Made possible by genomic engineering

What is the goal of a vaccine? It is simply to introduce to the body’s immune system a protein associated with a particular pathogen. The intent is to have the body recognize this protein as being antigenic (foreign), mount an immune response, and establish memory against this antigen and its associated pathogen in the future. In the case of conventional vaccines, a weakened, inactivated, or component of a virus is inserted into the body to accomplish this goal. The drawbacks of this approach are numerous.

One of the biggest drawbacks of traditional vaccines is that for diseases that change rapidly and evolve into many different strains, the genetic makeup of the antigen introduced to the body by the vaccine may be different than what it encounters in an actual pathogen in the future. Same pathogen, same antigen, different strain. Since the immune system isn’t looking for the mutated version of the antigen, it may not send out the soldiers to prevent or fight an infection.

Inovio's SynCon® vaccine design process steps beyond the conventional vaccine focus of creating one vaccine for one virus strain. Apart from the general advantages of DNA vaccines, Inovio’s synthetic DNA vaccines are designed to provide a potentially game-changing distinction. Rather than creating a vaccine from one strain of a virus or cancer, we base our design on multiple strains of the targeted pathogen.

We first gather multiple strains of the targeted infectious disease or cancer. Using extensive genetic data and sophisticated algorithms, we analyze the different genetic sequences for the specified antigen. We then synthetically create a consensus gene sequence for the antigen. This is a new sequence that does not naturally exist. It does not match, but is substantially similar, to the antigen gene sequences of the strains from which it is derived. This SynCon® vaccine provides an important step toward the goal of a universal vaccine able to protect against multiple unmatched as well as changing, newly emergent strains of a pathogen.

The goal of a universal vaccine is to be able to protect against a virus such as influenza even when the strain changes – as it regularly does. Our first human data, from a phase I influenza study, has provided early evidence that this goal may be achievable, showing in some patients levels of immune responses considered protective in humans against six different unmatched strains of H5N1 influenza. In a second phase I influenza study we reported protective levels of immune responses against nine different unmatched strains of H1N1 influenza.

Successful development of a universal vaccine would help protect against the genetic “drift” that occurs within subtypes of a virus (e.g. in influenza, H1, H2, H3 and H5) or the “shift” that can occur when sub-types reassort (e.g. when strains from different subtypes such as H1, H2, H3 and H5 merge to create new genetic combinations). HIV, hepatitis C virus (HCV), human papillomavirus (HPV), and influenza are examples of diseases subject to drift and shift and which require more universal protective capabilities.

For any particular disease of interest there are typically multiple proteins that are part of that pathogen that the body’s immune system will recognize as antigenic (foreign). Another valuable advantage of our DNA vaccine technology is that we can readily mix and match DNA plasmids coded for different antigens, enhancing the potential to trigger a broad immune response.
 

Creating an Inovio SynCon® Vaccine
SynCon vaccine design



More technically speaking, SynCon® DNA vaccine antigens are designed by aligning numerous primary sequences and selecting the most common amino acid at each site. The amino acid sequences are also selected for other critical properties such as important T-cell and antibody regions as well as sequences known to generate strong immune responses during natural infection that are associated with protection from disease.

These antigens are further optimized by choosing DNA-based triplets for efficient codon usage, improved mRNA stability, enhanced leader sequences for ribosome loading, and depending on the in vivo natural expression of the antigen, for antigen secretion, processing, and presentation. The DNA inserts are therefore optimized at the genetic level to give them high expression capability in human cells as well as to correctly mimic antigen processing and presentation to that achieved during natural infection, ensuring that the immune responses produced are relevant to preventing or controlling disease.

Inovio’s SynCon® vaccine technology was intended to overcome many different barriers to the induction of desirable immune response characteristics not achievable using conventional vaccines or other emerging technologies. To date the platform is displaying success in achieving these desired immune responses.