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. 2011 Jun 30:8:333.
doi: 10.1186/1743-422X-8-333.

Vaccination with dengue virus-like particles induces humoral and cellular immune responses in mice

Shuo Zhang  1 , Mifang Liang, Wen Gu, Chuan Li, Fang Miao, Xiaofang Wang, Cong Jin, Li Zhang, Fushun Zhang, Quanfu Zhang, Lifang Jiang, Mengfeng Li, Dexin Li
Affiliations

Vaccination with dengue virus-like particles induces humoral and cellular immune responses in mice

Shuo Zhang et al. Virol J. .

Abstract

Background: The incidence of dengue, an infectious disease caused by dengue virus (DENV), has dramatically increased around the world in recent decades and is becoming a severe public health threat. However, there is currently no specific treatment for dengue fever, and licensed vaccine against dengue is not available. Vaccination with virus-like particles (VLPs) has shown considerable promise for many viral diseases, but the effect of DENV VLPs to induce specific immune responses has not been adequately investigated.

Results: By optimizing the expression plasmids, recombinant VLPs of four antigenically different DENV serotypes DENV1-4 were successfully produced in 293T cells. The vaccination effect of dengue VLPs in mice showed that monovalent VLPs of each serotype stimulated specific IgG responses and potent neutralizing antibodies against homotypic virus. Tetravalent VLPs efficiently enhanced specific IgG and neutralizing antibodies against all four serotypes of DENV. Moreover, vaccination with monovalent or tetravalent VLPs resulted in the induction of specific cytotoxic T cell responses.

Conclusions: Mammalian cell expressed dengue VLPs are capable to induce VLP-specific humoral and cellular immune responses in mice, and being a promising subunit vaccine candidate for prevention of dengue virus infection.

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Figures

Figure 1
Figure 1
Construction strategies and secretion analysis of DENV1-4 VLPs. A) Schematic representation of three strategies to construct DENV1-4 VLP expression plasmids, pD1-D4prME include the entire prM and E gene regions of DENV. JEV signal sequence (JESS) is introduced to the N-terminal of pJD1-D4prME, and pJD1-D4prMEΔ20%JEV. The corresponding JEV-E sequence was constructed in pJD1-D4prMEΔ20%JEV to replace the 20% C-terminal region of DENV-E; B) Western blot analysis of DENV1-4 VLPs secretion, Concentrated culture supernatants from 293T cells transformed with pD1-D4prME, pJD1-D4prME or pJD1-D4prMEΔ20%JEV were tested by rabbit polyclonal serum specific against dengue E protein. Bound antibodies were detected by a HRP-conjugated goat anti-mouse antibody. The band corresponding to envelope (E) is indicated with an arrow to the right of the blot.
Figure 2
Figure 2
Morphology and size of dengue VLPs and virions. Purified dengue virions (arrow indicated in A) and VLPs (arrow indicated in C-F) were negatively stained and analyzed by TEM. Scale bar indicates 100 nm. A. Dengue virions, B. Negative control, C. DENV-1 VLPs, D. DENV-2 VLPs, E. DENV-3 VLPs, F. DENV-4 VLPs.
Figure 3
Figure 3
Virus specific IgG were enhanced by DENV VLPs or virions. BALB/c mice were intraperitoneally immunized with 100 μg monovalent DENV VLPs or virions (A-D), or tetravalent VLPs or virions (E 25 μg of each serotype) for three times at two-week intervals. At day 14, 28, 42, sera were collected and ELISA was used to test for rEIII specific IgG. Data were expressed as mean titer with a standard deviation (SD) bar. *indicates statistical significance (P < 0.05).
Figure 4
Figure 4
Serum neutralizing antibody titer of vaccinated mice. BalB/C mice were immunized with A) 100 μg monovalent VLPs or virions, B) tetravalent VLPs or virions (25 μg of each serotype) for three times at two weeks interval. At day 42, the serum neutralizing antibodies were assessed using CPE-determination assays. Data of each group was expressed as geometric mean titer (GMT) with an S.D. bar (n = 5). *indicates statistical significance (P < 0.05).
Figure 5
Figure 5
Dengue specific T cell responses evaluated by ELISPOT assay. BALB/c mice were immunized with DENV1-4 VLPs or virions in either monovalent A) or tetravalent B) formula. The immunized mice were sacrificed at day 42 and the collected spleen cells were isolated and stimulated in vitro with each of DENV1-4 VLPs. ELISPOT assay was performed to test IFN-γ production. The mean number of spot forming cells (SFCs)/106 splenocytes was shown as VLPs-stimulated plus mock-stimulated with an S.D bar. *indicates statistical significance (P < 0.05).
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