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.
Highlights
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]
We report a highly protective DNA vaccine against the yellow fever virus
Our results show that vaccination with this yellow fever DNA formulation elicited protective levels of neutralizing antibodies and very strong cellular responses at similar levels to the responses elicited by the live attenuated 17DD vaccine
Summary
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]. 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]. The development of alternative vaccination strategies, such as DNA-based vaccines encoding specific virus sequences, has been considered [13,14,15,16]
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