An interview with Dr. Hildegund Ertl,
Interview conducted May 14, 2022; posted May 28, 2022
I am delighted to be here today with Dr. Hildegund Ertl, who is the Scientific Founder of Virion Therapeutics, LLC, and a Professor in the Vaccine & Immunotherapy Center at The Wistar Institute. She has had a life-long interest in immunology and vaccine research, which has led to the development of various new vaccine technologies. Dr. Ertl and her colleagues originally began working with adenoviral vectors for gene therapy, but they soon realized that this research might be more useful in vaccine development.
Dr. Ertl, can you tell us how your work began with chimpanzee adenoviral vectors?
So, we started working with chimpanzee adenoviral vectors; my postdoc tested them… and they worked incredibly well.
“We started working first with human adenoviral vectors as vaccines. After a short period of time, we noticed that there was a problem with pre-existing immunity that would probably make this technology less useful in humans.
So, we started working with chimpanzee adenoviral vectors; my postdoc tested them… and they worked incredibly well.”
This led Dr. Ertl and her team to become pioneers of novel vaccines created from chimpanzee adenoviruses. Unlike human adenovirus vaccine platforms, humans lack neutralizing antibodies to chimpanzee adenoviruses, resulting in potent vaccine-induced immune responses. Chimpanzee adenoviral vectors are now widely used to combat many human diseases, including COVID-19 and cancers.
How exactly did your work evolve – from these activities – to your discovery of glycoprotein D?
“A graduate student from Brazil was trying to make a dual vaccine for HSV [herpes simplex virus] and HPV [human papillomavirus] by making a DNA vaccine that expressed proteins from each virus. For HSV antigen, he used glycoprotein D [gD] and for HPV he used the E7 oncoprotein, which he genetically fused into gD. When he tested the vaccine responses to E7, they were much better when the vaccine coexpressed gD. However, at this initial stage, we didn’t really understand what was going on.
So, there I was, sitting in a library in Brazil, reading a paper that had just come out that said that gD binds to HVEM [herpes virus entry mediator] – and then it hit me: maybe, this is an immune inhibitor that we are blocking with gD. When I returned to my lab, we tested this theory and, indeed, showed that gD, bound to HVEM, could block BTLA [B- and T-lymphocyte attenuator] binding. This provided the initial data for our hypothesis that gD increases both T cell and B cell responses and, since that discovery, we have confirmed this in many different disease models.”
This led to Dr. Ertl’s latest achievement to develop Virion’s Intelligent and Adaptable CD8+ T cell-based Immunotherapy (also known as VIACT™) platform, which uses a technology that contains a series of distinct chimpanzee adenoviral vectors, known as ChiVax™.
The VIACT platform comprises genetically encoded checkpoint modifiers combined with intelligently selected and optimized target antigens, which are inserted into ChiVax.
Can you explain the importance of antigen selection in the process?
“With vaccines, you want an antibody or T cell response or – even better – both. So, the first step in this process is that we must figure out what antigen(s) is likely to be protective – and recognized to a high degree – by T cells or antibodies. For T cells, it depends a little bit on the life cycle of the virus.
For tumors, you must pick an antigen that the tumor really needs, because if tumor cells can replicate without it, the tumor will simply lose that antigen, and your vaccine becomes useless.
So, once you figure out your target antigen or antigens, you must then put them together. In doing this, you also want to pick conserved regions that are full of T cell epitopes – which are specific pieces of the antigen to which the T cell receptor binds. If you want to make a B cell vaccine, you want to have a conserved region, but also a region that gives you a good neutralizing antibody response.”
With vaccines, you want an antibody or T cell response… We must first figure out what antigen(s) is likely to be protective
Most people are familiar with checkpoint inhibitors (CPI). Can you tell me how a checkpoint modifier is different from a CPI?
gD acts differently because it affects T cells during the process of activation by lowering the activation threshold… And that’s advantageous, especially for chronic infectious diseases and cancer.
“Checkpoint inhibitors – as the name implies – do one thing, they inhibit an inhibitor; one of the best-known examples of a checkpoint inhibitor is PD-1.
“You asked how a checkpoint modifier differs from this – well, it is something that can do multiple things: it can inhibit, but it can also activate, or allow for costimulatory signaling. In other words, it inhibits an inhibitor and/or activates an activator and/or allows for co-stimulatory signals. So, in our case, we are using HSV glycoprotein D, also known as gD, which is a surface protein of HSV. gD binds to HVEM at the same location as does BTLA and in so doing blocks BTLA from interacting with HVEM, resulting in increased T cell receptor signaling and allowing for co-stimulation through other molecules such as LIGHT that also bind to HVEM.
Current checkpoint inhibitors, such as PD-1, CTLA-4 and other immunoinhibitors, have revolutionized treatment, especially for cancer. However, in the case of anti-PD-1 antibodies, they only affect activated T cells. gD, on the other hand, acts differently, because it affects T cells during the process of activation by lowering the activation threshold. This allows T cells that are not normally activated– such as those to epitopes that are only expressed at low levels on the cell surface (known as subdominant epitopes) to become activated. And that’s advantageous, especially for chronic infectious diseases and cancer. The T cells that are activated by the tumor or infection to the dominant epitopes often undergo a process of exhaustion – meaning they gradually lose their functions – and they die. And what you’re left with are T cells that have not yet become activated against the subdominant epitopes, which are those that a gD adjuvant vaccine aims to stimulate.”
How does gD differ from the monoclonal antibodies currently used as checkpoint inhibitors for cancer?
“By encoding gD together with the antigen, it is a genetic vaccine – this vaccine must transduce, or infect, a cell and then make the protein composed of an antigen and gD. So, you only get expression of gD at the vaccine injection site or locally within the draining lymph nodes. As a result, you don’t get a systemic expression of gD, which is unlike what happens upon transfusion of monoclonal antibodies that have a wide distribution throughout the body – this can lead to autoimmune dysfunctions, which can be rather serious. We do not anticipate serious side effects with gD because most people are chronically infected with HSV without deleterious effects indicating that gD does not trigger serious adverse events and in addition gD has already been used in the clinic as a vaccine against HSV.”
What do you believe is the potential role of gD in treating chronic infections and cancers?
“So far, gD works beautifully in mice relevant to their T cell activation pathways. We know the core inhibitors and stimulators are fairly well conserved between mice and men, and we have shown that gD blocks human BTLA and HVEM interactions. Next, we need to formally prove that gD is functional in humans, which is what we are now planning for our first-in-human-study VRON-0200 HBV program.”
So far, gD works beautifully in mice in regarding T cell activation pathways… the core inhibitors and stimulators are fairly well-conserved between mice and men
What are some of the key research areas you and your lab are working on?
“We are working on developing immunotherapies for acute and chronic infectious diseases and cancers including oncogenic human papillomaviruses (which are still very common), melanoma, and COVID-19.”
Another achievement from Dr. Ertl’s laboratory is that her chimpanzee adenoviral vectors are currently being evaluated in an ongoing HIV prevention study in South Africa, sponsored by the National Institutes of Health. In addition, Dr. Ertl, in collaboration with Virion Therapeutics, is soon to initiate a first-in-human study (VRON-0200 program) in patients as a potential functional cure for people chronically infected with the hepatitis B virus.
Thank you for taking the time to do this interview with me today, Dr. Ertl. I look forward to continuing the discussion and sharing more of your research and activities in the near future.