It all started with EpiMatrix...

Applying computational approaches to immunogen selection and modification has set new standards in vaccine design. Consider codon optimization, a method which allowed scientists to circumvent codon usage bias in order to achieve high levels of difficult-to-express proteins outside their native hosts. Codon optimization has helped immensely in the development of HIV prototype vaccines where viral genes (gag, env, pol etc.) were expressed in the absence of the Rev-RRE system.

Achieving efficient expression of a vaccine agent in the target tissue/cell, however, does not always guarantee the desired immunogenic effect; and this is where companies like EpiVax can be very useful. Using the tools and technologies available by the company, one can identify putative T cell epitopes (EpiMatrix), MHC Class II epitope clusters (ClustiMer), human(or other species)-like peptides (BlastiMer), de-immunize a protein sequence (thereby creating alternative candidates with altered immunogenic profiles) (OptiMatrix-in combination with their DeFT service) and finally identify conserved epitopes (Conservatrix) in multiple sequences of highly mutating pathogens, such as HIV. The company has also recently introduced VaccineCAD, which is a vaccine-design algorithm that assists in alignment of selected immunogenic epitopes in a vaccine construct, avoiding (or at least reducing) the formation of "nonsense" epitopes, usually appearing at junctions between consecutive epitopes. If you want to check out the web versions of all of EpiVax's tools, head over to the iVAX website.

EpiVax looks a promising company with services that are already finding their way in multiple stages of vaccine design. In addition, we are convinced that its DeFT service can have a significant impact in the field of Gene Therapy, where de-immunization of transgenes is of paramount importance. The company has received several awards from the NIH and it is now making good strides in establishing itself as an one-stop-shop for immunoinformatics. For some more information, here is an article by EpiVax's Founder, CEO and CSO, Dr Annie De Groot.

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Immune Design steps up and gets noticed…again...and again!

Back in July, Immune Design raised $32 million in a Series B financing; that’s quite a bit of money and brings the total up to $50 million since 2008. Amongst the leading investors we can see ProQuest Investments (who also have in their portfolio companies like Aerovance, who develops asthma-combating drugs, and  Somalogic, who develops novel diagnostics tools for oncology, neurology and CV diseases), The Column Group, Versant Ventures and Alta Partners.

Now the company is making waves once again by licensing out its proprietary GLA (Glucopyranosyl Lipid Adjuvant) to MedImmune, for it to be used as an immunomodulating agent in vaccines for select infectious diseases. GLA is a TLR-4 agonist and is considered to be the next generation of MPL (Monophosphoryl Lipid A), an adjuvant originally developed by Corixa and currently being used in vaccines produced by GSK, following the latter's acquisition of Corixa. GLA was originally licensed to Immune Design by the Infectious Disease Research Insitute, IDRI, of Seattle.

Immune Design's approach to vaccine design and development is pretty straightforward: targeting of dendritic cells (DC) with their proprietary vector (DC-NILV, Dendritic Cell targeting Non-Integrating Lentivirus Vector)  coupled with GLA.  Not surprisingly, and given their “talent” for attracting investment, Immune Design had already been identified as an emerging drug developer by FierceBiotech in 2008.

The company has some big names on its Scientific Advisory board. Lary Corey is heavily involved in HIV vaccine clinical trials, Rafi Ahmed is involved in HIV vaccine research as well, David Baltimore developed the prototype lentivirus vector that Immune Design are now using (and of course has received the Nobel prize for the discovery of reverse transcriptase!), Philip Greenberg who works on modulating T-cell responses to viruses, Inder Verma, who develops gene therapy vectors and Ralph Steinman who is credited with the discovery of dendritic cells. Throw in the mix someone like Richard Klausner who was an Executive Director for Global Health at the Bill and Melinda Gates foundation and Director of the National Cancer Institute and you end up with a pretty strong team. David Baltimore and Richard Klausner are also on the board of Directors. Immune Design also has a strong executive team; you can find more info here. Given the structure of the Scientific and Exec boards, Immune Design venturing into the world of HIV vaccines pretty soon looks a real possibility.

Although the company appears a promising and investable package, it lacks in variety of antigen delivery systems and adjuvants. Looking at their technology, as shown on their website page, the company seems to have been built around a single vector-adjuvant system, not a particularly "safe" approach-a profitable one so far though, as the GLA licensing deal with MedImmune will give Immune Design $212 million. The ability, however, to directly and specifically target DC is a major advantage and should yield exciting results in the years to come. It can be expected that they will seek to partner with companies that are quite geared towards antigen modification for enhancement of immune responses, such as SEEK (formerly known as PepTcell) a company with universal flu and HIV vaccines in Phase II clinical trials.

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Inovio Pharmaceuticals

Inovio Pharmaceuticals specializes in creating vaccines with superior characteristics in terms of immunogenicity and T cell responses.

At the heart of the company's development pipeline lies its proprietary 

SynCon™ DNA Vaccine Platform technology which is described on the company's website as: 

"More technically speaking, SynCon™ DNA vaccine antigens are designed by aligning numerous primary sequences and choosing DNA-based triplets for the most common amino acid at each site. These antigens are further optimized for codon usage, improved mRNA stability, and enhanced leader sequences for ribosome loading. The DNA inserts are therefore optimized at the genetic level to give them high expression capability in human cells."

I am not so sure how much this differs from other codon-optimization approaches (see Geneart for example) but, coupled with Inovio's electroporation technology, makes the company a strong competitor in the field of genetic vaccines.

Inovio's list of Partners includes Merck and Co., the HIV Vaccine Trials Network (HVTN) and the National Institute of Allergy and Infectious Diseases amongst others (see here for more information).

The company has recently announced a $24.3 million registered offering, with the proceeds going towards further development of its DNA vaccine candidate against cervical dysplasias and cancers, as well as towards funding of other preclinical and clinical studies (the full announcement from the company can be found here).

We believe that DNA vaccines constitute one of the most important developments in the last 10 or so years, in the vaccine field. Technically speaking, a DNA vaccine consists of a DNA sequence coding for the desired immunogen, combined with an appropriate delivery method (most commonly used nowadays an intramuscular injection or a transdermal delivery approach) and preferably complemented with an immunomodulating adjuvant agent. Inovio Pharmaceuticals seems to be ticking all the boxes, or at least has made good progress towards developing truly novel DNA vaccines, with a gene optimization algorithm that allows for ehanced transcription/translation of its products and with an efficient delivery method in the form of electroporation. 

It is quite interesting to see vaccine companies such as Inovio Pharmaceuticals, making use of electroporation for the delivery of their vaccines; DNA vaccines, especially the very first ones that were based on early generation plasmid backbones, are inherently difficult to deliver to the target site and achieve long-lasting expression or even a strong immune response to begin with. Electroporation seems to solve the delivery problem and in certain cases can also have an adjuvant effect through associated cell death and local site inflammation following vaccine delivery. Of course the debate over usefulness and the best delivery method between viral vectors and approaches such as electroporation still holds on, but for the time being, and until we start seeing these approaches reaching late stage clinical trials and the market, one should choose the most appropriate method depending on their needs. 

In the meantime, Inovio Pharmaceuticals looks to be well positioned for a strong "push" forward. The company is currently running clinical trials in the cancer (cervical, breast, lung and others) and infectious diseases (HIV and influenza) fields. More information on positive results from its Phase I HIV vaccine trial can be found here.

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