COVID-19 Researcher Spotlight: Interview with Bijoyita Roy 

Listen as NEB senior scientist Bijoyita Roy explains the landscape and timeline of COVID-19 vaccine development, focusing on the mRNA vaccine platform and how NEB is helping improve mRNA vaccine development and production.

Script

Lydia Morrison:
Welcome to the COVID-19 Researcher Spotlight Series. Today, I interview senior scientist, Bijoyita Roy who leads the lab in the RNA research department here at New England Biolabs. Bijoyita will walk us through the process of COVID-19 vaccine development, including the various vaccine platforms, timelines for development and promising candidates. She'll also discuss with us how NEB research scientists are working to improve and streamline mRNA synthesis workflows. Bijoyita, thanks so much for joining me today.

Bijoyita Roy:
Hi, Lydia. Thanks for having me.

Lydia Morrison:
I was hoping that you could tell our listeners a little bit about your background and what your role is here at New England Biolabs.

Bijoyita Roy:
Sure. So I have been trained as an RNA biologist and I have been interested in different aspects of post-transcriptional regulation of gene expression and their therapeutic intervention. So before coming to NEB, I worked at PTC Therapeutics and I was interested in understanding the mechanism of action of small molecule drugs that affect RNA-based processes. Now here at NEB, I lead a research group and the focus of my lab is to develop tools and methods for RNA synthesis, specifically for therapeutic, diagnostic, and synthetic biology applications. And our goal is to improve the enzymatic RNA synthesis process and the platform for therapeutic messenger RNAs, and mRNA based vaccines.

Lydia Morrison:
Awesome. So we're here today to talk about vaccines. Could you walk our listeners through how vaccine development works?

Bijoyita Roy:
Sure. So, the way I see it is the vaccine development, the workflow can be divided into different aspects, very distinct aspects. So you have the scientific aspect where it can take years of research and exploration to get the proof of concept data that a specific molecule might be administered as a vaccine and have some basic idea about for the mechanism of action of that molecule could be. So Lydia, this is your early discovery phase. This is then followed by clinical evaluation, where you start looking into the safety and efficacy of the vaccine in human subjects. Then you have the regulatory aspects which actually involves getting ethical approval for designing the clinical trial, performing the clinical trials, approval for the manufacturing process and the different practices that are involved in each and every step.

Bijoyita Roy:
The final assessment of whether the potential vaccine protects against the disease dictates whether or not it will get approved for use and be commercially available. So in the United States, the FDA is responsible for approving different vaccines. Generally speaking, if a vaccine candidate passes scientific clinical phases, achieves the end points, the product that needs to be approved by these regulators and then it is manufactured at a large scale and then distributed. This whole process I know I make it sound like it's a linear process, but it's actually a cyclical process.

Lydia Morrison:
So how long do each of the phases of the clinical trial, how long did each of those steps take?

Bijoyita Roy:
So typically the clinical development involves testing potential vaccines in distinct phases, and no matter where you're trying to get approval, it's pretty much similar for most of them. So the first is preclinical evaluation where a potential vaccine is tested in cells and animal models. And sometimes even non-human primate to see if it's safe and produces an immune response. So that can take up to two to three years and sometimes even longer because it's very early on proof of concept evaluation that you're doing. Now based on this safety and efficacy profile, it can then be moved or it is then move to a phase one clinical trial where you actually start testing that drug or the vaccine, in a small number of healthy human subjects. And you look for its safety and its tolerability. This phase one trials can also take up to a few years or so, then you have phase two trial.

Bijoyita Roy:
And this transition from phase one to phase two, it relies on the immunogenic and toxicity results from phase one and phase two will consist of more healthy volunteers, human subjects, and typically a diverse set of individuals. It also evaluates multiple doses and takes couple of years. Finally, you have phase three where you actually start looking into whether a vaccine candidate protects against the disease and it requires thousands and thousands of people to participate in phase three. Sometimes you have something called phase four. This typically is done after commercialization of a vaccine. And the main goal for phase four trials are to monitor long-term effects of a vaccine or a drug.

