mRNA Vaccines – A Novel Weapon Against Coronavirus

The arrival of SARS-CoV-2 has focused attention on a potential new way of making vaccines – one that promises to be quicker and cheaper than traditional methods and more reactive to novel virus outbreaks, but also one that remains to be validated.

A major campaign in biopharma’s war against COVID-19 is the development of effective vaccines against the novel virus.

While industry scrambles to repurpose drugs against the disease – antivirals against the pathogen and immunomodulators to help the symptoms – vaccine companies are needed to play a longer game. Lockdowns and social isolation, while necessary to “flatten the curve” in the short term, will not make the virus disappear, and no country has a clear exit strategy that will guard against rebound.

Traditional vaccines take a long time to develop, typically longer than the average drug. Although big players like Sanofi, Janssen Pharmaceutical Cos. (Johnson & Johnson) and GlaxoSmithKline PLC with Clover Biopharmaceuticals have already taken up the mantle, their products have yet to enter the clinic and are likely 18-24 months away from the market.

However, there are a number of novel vaccine approaches already in development to try to reduce development times, and one strategy – based on messenger RNA (mRNA) – has found itself at the center of attention following rumors that President Trump wanted to secure German biotech firm CureVac AG’s mRNA vaccine technology for the sole use of the US against COVID-19.

In addition to CureVac, two other mRNA vaccine companies make up the vanguard against SARS-CoV-2: Moderna Inc. and BioNTech SE – although Russia’s BIOCAD has also announced its intention to start animal studies by late April.

It is not just Trump who finds the prospect of mRNA vaccines attractive; analysts too think the idea has legs. “Based on our initial assessment, mRNA may be the world's best bet for a scalable vaccine to be approved in 2021,” said Bernstein analysts in an 18 March research note. But they say it is simply too soon to know whether the technology will live up to its promise. “The reality is with limited data and no precedent for mRNA vaccines on the market, it is always tough to have a strong view here.”

The appeal of mRNA vaccines is that they will be nimbler than their more traditional counterparts, and not just in their speed of development. They offer shorter manufacturing lead times that would make them cheaper to produce and they should also be more easily adaptable to tackle different disease outbreaks – if the technology can be proven to work. With mRNA vaccines, once the sequence coding the immunogen is available clinical batches of vaccine can be made within weeks.

By contrast, traditional vaccine development is a convoluted process that takes much capital investment in fixed manufacturing facilities that cannot easily be redirected towards a different pathogen. It can involve hundreds of complex steps: basically, antigens are produced using a bacterial, viral or cell culture from which they are harvested, purified and characterized. The vaccine then has to be assembled, formulated and filled into a vial or syringe, then freeze-dried, packaged and shipped.

An mRNA vaccine differs in that it outsources the key element in this process – antigen production – to the recipients’ own cells, thereby doing away with the need for much of the rest.

The mRNA construct used contains the genetic code for the required antigen, giving the cell the necessary instructions on how to make it. The proteins produced are then presented on the cell surface to the immune system in a manner that more closely mimics a natural infection than traditional vaccines, and is thought to be all the more potent for it.

Overall, these vaccines are also posited to be safer as they require no use of live viruses, and the amount of vaccine needed per dose is less. Plus there is the hope that they may also work against diseases that have resisted vaccine attempts to date.

Technical Issues

On paper, the technology is enticing, but the method does have issues. “The science/theory makes attractive reading (at least from our initial quick reading) but does come with its own challenges so clearly not bullet proof,” commented analysts from Bernstein.

First, the vaccine needs to be delivered (using liposomes) to the host cell cytoplasm without being degraded. Then, the cells’ ribosomes (the cellular machinery that links up amino acid strands according to the mRNA code) have to accept the foreign mRNA as legitimate, and express enough of the immunogen for it to elicit an adequate immune response once presented on the cell surface. These twin challenges of delivery and translation efficiency are two major areas of research focus in the field, say experts writing in an article entitled, ‘The promise of mRNA vaccines: a biotech and industrial perspective’ in the Nature journal npj Vaccines published on 4 February.

“Humoral elicited responses have been generally underwhelming, compared with the established potency in the field of protein or live attenuated vaccines,” they write. “This indicates that much formulation work is still needed to achieve sufficient immunological potency of different vaccine candidates, while maintaining acceptable tolerability – but we can be encouraged by incremental progress to date.” The experts add that very limited data exist on repeat administration of mRNA vaccines in humans; these data are important as most vaccines generally require a booster dose.

The vaccine candidates so far can be divided into two types of mRNA constructs: non-replicating mRNA and self-amplifying mRNA constructs. Non-replicating mRNA constructs are translated by ribosomes straight away to produce the protein of interest, which undergoes subsequent post-translational modification.

