"Shaping" new vaccines

On March 8th 2011, Liquidia Technologies announced that it has received $10 million from the Bill and Melinda Gates Foundation, in order to develop new vaccine candidates utilizing its proprietary PRINT (Particle Replication In Non-Wetting Templates) technology. For those that have been following the activities of the Gates Foundation, it will immediately be evident that this type of activity, i.e. akin to a VC firm, is quite different to the normal grant process that the Foundation was, and still is, employing when financing a project. One can refer to the Collaboration for AIDS Vaccine Discovery (CAVD), a network of research teams that the Foundation set up and funded with $355 million in order to work towards development of an HIV vaccine, to understand the scope and basic functions of this charity organization.

Liquidia Technologies was founded in 2004 and is currently being backed up (besides the Gates Foundation) by New Enterprise Associates, Canaan Partners, Pappas Ventures, Firelake Capital Management, the Wakefield Group as well as private investors. This is a strong group of investors that, in theory, could assist Liquidia in its plans for rapid growth. Canaan Partners are well known and active investors in companies such as VaxInnate (recently in the news for receiving $117.9 million over three years-potentially rising to $196.6 million over five years- by the HHS, for development of influenza vaccine candidates) and Chimerix, a company that develops orally available antiviral agents, using its Phospholipid Intramembrane Microfluidization (PIM) technology.

What is really exciting about Liquidia's PRINT technology is the ability to control and modify at will the shape, size, chemical composition and, in general, most parameters that play a role in the immunomodulatory properties of a vaccine candidate. The company proposes formulating a vaccine agent or a drug, on a PRINT-produced dissolvable particle. Making use of the ability of the immune system to recognize and distinguish between 3D shapes of proteins and pathogenic/self structural components, such a particle could possess the shape of a bacterial component that triggers a specific immune response, or the structural conformation of a cytoplasm-localized protein, that would facilitate transport of the active ingredient through the cell membrane.

From an investor's perspective, Liquidia constitutes an attractive case. PRINT technology should generally increase the efficacy of a vaccine and could be employed to generate an adjuvant effect; these features will drive costs of vaccine production down and discard the need for use of non-approved adjuvant agents (the FDA is known for its reluctance to approve novel adjuvants). PRINT particles can also be combined with existing vaccines, and this opens up a wealth of opportunities for Liquidia. The company has recently announced the initiation of its first clinical trial, testing its lead seasonal flu vaccine candidate, LIQ001. A quick look at the clinicaltrials.gov website reveals that LIQ001 is being tested as a combination with sanofi's Fluzone; the trial has finished recruitment and is expected to complete in late 2011 with results available in early 2012. As this trial constitutes the company's first attempt of progressing the PRINT-based technology from proof-of-concept into the clinic, we are waiting impatiently to see the results. Liquidia has also signed an agreement with the PATH Malaria Vaccine Initiative (MVI) for the use of PRINT technology in the development of a new generation of malaria vaccines; we believe this is a strategic step, crucial for the company's further development and a collaboration that should yield large amounts of clinical trial data, necessary for further evaluation of PRINT.

Looking into the future, a company such as Liquidia, constitutes an attractive target for acquisition/partnership from a larger biotech or pharma company. Despite the company's recent investment influx and collaborative agreements, it still remains very interesting to see how PRINT technology will navigate the regulatory path and to pressure-test its limitations and advantages.

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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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