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An Interview with Annie De Groot, MD – Vaccine Researcher

Tell us how you decided to become a vaccine researcher.

I always tell people that I learned the importance of vaccines in the back of a Toyota truck. The truck was transporting two small children and their mom to a mission hospital, from a remote Congolese village. I was a medical student at that time, working to vaccinate children against measles. In this case, our team arrived too late, and the village children already had measles.  What happened next was that one of the two sickest children died on the way back to the hospital. Her mother was heartbroken.

Even then, measles was completely preventable, but lack of access to vaccines and the need for refrigeration impeded distribution of the vaccine. That experience shaped my career. I have been dedicated to the development of vaccines that are affordable, accessible, safe, and transportable ever since.

What are you most excited about in the field, recently?

I’m really very excited about how the Institute for Immunology and Informatics at University of Rhode Island (URI’s iCubed), is coming together. As you know, we only started it a few years ago, but we’ve already been able to develop and validate immunoinformatics tools that dramatically accelerate development of vaccines directly from genomic sequences, even as we pay close attention to aspects of vaccine design that will improve their safety profiles. We are now turning our collective attention to transforming these discoveries into products, leading to the production and deployment of vaccines that will have a significant impact on global and individual health. There is hard work left to do, but I think we have a Hepatitis C vaccine on the launch pad, along with a vaccine against Helicobacter pylori, a type of bacteria that can cause stomach cancer.

What’s the source of funding for your research, and who are you working with?

I’m lucky to work in two very different places. On the one hand, I work at EpiVax, a ‘boutique’ vaccine design company located in Providence. EpiVax is an innovative think tank for new approaches, and has turned that creative thinking into commercial success. Most of the funding for EpiVax comes from SBIR grants and contracts from large Pharma companies. The company has a great group of scientists, including Lenny Moise and Bill Martin who are thought leaders in the arena of vaccine design.

I also work at the University of Rhode Island’s Institute for Immunology and Informatics. The institute has received significant support through the Collaborative Centers for Human Immunology (CCHI, DAID, NIAID) for the discovery and development of epitope-driven vaccines. When Alan Rothman joined the group in 2011, the Institute expanded to 20 faculty and staff researchers. Our two paths have very nicely converged to this point from very different directions. He brings extensive knowledge of immune responses to viruses and a deep repertoire of immunology assay experience, while I can contribute my experience in translational vaccine research. Denice Spero, who was formerly a senior scientist at a local biotech company, has been helping the team with vaccine development, project management, patent filings, and translational research planning. Together, we will move our pipeline of well-developed vaccine programs to the clinic.

What’s new about your approach to vaccines?

At EpiVax and now at the iCubed, our focus has been on defining the ‘minimum essential components’ of vaccines, sort of like ‘nouvelle cuisine’ (I am sure people know what I mean when I use that analogy). Until 15 to 20 years ago, people still made vaccines using what we call the ‘shake and bake’ approach, turning whole bacterial cultures into vaccines by killing them with heat or chemicals. By that I mean growing up bacteria in big flasks (images of Louis Pasteur and his goose-neck flasks should come to mind) and then baking it, or killing it with chemical treatments, and injecting the whole (dead) bacteria or virus into a person.

We’ve come a long way since “shake and bake” was the only way to make vaccines. In my group, we’ve been working on taking apart the bacteria and viruses and stripping vaccines down to the very essence of a vaccine, or just the parts that are needed.

We like to say that a vaccine can be made out of three components: ‘Payload’ (the information that tells the immune system to fight against a specific pathogen) + Adjuvant (the danger signal needed to trigger a response) + delivery vehicle (the packaging that gets the vaccine to the right place in the body).

Recombinant vaccines offer a number of wonderful advantages over the shake and bake methods of the past. For one thing, It’s now possible to identify the ‘critical antigens’ or key proteins that are important for immune defense against pathogens, in many cases, and these key proteins can be produced in using methods that are more easily replicable and quality controlled than ‘shake and bake’, and faster, and in higher volume.

There are other significant disadvantages to the ‘shake and bake’ method that include poor immunogenicity and potentially adverse reactions to the proteins or lipids in the mixture. And, from a purely immunological standpoint, the amount of information being delivered to the immune system was probably unnecessary, if not excessive. Not that the immune system can’t handle it, but we’re beginning to rethink the whole concept of ‘whole protein’ and, beyond that ‘whole bacteria’ or virus, because we are finding evidence that immune responses overlap, between bacteria and their hosts. So, if you really think about it, we should probably be stripping vaccines down to the bare minimum.

So we can reduce the amount of information that is being put into vaccines to the minimal amount that is necessary, potentially reducing ‘off target’ effects.