Self-amplifying mRNA constructs are a little more complicated but the idea is that they will produce a stronger immune effect. They are immediately translated by ribosomes to produce the replicase machinery necessary for self-amplification of the mRNA. The self-amplified mRNA constructs are then translated by ribosomes to produce the required protein.

The Candidates

Of the three leading companies, Cambridge, MA-based Moderna was quickest off the mark, getting from sequence selection to dosing its first Phase I trial participant in 63 days. The sequence of the coronavirus was first published on 11 January.

Its candidate, mRNA-1273, encodes for a prefusion stabilized form of the Spike (S) protein found on the surface of SARS-CoV-2. This target was selected by Moderna in collaboration with investigators from the Vaccine Research Center at the US National Institutes of Health’s National Institute of Allergy and Infectious Diseases.

The Phase I study is evaluating the safety and immunogenicity of three dose levels of mRNA-1273 (25, 100, 250μg) administered on a two-dose vaccination schedule, given 28 days apart, in 45 participants.

“This study is the first step in the clinical development of an mRNA vaccine against SARS-CoV-2, and we expect it to provide important information about safety and immunogenicity. We are actively preparing for a potential Phase II study under our own IND,” said chief medical officer Tal Zaks.

Tübingen, Germany-based CureVac’s product also codes for one specific (unnamed) surface protein of the coronavirus, which it says should be sufficient to activate the immune system against the pathogen.

It is currently testing two possible vaccine constructs in animal models, and hopes to get into the clinic by early summer. Chief technology officer Mariola Fotin-Mleczek said its technology did not involve chemical modification to the mRNA for its candidates. “This is exactly what will help us get this very natural immune response and immune activation.”

Going on data gleaned from its Phase I rabies vaccine program (CV7202), CureVac is optimistic that small doses will be sufficient to provide protection and allow for greater production. Recent results for the rabies vaccine candidate showed two 1μg doses were enough to protect humans, Fotin-Mleczek said. (Also see "CureVac Denies Takeover Reports As It Slates Phase I Coronavirus Vaccine Study For Early Summer" - Scrip, 18 Mar, 2020.)

Fellow German firm BioNTech expects its product, BNT162, to enter clinical trials in late April 2020. Earlier this month it extended its partnership with Pfizer to cover COVID-19 vaccine development and distribution while Fosun Pharma took Chinese rights.  (Also see "Pfizer, Fosun Partner BioNTech On mRNA COVID-19 Vaccine" - Scrip, 17 Mar, 2020.) BNT162 is a uridine-containing, nucleoside-modified and self-amplifying mRNA that it says can provide high immunogenicity. It is delivered using lipid nanoparticles.

BIOCAD said its mRNA vaccine against SARS-CoV-2 would be based on previous pipelines for mRNA-oncovaccines. The first animal studies are scheduled for the end of April.

It said researchers from the Dongfang Hospital at Shanghai Tongji University and the Chinese biotechnology company Stemirna had been working on the vaccine since the end of January. They have synthesized mRNA with several sequences of different antigens.

Manufacturing Muscle

Even while much still needs to be proven, the potential of mRNA vaccines is such that the three leading companies in the space had attracted interest from big pharma way before the current crisis. In August 2018, BioNTech signed a deal with Pfizer Inc.for mRNA flu vaccines for $120m up front. (Also see "Interview: BioNTech And Pfizer Explore mRNA Flu Vaccines In $120m+ Deal" - Scrip, 16 Aug, 2018.)

Moderna has a deal with Merck & Co. Inc. for respiratory syncytial virus (its candidate is in Phase I) and CureVac has deals in place for its cancer candidates with Boehringer Ingelheim International GmbH and Eli Lilly & Co.

This big pharma might should stand them in good stead when it comes to manufacture on a large scale, said the Bernstein analysts. Since they expect regulators to be supportive, this leaves manufacturing as the chief hurdle.

“Our main concern is simple – the world has never approved and manufactured at scale an mRNA vaccine. In this scenario, we would need to do both quickly and we suspect all companies … will need help from one of the major vaccine players (Sanofi, GSK, Merck, Pfizer – some already have it).”

Moderna says manufacture of the mRNA-1273 material for a potential Phase II trial, which could begin in a few months, is underway, and it is preparing for rapid acceleration of its manufacturing capabilities to allow for the future manufacture of millions of doses if successful.

CureVac, meanwhile, has just secured an €80m funding from the European Commission to put towards upscaling its manufacturing capabilities.

Currently the firm has three manufacturing suites, and the money will be used to accelerate construction of a fourth facility that would significantly boost its production capabilities for any successful vaccine. While the right dose is still to be determined, using the rabies vaccine as a model, the company would be able to provide up to 10 million doses per run from its existing facilities, but this would expand to the billion dose range.

BioNTech said BNT162 would use its fully owned GMP manufacturing infrastructure for mRNA vaccine production.