Viral Vector Vaccines Expressing the E Protein of Dengue Virus Type 2

George, Junu A.; Eo, Seong-Kug

doi:10.4110/in.2011.11.5.268

Distinct Humoral and Cellular Immunity Induced by Alternating Prime-boost Vaccination Using Plasmid DNA and Live Viral Vector Vaccines Expressing the E Protein of Dengue Virus Type 2 원문보기

Immune network : official journal of the Korean association of immunobiologists, v.11 no.5, 2011년, pp.268 - 280

George, Junu A. (College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) , Eo, Seong-Kug (College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University)

Abstract ▼ AI-Helper

Background: Dengue virus, which belongs to the Flavivirus genus of the Flaviviridae family, causes fatal dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) with infection risk of 2.5 billion people worldwide. However, approved vaccines are still not available. Here, we explored the immune responses induced by alternating prime-boost vaccination using DNA vaccine, adenovirus, and vaccinia virus expressing E protein of dengue virus type 2 (DenV2). Methods: Following immunization with DNA vaccine (pDE), adenovirus (rAd-E), and/or vaccinia virus (VV-E) expressing E protein, E protein-specific IgG and its isotypes were determined by conventional ELISA. Intracellular CD154 and cytokine staining was used for enumerating CD4+ T cells specific for E protein. E protein-specific CD8+ T cell responses were evaluated by in vivo CTL killing activity and intracellular IFN-${\gamma}$ staining. Results: Among three constructs, VV-E induced the most potent IgG responses, Th1-type cytokine production by stimulated CD4+ T cells, and the CD8+ T cell response. Furthermore, when the three constructs were used for alternating prime-boost vaccination, the results revealed a different pattern of CD4+ and CD8+ T cell responses. i) Priming with VV-E induced higher E-specific IgG level but it was decreased rapidly. ii) Strong CD8+ T cell responses specific for E protein were induced when VV-E was used for the priming step, and such CD8+ T cell responses were significantly boosted with pDE. iii) Priming with rAd-E induced stronger CD4+ T cell responses which subsequently boosted with pDE to a greater extent than VV-E and rAd-E. Conclusion: These results indicate that priming with live viral vector vaccines could induce different patterns of E protein-specific CD4+ and CD8+ T cell responses which were significantly enhanced by booster vaccination with the DNA vaccine. Therefore, our observation will provide valuable information for the establishment of optimal prime-boost vaccination against DenV.

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문제 정의

To achieve the practical development of vaccination strategies against dengue virus, the prime-boost vaccination using DNA vaccine and/or live viral vector vaccine expressing tetravalent antigen is recommended. Therefore, our observation will provide valuable information for the establishment of optimal prime-boost vaccination against dengue virus.

제안 방법

We demonstrate that DNA vaccine, adenovirus, and vaccinia virus expressing E protein of DenV2 induced differential immune responses. Among three constructs, VV-E induced the most potent IgG responses, Th1-type cytokine production by stimulated CD4＋ T cells, and CD8＋ T cell response. rAd-E showed higher production of Th2-type cytokine IL-4 compared to other constructs, DNA vaccine and vaccinia virus.
Plasmid DNA encoding E protein of dengue virus type 2 (DenV2) under the control of the cytomegalovirus (CMV) promoter (pDE) was constructed by inserting cDNA of the E protein gene into pCI-neo vector (Promega, Madison, WI). For immunization, plasmid DNA was purified by polyethylene glycol (PEG) precipitation as described previously (35).
To better understand immune responses induced by plasmid DNA, live viral vectors expressing E protein of DenV2, we examined the in vivo CTL killing activity specific for E_331-339 (SPCKIPFEI) epitope. Similarly, immunization with VV-E showed the most potent activity of in vivo CTL, compared to other types of immunization (Fig.
To evaluate the immune responses induced by plasmid DNA (pDE), recombinant adenovirus (rAd-E) and vaccinia virus (VV-E) expressing E protein of DenV2, groups of mice were immunized with these constructs and the levels of E-specific IgG in sera were determined 10 days post-immunization. pDE was observed to induce lower levels of E-specific IgG, when compared to live viral vectors (Fig.

대상 데이터

Female BALB/c (H-2^d) mice, 5 to 6 weeks of age, were purchased from Samtako (Osan, Korea). The mice were maintained in the animal facility at Chonbuk National University under standard conditions.

데이터처리

Data are expressed as the average±standard deviation (SD) of the individual results. Where specified, the data were analyzed for statistical significance using an unpaired two-tailed Student t test. A value of p＜0.

성능/효과

In general, it was observed that the levels of E-specific IgG in sera rapidly decreased when VV-E was used as immunogen of primary vaccination. Furthermore, priming with VV-E and boosting with rAd-E led to production of E-specific IgG1 isotype with higher levels than the other group, when the levels of E-specific IgG isotypes, IgG1 and IgG2a, were determined (Fig. 4B and C). Notably, if VV-E was used for primary vaccination, the levels of E-specific IgG1 isotype were maintained till 14 days post-boosting, but E-specific IgG2a levels decreased.
Of particular interest, priming with pDE showed inhibited CD4＋ T cell responses after boosting with either rAD-E or VV-E. Taken together, these results indicate that CD4＋ T cell responses achieved by priming with adenovirus expressing E protein and boosting with DNA vaccine were superior to other immunization protocols, and primary responses induced by DNA vaccine may interfere with CD4＋ T cell responses of liver viral vector as booster.
In contrast, priming with rAd-E induced stronger CD4＋ T cell responses which subsequently boosted DNA vaccination more than others, as determined by intracellular CD154 and IFN-γ staining. Therefore, these results indicate that priming with live viral vector vaccine could lead to a different pattern of E protein-specific immune responses that were significantly more enhanced by booster vaccination with DNA vaccine, compared to live viral vector vaccine.
When CD8＋ T cell responses specific for E protein of DenV2 were determined by in vivo CTL killing activity, the results revealed that priming with VV-E and boosting with pDE showed the most potent in vivo CTL killing activity (Fig. 7A). This exceeded the results achieved by priming and boosting with the same vaccine VV-E, and was superior to responses induced by priming with rAD-E and boosting with pDE.
VV-E induced significantly higher levels of E-specific IgG than rAd-E at the equivalent amount of immunogens (10⁶ PFU/mouse). When the distribution of E-specific IgG isotypes, IgG1 and IgG2a, was evaluated, VV-E showed significantly higher levels of E-specific IgG1 and IgG2a, compared to pDE and rAd-E (Fig. 1B and C). However, three constructs expressing E protein of DenV2 showed comparable ratios of IgG2a to IgG1 each other (Fig.

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