What might be some disadvantages of the ‘reductionist approach’ to making vaccines?

On the opposite end of the spectrum, sometimes too little information is delivered. This is something that we have seen in therapeutic vaccines against cancer, in particular, and sometimes we have seen this in clinical studies of vaccines against infectious diseases. One clinical study, for example, involved treating a patient who had HIV with a peptide that was the ‘key antigen’ for his specific virus. Initially, the amount of virus that was in his blood was reduced, but when it rebounded, the researchers discovered that his virus had mutated its sequence to escape the immune pressure of the vaccine.

We think that this might also occur for vaccines against cancer, which can also vary in response to immune pressure by ‘escaping’ from a single antigen that might be included in the anti-cancer vaccine.

In response to the problem of immune escape, our approach has been to combine multiple ‘key antigens’ or even very small pieces of these key antigens, called epitopes, in a single recombinant vaccine. These epitope-based vaccines can be produced from the genomic information of a single pathogen, or all of the known sequences for a single pathogen. In the case of cancer, we can combine epitopes from different antigens. Or, for viral pathogens, we can scan the variant sequences for conserved elements and combine those into a vaccine. For example, there are hundreds of thousands of sequences for HIV, and our computer tools can find the conserved epitopes from all of those strains to put in a single vaccine – we are working on such a vaccine (two papers on the approach were published this year (Paper 1, Paper 2) that we call the “GAIA” HIV vaccine, because it could be used anywhere in the world and would work against any strain of the virus.

What are the new tools that you have been working on?

Since we believe that putting multiple epitopes into a vaccine is the best approach, we have developed a whole suite of tools that can turn genomic information into a string of epitopes that can be expressed as a vaccine. The tools are packaged together in a “workflow” management system called iVAX.

The iVAX toolkit has been tested on several different vaccines over the past 10 years with great results (at least in mice). Examples include H. pylori (the cause of gastritis and stomach cancer) and a new smallpox vaccine (we call it VennVax) (both are published). What’s exciting is that our iVAX toolkit can essentially design vaccines ‘in silico’ (on a computer chip). These vaccines can then be produced recombinantly using any number of methods (DNA, protein fusions, peptides in liposome are the approaches we have tested so far). In theory, we could design a vaccine within just hours of being provided with a pathogen’s genome.

That sounds exciting, is it really happening?

We’re currently testing that theory in collaboration with Mark Poznanksy of NIH, who obtained funding from DARPA to pull together a consortium to make “vaccines on demand”. We provide the vaccine design technology (using the iVAX toolkit) for what is now called the VaxCelerate Consortium.

If you want to be really futuristic, imagine using our tools in combination with the “3-D printers” that are all the rage now – in silico design of vaccines could, in theory, produce vaccines ‘on demand’ for a single person, tailored to their own genetic make up and whatever specific pathogens they are exposed to. I don’t think it’s too far fetched to imagine designing vaccines for personal use, that could be produced at home. It could be done, using the iVAX toolkit that we have designed.

How far has the industry come over the last decade in optimizing issues related to vaccine production, delivery and safety?

There are a number of companies that have developed great vaccine delivery vehicles, such as DNA – yes, genes that express the vaccine message, so that the vaccine actually gets made right in your own body. A great example of a vaccine company that is leading the way is Inovio. They have quite a few DNA vaccines in clinical trials, and they have an excellent safety track record. They’ve been working on optimizing the delivery of vaccines by electroporation, and have been working on making smaller and smaller versions of the electroporation delivery system. It’s really very exciting, what they’re up to! I believe that DNA vaccines are really the way to make vaccines in the future.

Other examples of “faster” vaccines that have been developed include the cell-culture based vaccines that are being developed by Novartis and Baxter. I think that these are very exciting developments but I also have concerns about the potential for host-cell proteins that might get into those vaccines. By that I mean – the proteins that are present in the cell culture medium. I’m just putting that idea out there, without knowing a lot about the processes that these very accomplished companies use to rid the final product of mammalian proteins. I know that “HCP” are a concern for biologics developers, so I can’t imagine that they won’t also be an issue for vaccine developers that use the same cell culture methods.

How will Epivax’s immunoinformatics platform continue to drive innovation to address the challenges that remain in this area?

We’ve been working on some really cool approaches to understanding immune responses using our computer tools. For example, we think that the ‘critical antigens’ of that should be put into vaccines should include proteins that are somewhat conserved with proteins that are present in our own gut micro biome. Turns out that our gut micro-biome probably educates our T cells, so the elements of pathogens that are somewhat conserved with elements of the gut micro biome could be the most effective ‘critical antigens’ to put into a vaccine. Stay tuned for more on that story!