Phenotypeca, a biotech business from Nottingham, UK, has been working with the Bill & Melinda Gates Foundation to produce albumin for low and middle-income countries (LMICs), offering a catalyst for making life-saving vaccines affordable globally.
Global vaccine production faces several challenges. Limited availability and the high costs associated with recombinant albumin act as a barrier to achieving vaccination equity. Developing a vaccine from concept to market can cost $200-$500 million and, even with the introduction of artificial intelligence to speed processes up, it can take five to 18 years.
Additionally, it costs an estimated $50-$700 million to construct, equip and commission a vaccine manufacturing facility, taking on average seven years.
Phenotypeca’s solution is to use quantitative trait loci (QTL) technology to produce albumin at a commercial scale. QTL can deliver consistent quality and exact bioequivalence at a lower cost of manufacture – with significantly less plant required.
To tell us about Phenotypeca’s work, and how it’s making a difference, we spoke with the company’s CEO, Johnny Cordiner, and research and development director, Professor Ed Louis.
Unlocking the yeast genome
Louis explained that Chris Finnis, one of Phenotypeca’s founders, is one of the world experts in the traditional industrial approach to baker’s yeast, as a microbial chassis for recombinant protein production.
“Various lessons were learned either from academia or from R&D within the industries of engineering steps that would improve recombinant protein production,” Louis explained.
“For example, there’s a well-known protease that was discovered in the 70s that is now incorporated into every production strain and it’s long off patent so everybody can use it. But also, random mutagenesis was used. So, you would mutate your strain, screen for things that were better, use that for production, do more and more rounds of mutagenesis.”
However, Louis said, the problem with that is it’s random. The key, he explained, came from genome sequencing of yeast.
“We sequenced many genomes in the old-fashioned way. We measured traits, 201 traits, actually, across dozens of strains, and showed there was a strong correlation between these phenotypes and the genotypes, which led us to the realization that by classical breeding between these strains, we should be able to determine the underlying genetic variation that underpins the improvement of a trait.
“So, if you were making more ethanol, for example, or less ethanol in a wine or brewing in this situation, you could not only generate strains that do this, but find the underlying genetic variation that can do this. If you’re trying to express a protein in yeast and get it secreted, that is the level of expression, the amount of secretion, the amount of post-translational modifications, those are all phenotypic traits, and there is variation in those phenotypic traits when you look at a wider variety of strains.”
“As a consequence of that, you can do bespoke optimization, genuine multi-parameter optimization,” Cordiner said.
“There are certain commercial and technical spots where the ability to optimize creates a premium product, which can command market share and is commercially valuable. In essence, that’s what we do. We carefully scope out where the skills of our technology answer a commercially and technically relevant problem, and we bring it to bear on those cases.”
What is recombinant protein technology?
Louis explained: “The brief definition is expressing from a synthetic piece of DNA on some kind of expression vector or integrated into the genome, a protein that is not found in your chassis, whether it’s yeast, E. coli, Chinese hamster ovary cells, insect cells, whatever your chassis is, a recombinant protein is heterologous. It comes from another place. In our case, they’re usually human proteins, but it doesn’t have to be.”
In the commercial context, it is a rapidly expanding field across different industry sectors. In the therapeutic world, it’s already by far the most dominant player in terms of frontline treatments of critical diseases that will be familiar to everybody but also the largest revenue drugs in the world the majority of those are recombinant in nature.
Cordiner added that, in various industrial sectors, there is a great deal of interest about recombinant proteins.
“They’re looking for a catalyst that can make that affordable at the right levels. In some cases, that’s already the case. In some cases, they need some technology barriers to come down, of which we can be part of that discussion.”
What are the issues about supply and affordability related to vaccines?
Cordiner explained that, for vaccines, there has traditionally been a premium for recombinant albumin. The Bill & Melinda Gates Foundation identified the need for albumin at affordable levels for low and middle income to catalyze the affordability of particular vaccines, starting with measles and rubella for children.
He added that the foundation is looking to ensure that supply is more readily available, and that the consumers, the vaccine manufacturers, have access to more affordable albumen, which would then bring down the cost of the vaccines to whoever pays for them in LMICs.
Helping improve affordability
“There are a number of therapeutics that are now off-patent or are approaching being off-patent for which biosimilars can be developed,” Cordiner said.
“We can use the full power of biology to develop those biosimilars, which may be technically otherwise challenging to do, or certainly technically to do it to bring down the cost substantially. That’s part of our DNA, of what we’re trying to do, and bring them down to affordable levels in different parts of the world.”
He explained that manufacturing could be done regionally.
“You can see a regional hub-type model where you can put in place strains and make things affordable to vast chunks of the world’s population that are not presently available. We see ourselves as being a catalyst for that.
“I am not suggesting that there are big dark monsters out there in terms of these big companies, but they all have shareholders to answer to. They have to behave in a way that is in accordance with that so that perhaps don’t have the freedom to do certain things that we can do.”
What is QTL technology?
Louis explained the company’s QTL – quantitative trait loci analysis – technology.
“We start with a handful of original progenitor parents, and we interbreed them for a number of generations, mixing up the tens to hundreds of thousands of genetic variants they have between them, creating this near-infinite variety of genotypes. And then we apply the statistical associations studies to phenotypic traits and this population of diverse individuals.
“So, it’s a combination of using informed genetics to design the breeding and reasonably sophisticated statistical analyses.”
How to tackle measles and rubella
Cordiner said the partnership with the Bill & Melinda Gates Foundation arose from the problem of the measles-rubella vaccine being essentially unavailable to a large part of the world because of the expense.
“The most expensive part was recombinant albumin,” Cordiner noted.
“We had already started making it under a grant. It was one of our test proteins along with a variety of others. They encouraged us to write a grant that would start the process of trying to produce recombinant albumin at low cost of goods, which was the major driver for the lack of supply, although there was tremendous demand in lower middle-income countries.”
“I am not suggesting that there are big dark monsters out there in terms of these big companies, but they all have shareholders to answer to.”
Louis added: “This was a tremendous challenge. As we were going through this, we identified several technical and other challenges along the way, obtained an addendum supplement to this grant to deal with a couple of those challenges and actually identified further challenges, both to get the cost of goods reduced as well as reduce some of the unwanted, undesired byproducts that were there, which would have a knock-on effect of reducing the cost of goods, as well as increase the titer.
“We met the quality goal very quickly. Our recombinant albumin is as good as the gold standard that’s out there. The last thing is just getting the titer just a little bit higher, but we’re almost there. And the final thing is to identify a manufacturing partner to take it to the lower middle-income countries. We’re relying on interactions with the Gates Foundation to identify the appropriate potential partners, which will eventually end up being local producers in the various lower middle-income countries producing for their own markets. And that’s probably the best way forward.”
Cordiner said the rollout will depend on several factors, including the buyers of the vaccine, health organizations for distribution and delivery, the manufacturer of the vaccine and the manufacturer of the albumin.
Louis added Phenotypeca has provided samples to academic institutions, to mix the vaccine with the albumin to see if it works.
To learn more about this topic:
Here are some links to more articles on the subject of recombinant proteins and driving down the cost of vaccines:
- How can Recombinant Proteins be used in Veterinary Medicine?
- Is Africa ready to become the next big biopharma and vaccine manufacturing destination?
- Global partners announce The Big Catch-up vaccination effort
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