“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.

“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.”

“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.”

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.”