Highly Efficient Induction of Protective Immunity by a Vaccinia Virus Vector Defective in Late Gene Expression

Abstract

Vaccinia viruses defective in the essential gene coding for the enzyme uracil DNA glycosylase (UDG) do not undergo DNA replication and do not express late genes in wild-type cells. A UDG-deficient vaccinia virus vector carrying the tick-borne encephalitis (TBE) virus prM/E gene, termed vD4-prME, was constructed, and its potential as a vaccine vector was evaluated. High-level expression of the prM/E antigens could be demonstrated in infected complementing cells, and moderate levels were found under noncomplementing conditions. The vD4-prME vector was used to vaccinate mice; animals receiving single vaccination doses as low as 104 PFU were fully protected against challenge with high doses of virulent TBE virus. Single vaccination doses of 103 PFU were sufficient to induce significant neutralizing antibody titers. With the corresponding replicating virus, doses at least 10-fold higher were needed to achieve protection. The data indicate that late gene expression of the vaccine vector is not required for successful vaccination; early vaccinia virus gene expression induces a potent protective immune response. The new vaccinia virus-based defective vectors are therefore promising live vaccines for prophylaxis and cancer immunotherapy.

Smallpox vaccines for biodefense

“…[69][70][71] A replication defective vaccine based on the Lister strain (dVV-L) was created through the deletion of the uracil-DNA-glycosylase (UDG) gene. [72] The resulting vaccine, while replication incompetent outside of certain cell lines which provide exogenous UDG is still capable of initial infection and early gene expression. Early work found that this vaccine candidate had an enhanced safety profile compared to wild-type Lister vaccine.…”

Production of a Chikungunya Vaccine Using a CHO Cell and Attenuated Viral-Based Platform Technology

“…The SCV vaccine was generated by targeted deletion of the D13L gene, which encodes an essential viral assembly protein. 18 , 19 This approach to VACV attenuation was chosen, instead of targeting the viral genome replication machinery, 20 to preserve genome amplification, thereby permitting late-phase expression of vaccine antigens from the amplified genomes. Production of SCV vaccines in the SCS line was enabled by the in trans provision of D13 and the host-range protein CP77, which provides VACV multiplication capability in CHO cells.…”

Tick-Borne Encephalitis Virus: A Quest for Better Vaccines against a Virus on the Rise

“…Additionally, immunized mice or mice treated with serum of vaccinated non-human primates were protected against TBEV challenge [ 182 , 193 , 194 ]. Moreover, in situ generation of TBEV VLPs by vaccination of mice with a late-defective recombinant Vaccinia virus (rVACV) encoding for the prM and E proteins, induced VN antibodies and a robust protection upon challenge infection with TBEV [ 195 ]. Altogether, these data suggest that co-expressed prM and E induced superior immune responses with higher protective efficacy than the E protein alone.…”