Lydia Morrison:
So why is the timeline so much quicker for the COVID-19 vaccine?

Bijoyita Roy:
Yeah. So several of these stages are the clinical trial phases that I mentioned earlier. So they're actually being conducted in parallel and that has been key and it can actually accelerate your vaccine development program quite a bit. At the same time, multiple vaccine candidates have been funded. They are being developed in parallel. Multiple vaccine platforms are being evaluated, clinical trial sites were created across the world. And for an ideal vaccine, you would need billions and billions of doses. So global manufacturing capacity is also being built.

Bijoyita Roy:
So typically you really don't dive into the manufacturing part of it till you have promising safety and efficacy data from a clinical trial. However, the production of the vaccines are being ramped up and are really ready for a larger trials, even before we saw some of the safety and efficacy data for some of these COVID-19 vaccines that are being evaluated.

Lydia Morrison:
I understand. So what are the different platforms that are being used to create the vaccines?

Bijoyita Roy:
Right. So like I mentioned, there are multiple platforms being evaluated simultaneously. So, you have the conventional platforms like DNA vaccines, recombinant protein vaccines, then you have viral vector-based vaccines, live attenuated vaccines, inactivated vaccines. Interestingly, some of the most advanced candidates are from a new vaccine platform and these are messenger RNA based vaccines, combined there are about over 60 candidates that are being evaluated in human subjects. So these are not the preclinical evaluations. These are the ones that are advanced and being tested in human subjects.

Lydia Morrison:
So you mentioned that mRNA vaccines are relatively new. What are the advantages of that platform?

Bijoyita Roy:
Right. So messenger RNA is transient and in expression, and its expression is rapid. It's easy to titer and messenger RNA can also be synthesized and standardized and it can also be scaled much easily. So these are some of the most prominent advantages of the mRNA based platform. Now, mRNA based vaccines are emerging as an alternative to conventional vaccine approaches. So the idea here is really simple. You make an RNA or a messenger RNA in a tube, and you introduce it into a cell to hijack the cells machinery, to make any protein you are interested in. And once it is delivered in the cell, it gets translated by the cellular machinery resulting in the synthesis of the protein antigens. Now these antigens are then recognized by the immune system and you see immune responses. So what's happening here is, the cell itself acts as a bioreactor to make any protein of interest.

Bijoyita Roy:
So all you really need is the DNA sequence to make the RNA that you are interested in, the rest of the process it's very generic. So you use the same process for any protein, and that makes this entire platform really lucrative, and it streamlines a lot of early development and discovery work. And just as an example, once the sequence of SARS-CoV-2 genome was released, the DNA sequence of interest that could potentially be used as a vaccine target were generated in a matter of few days, and the mRNA molecule that could actually encode for the spike protein was actually synthesized in a matter of weeks.

Lydia Morrison:
Wow. That's really interesting. So there are two vaccine candidates that were recently approved by the FDA. Could you tell us about those?

Bijoyita Roy:
Sure. So in the US, we now have two vaccines that have been approved by the FDA for emergency use. And both of these are mRNA based vaccines-

Lydia Morrison:
Oh, interesting.

Bijoyita Roy:
Yeah, interesting, right? So going back to your question, why is it so much quicker this time? So just to give an example, the FDA approved one of these vaccines on December 11th from Pfizer and BioNTech and on December 13, trucks were getting loaded with the vaccine for shipment and delivery. And the first vaccine was actually administered on December 14th. Incredible, right?

Lydia Morrison:
Yeah.

Bijoyita Roy:
The FDA authorized the second mRNA based vaccine on December 18th and now it is getting distributed across US. So mRNA based vaccines have also been approved for use in other countries. So UK was the first Western country to authorize the use of mRNA based vaccines in early December. And like I said, it's a brand new platform, but it's looking really promising at this point.

