You’ve invested millions of dollars, spent over a decade conducting trials and it’s only when you reach the final phase that you realize your product doesn’t even work.
That can be the unfortunate reality for vaccine development.
Few understand this better than Thomas Lingelbach, CEO of Valneva, a company focused on the development of innovative vaccines in areas of unmet medical need. With over twenty years of experience in the industry, having worked for Chiron, Novartis and Intercell, Thomas has overseen numerous vaccines go from bench to market.
With vaccines to tackle Lyme disease and Chikungunya both in clinical development, Thomas chats to Pharma IQ about ongoing challenges vaccine developers face, how to prepare for Phase III success and the changes set to disrupt the market in coming years.
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Pharma IQ: Having worked within the vaccine industry for over 20 years, what do you see as the core challenges companies face when bringing a potential vaccine through clinical development?
Thomas: Well the world of vaccines is highly regulated. This is largely because we are focusing on prophylactic vaccines, so dealing with healthy people, not patients, which is a big difference to many other parts of the industry.
Of course, the major challenge from vaccine development and vaccine clinical trial design compared to pharmaceuticals is that you typically have no hint of efficacy until you see potential efficacy during large-scale Phase III trials. In other areas of the pharmaceutical industry, you will have signals for potential effectiveness in Phase I or II. You may not know fully, but you do get a first hint.
In vaccines, you typically only see this with large numbers in a Phase III trial. In Phase I and II for vaccines, you’re looking at immunogenicity and there are very few disease areas where there are so-called correlates of protection established. And for the novel vaccines we develop, these correlates do not exist at all.
This means you need to run up to Phase III without knowing whether your underlying hypothesis is going to fly.
Vaccine developments takes between 10 to 15 years depending on the disease area and complexity, with Phase III typically being conducted in the last three years of clinical development. So that means you have a large number of years and a high investment to undertake before you come to your moment of truth.
Pharma IQ: So when you have to undergo a high level of up-front investment in time and resources, how do you ensure you go into Phase III in the strongest position?
Thomas: First of all, we try to build comprehensive animal models in the pre-clinical phase to give us a clear idea on the possibility to create anti-bodies.
At the same time, we are working intensively to get the vaccine antigen developed as quickly as possible.
In vaccines, you may hear the saying that the product is the process and vice versa. This has to do with the fact that vaccines are still, to a large extent, highly complex biologics.
As they are not fully characterized with analytical methods, it’s critical to ensure there is no change to a product candidate all the way from pre-clinical to life ensure.
Before you even go into human testing, you need to put emphasis on the C&P development. This is again different to other drugs where you have up-scales, tech transfers and changes to the process laid on, as you can always test and measure whether the product is still the same.
Also, as we are dealing with healthy people, the vaccine Phase I safety trials typically need to have higher numbers than you would see in other areas of drug development as you want to create a strong safety database pre Phase II. Typically, this is almost a factor of ten between what you see in Phase I vaccine trials versus another highly specialized drug development area.
Another thing we do is related to immunogenicity; measuring the immune response to measure antibodies. You need to determine which antibodies you want to measure and which should be functional against the respective disease. You have to put substantial effort into the development of immunological assays. This can be easy things like developing analyzer that is coded against the native pathogen. But it is something you must do at the beginning whether you are talking about a perceived good or bad immune response.
The other thing we do is build a model, called a passive or active immunization, which operates as a challenge model.
To give an example, with animal models you can put sera from a human, who was part of a clinical trial and should have developed the respected antibodies against the disease, into modified mice. Then you can challenge the mouse with the pathogen and test whether the human sera showed some level of protection. This is what you want for your vaccine. And it’s something you cannot necessarily do the same way for other drug developments.
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Pharma IQ: Do you think there is more scope to be innovative in the way we approach clinical trials for vaccines?
Thomas: For vaccine trials, there are two things we haven’t really done broadly in the past but there are opportunities for us to start doing.
To use the example of our chikungunya candidate, we conducted a very broad Phase I trial for a live attenuated vaccine with a single shot to protect people against chikungunya fever. For this, the data generated in the non-human primate phase may be sufficient enough to lead to a straight move into Phase III. As the Phase II requirement for vaccines is dose and schedule, when you only have one shot there is no objective for Phase II. This is an example of how you can be innovative when it comes to introducing more flexibility to the process.
There is scope to be innovative when it comes to the timelines for clinical trials
Another point is that there have been great success stories when countries, due to national urgencies or priorities, decide to combine state controlled or state overseen vaccination programs with a large Phase III objective.
A good example is how meningitis B in infants and toddlers was addressed in New Zealand. A product candidate was available at the end of Phase II, with safety data on about 500-600 people. As meningitis B was a big issue in New Zealand, the government decided to go through a state overseen vaccination campaign for more than a million children and toddlers off the back of this Phase II data. This allowed them to basically monitor the safety and effectiveness in real time.
This combination of a catch-up program to address a huge unmet medical need and at the same time allowing this to meet the Phase III needs is a fascinating example of what can be done. Especially when we are facing other outbreaks, I believe there is something we can learn here from a vaccine development point of view.
Pharma IQ: What developments do you foresee changing the way we operate vaccine clinical trials in the next five years?
Thomas: Firstly, I think that the overall inclusion and exclusion criteria will be much, much more stringent and much more controlled and regulated than it used to be.
I expect the number of tests being conducted before a patient is included in a vaccine trial to be substantially higher than it used to be. This is because you don’t want a side signal coming from completely unrelated diseases or to have other negative influences that are unrelated to the vaccine itself.
I would also expect people committing to more things during the course of the trial in order to not have false safety signals.
Finally, I expect that there will be an increase in the quantity of documentation, including the degree of pre or early human data and pre-clinical data, needed to support the judgment of committees before allowing certain trials to go ahead.