Research Article: A DNA Vaccine against Yellow Fever Virus: Development and Evaluation

Date Published: April 13, 2015

Publisher: Public Library of Science

Author(s): Milton Maciel, Fábia da Silva Pereira Cruz, Marli Tenório Cordeiro, Márcia Archer da Motta, Klécia Marília Soares de Melo Cassemiro, Rita de Cássia Carvalho Maia, Regina Célia Bressan Queiroz de Figueiredo, Ricardo Galler, Marcos da Silva Freire, Joseph Thomas August, Ernesto T. A. Marques, Rafael Dhalia, Kenji Hirayama.

Abstract: Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE) or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE), aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies.

Partial Text: The yellow fever (YF) virus is considered the prototype member of the family Flaviviridae, which includes several other viruses of medical importance, such as the dengue, Japanese encephalitis, tick-borne encephalitis and West Nile viruses [1]. According to the World Health Organization (WHO), more than 200,000 cases of YF infection, including 30,000 deaths, occur annually, with 90% of cases occurring in Africa [2]. The safest strategy for preventing YF infection is still vaccination because there is currently no drug that is effective against YF virus infection. In the last 70 years, more than 500 million people around the world have been vaccinated with the YF 17D/17DD virus-attenuated vaccines with a remarkable record of safety and efficacy [3]. Attenuated YF virus vaccines generate both long-lasting neutralizing antibodies and T-cell responses [4, 5]. However, despite several improvements in the manufacturing process and quality control, severe side-effects resulting from vaccination continue to be reported [6–9]. In some cases, vaccination was associated with increased severity of symptoms [10] and on rare occasions with fatal reactions [11, 12]. In view of this, the development of alternative vaccination strategies, such as DNA-based vaccines encoding specific virus sequences, has been considered [13–16].

YF infection continues to be a worldwide problem, especially in tropical areas [11], but this may change as the world continues to be affected by climate change. Despite the high efficiency of commercially available YF vaccines, 17D and 17DD, there are a few reports of rare but fatal side-effects after vaccination [9, 11, 12]. Furthermore, these vaccines are not recommended for infants, pregnant women, immunodeficient subjects, or those allergic to the egg components present in the vaccine formulations [36]. In light of these factors, there is reason to pursue complementary or alternative YF vaccine strategies that could replace the use of the virus-attenuated vaccine version.



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