Lydia Morrison:
So what are the similarities and differences between the two FDA approved vaccines?

Bijoyita Roy:
Right. So, the main similarity is that both of these vaccines that contain the genetic instructions for building a specific Coronavirus protein, the spike protein. So when injected into the cell the vaccine causes them to make spike proteins, which then gets released into the body, and it involves an immune response from the immune system. What is really interesting is that two independent vaccines, the mRNA molecule, the sequence is very different, but the mechanism of action for both the BioNTech Pfizer, as well as the Moderna vaccines, the mechanism of action is exactly the same and they are showing similar efficacy.

Bijoyita Roy:
So, for both of these you still need two doses. The doses are a little different and one needs to be administered three weeks apart. And for the other one, it needs to be administered four weeks apart. We anticipate that the formulations are a little different and one needs to be stored at minus 70 degrees centigrade. And the other can be actually refrigerated for about 30 days, and is also stable for six months in minus 20 degrees centigrade.

Lydia Morrison:
Hmm. So the basic methodology is the same, but there are differences in the RNA sequence that are contained in each vaccine-

Bijoyita Roy:
Right, right. But the mechanism of action, the biology is exactly the same for both of them.

Lydia Morrison:
So are there mRNA vaccines for anything other than COVID-19?

Bijoyita Roy:
Approved? No, not really. So the two vaccines for COVID-19 are the first mRNA based vaccines that have been approved by the FDA. So there are a lot of mRNA vaccine candidates that are undergoing early stage clinical evaluation. So mRNA vaccines have been tested in humans for at least four other infectious diseases. And this platform is also being evaluated for immuno-oncology and protein replacement therapeutics, but early stage clinical evaluation.

Lydia Morrison:
Interesting. So a lot of similarities, but some differences as well. Have there been any major failures in the COVID-19 vaccine development world yet?

Bijoyita Roy:
There are multiple platforms being evaluated, right? And there have been road bumps. It's not unusual because whenever you're doing large clinical trials, there will be reasons why they will be halted, adverse events, whether it's an illness or an accident, it is expected along the way because we are monitoring thousands and thousands of human subjects. So patient enrollment were halted for some of the trials in response to safety concerns. And we have been racing so fast to develop vaccine, do we really want to make sure that the safety guardrails are in place and these temporary halls are part of it. So there is one vaccine from Australia's University of Queensland, which has been discontinued, not for safety concerns actually, but it was based on how the vaccine was designed, remember I said it's a cyclical process. So you have to design, redesign, test, go back so... And it's pretty normal for any vaccine development platform.

Lydia Morrison:
So how is New England Biolabs supporting mRNA vaccine development or vaccine development in general?

Bijoyita Roy:
Right. So NEB supports the manufacturing of these mRNA based vaccines in many different ways. So the actual synthesis process of the synthetic messenger RNA molecule, it's actually an enzymatic process. So most workflows require at least four enzymatic components to synthesize the mRNA molecule of choice. Now there are variations of the workflow and some workflows can use up to seven different enzymes for synthesis of the mRNA molecule, the vaccine. And we have had these enzymes in our catalog for a long time and our teams of research development and production scientists, they understand how these enzymes behave and have been continuously working on improving the manufacturing of these enzymes.

Bijoyita Roy:
What this has actually done is, it has enabled New England Biolabs to provide both research grade, as well as GMP grade reagents, the enzymatic components at scale that enables both bench scale to commercial scale mRNA manufacturing. And it also enables a seamless transition to large-scale therapeutic mRNA manufacturing. So the scale of the vaccine, it's really critical because you need billions and billions of doses. So it's really important that some of these critical components, the enzymatic components are also available in those scales.

Lydia Morrison:
So what are some of the challenges of mRNA manufacturing, is scale a challenge?

