A DNA Vaccine against Yellow Fever Virus: Development and Evaluation

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.

Current status and future prospects of yellow fever vaccines

“…The study not only demonstrated protection and immunogenicity of the constructs, but also high apparent safety in mice, as the vaccines themselves were not neurotropic when administered at doses exceeding the that required to induce protection. A plasmid-vectored DNA vaccine was constructed by fusion-ligation of the 17DD substrain prM/M-E onto that of human LAMP-1, a strategy designed to target the antigen structural subunit for efficient trafficking to MHC-II compartments and consequent presentation and stimulation of cellular immune responses [75]. A 45 day, three-dose course of the LAMP-1 plasmid construct was protective when assayed in mice against live 17DD virus delivered intracerebrally.…”

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

“…However, the decline in herd immunity and discontinuation of mosquito control measures in many parts of Africa are considered the major causes for the resurgence of yellow fever and periodic epidemics in East and West African countries during the last 2 decades (4). In addition, recent clinical studies also showed that an activated immune microenvironment with other microbial infections prior to vaccination impeded efficacy of the YFV-17D vaccine in an African cohort, suggesting that vaccine regimens may need to be boosted in African populations to achieve efficient protective immunity (5)(6)(7). It has been estimated that up to 1.7 million YFV infections may occur in Africa each year, resulting in 29,000 to 60,000 deaths (8,9) (http://www.who .int/csr/disease/yellowfev/yellowfeverburdenestimation _summary2013.pdf).…”

In Silico Approach To Design a B-cell Epitope Based Vaccine Target Against Yellow Fever Virus

“…In the U.S an inactivated 17D vaccine was produced and tested clinically but failed to go for commercialization 4 . Two non-viral DNA based antigens were also evaluated as vaccine candidates and revealed potency but further development studies are required 40 .Considering these factors, the idea of designing an alternative vaccine for yellow fever virus to replace or complement the existing live attenuated one can be pursued.…”