A CHO cell derived Dengue virus-like particle vaccine induces protective immunity to DENV infection in mice Makoto Fujii1, 2, Tadaki Suzuki1, Akiko Sataka1, Yoshiyuki Yamaguchi1, Kaori Sano1, Asato Kojima1, Akira Ainai1, Tsugumichi Sato2, Hideki Hasegawa1 1Department of Pathology, National Institute of Infectious Diseases; 2Graduate School of Pharmaceutical Sciences, Tokyo University of Science
Dengue virus (DENV) is the etiological agent of dengue fever and is prevalent worldwide. The only vaccine available today is a live attenuated tetravalent vaccine, but safety concerns of this vaccine were pointed out recently. A retrospective analysis of those who participated in phase III trials of this attenuated vaccine revealed that the vaccine had an increased risk of severe DENV infections such as dengue hemorrhagic fever and dengue shock syndrome for those who were naïve for any dengue virus at the time of vaccination. Therefore, interests in developing a safer inactivated dengue vaccine available for these age groups have been stimulated. However, the low proliferation of DENV in vitro hampers the production of conventional inactivated vaccines using purified virions. Thus, we explored to generate a DENV vaccine antigen candidate using VLPs (Virus Like Particles) and evaluated its potency of immune induction in mice models. We established a CHO cell line constantly expressing DENV type 1 (DENV1) VLPs and a VLP purification system. The immunogenicity of the purified DENV1 VLP was evaluated by subcutaneous injection of 7-week-old C3H mice two times at two times. Then, a significant increase in anti-DENV1 antibody titer was observed in the DENV1 VLP injected group. Furthermore, the protective immunity against DENV infection was evaluated by subcutaneous vaccination of 8-week-old BALB/c mice with DENV1 VLPs twice. Three weeks following vaccination, mice were intraperitoneally inoculated with anti-interferon αR1 antibodies and were infected with DENV1 the following day. Detection of DENV1 in serum collected 3 days post infection was done by real-time PCR. DENV1 RNA was detected only in the plasma of the DENV1 VLP non-vaccinated group, whereas the DENV1 RNA copy number was below the detection limit in the vaccinated group. These observations suggested that the VLP vaccine induced protective immunity against DENV1 infection in mice, and the VLP derived from a CHO cell is a promising candidate of vaccine antigens for an inactivated DENV vaccine.
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