Bijoyita Roy:
It's a brand new platform, right? And the current mRNA vaccine landscape, it's highlighting some of the possibilities that can be explored for this new platform. However, there are certain aspects where there's plenty of room for improvement, for example designing the mRNA molecule, the actual sequence, there's a lot of potential there, understanding how a synthetic mRNA might behave in vivo, in the cell and how it can be modified to have a prolonged effect. These are all outstanding questions. However, from a manufacturing perspective, scaling up the mRNA synthesis process, like you mentioned, as well as streamlining it, would definitely have an advantage especially for a vaccine platform where you need to make billions and billions of doses. Now, even though the synthesis process is really robust, we understand that there are opportunities where you can improve and streamline the entire mRNA synthesis process, those enzymatic steps.

Lydia Morrison:
Absolutely. And is that something that your group is working on?

Bijoyita Roy:
Sure. So, the enzymatic RNA synthesis process has been around for a long time. Like I said, it's quite simple. It has been used for a lot of different biotechnology applications however, because it is not being used for therapeutics and for generating vaccines, the requirements are a little different. So two different aspects that are really important is that, you should be able to make really clean, precise RNA molecule of interest, and at the same time, be able to scale it up, the actual synthesis of the RNA. So at NEB, we have active research programs where we are looking at new and improved enzymes that might actually have an advantage over the current enzymes that are being used for the vaccine production workflows.

Bijoyita Roy:
What we really hope to do is understand the enzymatic mRNA synthesis process so that we can come up with alternative manufacturing platforms that are more streamlined and can be scaled up easily. And we are doing so by discovery and characterization of new enzymes that are better suited for both synthesis as well as modification. And I'm just going to give you a small example. So one aspect that my group has been focusing on is to understand some of the byproducts in the RNA synthesis process that are known to be detrimental for in vivo applications.

Bijoyita Roy:
And what we have decided to do is we have taken complimentary approaches. First, we want to understand what these byproducts are, how they are made, their source, what they look like. And second, we also wanted to figure out how can we actually reduce formation of these byproducts and their reaction. So in the research division at NEB, we have a research program to engineer RNA polymerases, and RNA polymerases are enzymes that are used to actually make the RNA in the tube. So what this allowed us to do is perform the RNA synthesis reaction at a higher temperature than it's normally done. And what we actually observed was that it prevented the formation of some of those detrimental RNA byproducts and their reaction, which are typically eliminated via purification processes. So what we are hoping here is that we can come up with innovative workflows that can further streamline this entire synthesis process.

Lydia Morrison:
So are you envisioning a workflow in which purification steps won't be necessary?

Bijoyita Roy:
At least some of them. We can actually override, that's what we are hoping for, and that will allow us to streamline the entire synthesis process. Yes.

Lydia Morrison:
Absolutely. That's really interesting. Thanks so much for taking time out of your day to explain how vaccine development works and about the new vaccines that are currently out there. And thanks for your work and your group's work in looking to streamline and improve manufacturing possibilities for future vaccines.

Bijoyita Roy:
No, thanks Lydia. Like I said, it's an interesting time to work on messenger RNAs, and we hope that this multi-pronged approach that we have taken at New England Biolabs of merging discovery development and enhanced manufacturing capabilities of the enzymatic tools will address some of the future needs.

Lydia Morrison:
Absolutely. Thanks again Bijoyita.

Bijoyita Roy:
Thanks for having me today, Lydia.

Lydia Morrison:
Thanks for joining us for this episode of the COVID-19 Researcher Spotlight Series. You can find more information about how New England Biolabs is supporting SARS-Cov-2 detection, sequencing, and vaccine development and production at wwwdotneb.com/COVID19. Tune into our next episode, when I'll be joined by senior application scientist, Bjeorn Textor of NEB Germany, as we interview Bas Oude, Munnink of Erasmus MC about the impact of multiple circulating strains of SARS-CoV-2, and what he's learned from his work on COVID-19 that could aid in identifying and stopping outbreaks of COVID-19 or other pathogens in the future.


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