DNA and MVA as Vaccine Vectors

Our HIV vaccines incorporate two delivery components (or vectors): a recombinant plasmid DNA vaccine, and a recombinant MVA (modified vaccinia Ankara) vaccine. Our Ebola and Marburg vaccines use only the MVA vector. Both our DNA and MVA vaccines express sufficient vaccine genes to support the production of non-infectious VLPs. The VLPs cannot cause disease because they contain mutated or deleted enzymatic functions that are essential for virus replication. The VLPs display trimeric membrane bound forms of the viral envelope glycoprotein (Env for HIV or GP for Ebola or Marburg). This is important because the natural form of the envelope glycoprotein elicits multi-target antibody capable of recognizing incoming virus and blocking infections. Expression of multiple proteins by the vaccines is essential for the formation of VLPs. The multiple proteins also provide more targets for immune responses such as cytotoxic T-cells. Elicitation of multi-target humoral and cellular responses limits immune escape, just as multi-drug therapies limit drug escape.
                    
We selected MVA for use as the live viral component of our vaccines because of its well-established safety record and because of the ability of this vector to carry multiple proteins required to produce VLPs. MVA was originally developed as a safer smallpox vaccine for use in immune compromised humans. It was developed by attenuating the standard smallpox vaccine by making over 500 passages of the virus in chicken embryos or chick embryo fibroblasts which resulted in large genomic deletions (~30,000 nucleotides). These deletions increase the capacity of the vector to accommodate large and multiple antigens, limit the ability of MVA to replicate in human cells, hence increasing the safety of the vaccine, but do not compromise the ability of MVA to grow on avian cells that are used for manufacturing the vaccine. The deletions also resulted in the loss of immune evasion genes which assist the spread of wild type smallpox infections, even in the presence of human immune responses. MVA was safely administered to over 120,000 people in the 1970s as a smallpox vaccine.