Recombinant Yellow Fever Viruses Are Effective Therapeutic Vaccines for Treatment of Murine Experimental Solid Tumors and Pulmonary Metastases

Abstract

We have genetically engineered an attenuated yellow fever (YF) virus to carry and express foreign antigenic sequences and evaluated the potential of this type of recombinant virus to serve as a safe and effective tumor vaccine. Live-attenuated YF vaccine is one of the most effective viral vaccines available today. Important advantages include its ability to induce long-lasting immunity, its safety, its affordability, and its documented efficacy. In this study, recombinant live-attenuated (strain 17D) YF viruses were constructed to express a cytotoxic T-lymphocyte epitope derived from chicken ovalbumin (SIINFEKL). Yellow fever (YF) virus 17D is an extremely safe and effective live viral vaccine, prepared from infected chicken embryos under standards developed by the World Health Organization. After vaccination, immunity is elicited within 10 days in over 95% of vaccinees (42) and neutralizing antibodies directed against the virus can be detected for more than 35 years (40). The vaccine safety record is outstanding: serious adverse reactions to YF virus 17D vaccine are extremely uncommon, and reversion to wild type is virtually nonexistent (4, 52).YF virus is an enveloped, positive-stranded RNA virus and a member of the Flavivirus genus within the family Flaviviridae.

A stable full-length yellow fever virus cDNA clone and the role of conserved RNA elements in flavivirus replication

“…Finally, as one of the safest and most effective human vaccines, YF-17D recombinants are being vigorously explored as candidate vaccines for other flavivirus diseases, such as JE (Monath, 2002), DEN (Der Most et al, 2000) and West Nile virus (Monath, 2001), as well as for cancer vaccines (McAllister et al, 2000). The availability of fulllength stable YF cDNA clones should help in these efforts.…”

The yellow fever 17D virus as a platform for new live attenuated vaccines

“…The expression of small epitopes by this methodology seems to not considerably interfere with the maturation of viral proteins, since the viral proliferation properties of this kind of recombinant viruses are similar to the vaccine counterpart. [54][55][56][57] However, the foreign sequence cloning into the NS2A-NS2B, NS3-NS4A, and NS4A-NS4B junctions did not allow the recovery of a viable virus. Interestingly, the same YF cloning strategy was employed in a subsequent work to express a Plasmodium yoelli CD8 + T cell epitope.…”

“…In this study, a short ovalbumin immunodominant cytotoxic T cell epitope (SIINFEKL) was expressed at the junction of the NS2B and NS3 genes. 54 The rational of this methodology was based on endowing both sides of the heterologous sequence with the viral protease recognition motif. Consequently, the insertion was cleaved off the polyprotein due to the duplication of the viral protease NS2B/3 cleavage site.…”

Viral vectors for use in the development of biodefense vaccines

“…Vaccinating mice with the KUN vector expressing murine polyepitope stimulated protective CTL responses in the mice against a recombinant VV or against a B16-OVA tumor challenge [104]. Similar to KUN, YF virus engineered to express OVA was able to elicit protective CTL responses in vaccinated mice against a lethal challenge with malignant melanoma cells expressing OVA [105]. The flavivirus vaccine vectors represent a class of vectors that could be useful against diseases that require CTL responses to neutralize the virus-or bacteria-infected host cells.…”