Alphavirus-Based Vaccines

Lundstrom, Kenneth

Alphaviruses have found frequent applications in the area of tumor vaccine development (Table 3) . In this context, naked RNA, replication-deficient particles and DNA layered vectors have been employed as delivery vehicles. For instance, mice have been subjected to immunization with naked SFV RNA replicons carrying the LacZ gene [74] . Interestingly, a single injection of only 1 μg of SFV-LacZ RNA presented complete tumor protection. Furthermore, when tumors were administered two days prior to the immunization, the survival was extended by 10-20 days. Among DNA-based tumor vaccine approaches, SIN vectors expressing mouse and human tyrosine-related protein-1 (TRP-1) were evaluated in a B16 mouse melanoma model [75] . Intramuscular injection was capable of breaking immune tolerance and provided protection against melanoma when mice were vaccinated five days prior to cancer challenge. In another study, alphavirus replicon-based expression of melanoma differentiation antigen (MDA) tyrosine demonstrated the inhibition of the growth of B16 transplantable melanoma [76] . In this context, the vaccine encoding tyrosine related protein 2 (TRP-2) relied on a novel immune mechanism, which required the activation of both IgG and CD8 + cell effector responses. Furthermore, vaccination with recombinant particles expressing the P1A gene [105] and the human papilloma virus (HPV) E7 gene [89] from SFV and VEE vectors, respectively, provided protection against further tumor development in mice. Attempts have also been made to improve the efficacy of SFV-based HPV vaccines by supplying SFV-based IL-12 expression in mice [90] . At low doses, IL-12 stimulated antigen-specific CTL responses and enhanced anti-tumor responses after SFV-based HPV16-E6E7 immunization. Subsequent increases in dosage, however, neither improved the immune responses, nor tumor regression. SIN DNA vectors have been employed for the expression of the murine melanoma cell adhesion molecule (MCAM/MUC18) as a vaccine against murine melanoma, which resulted in the induction of humoral and CD8 + T-cell immune responses against melanoma [97] .