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Translate Bio brings chronic disease-scale manufacturing to COVID-19 mRNA vaccine

Chronic disease focus teed up company’s capacity to make hundreds of millions of doses of mRNA vaccine

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Translate Bio and Sanofi’s bid to develop a COVID-19 mRNA vaccine highlights how manufacturing capacity is among the most visible differentiating factors at this stage in the pandemic counter-response.

The partners’ program is one of at least nine preclinical mRNA vaccines in development for COVID-19, behind clinical candidates from Moderna Inc. (NASDAQ:MRNA) and BioNTech SE (NASDAQ:BNTX) (see “COVID-19 Therapies and Vaccines: Clinical and Preclinical”).

While it’s too soon to say which sponsor’s target strategy, RNA chemistry or delivery vehicles will induce the best protection against SARS-CoV-2, a handful of companies stand out for promising to deliver at least a hundred million doses per year should their vaccine prove effective (see “End of the Beginning for COVID-19 Vaccines”).

On its May 7 earnings call, Translate Bio Inc. (NASDAQ:TBIO) said it plans to bring a candidate to the clinic in 4Q20, and estimates it will be able to produce 90-360 million doses per year by 1H21. The company is evaluating multiple candidates for in vivo immunogenicity and neutralizing antibody activity.

CEO Ron Renaud told BioCentury Translate Bio’s manufacturing infrastructure could be readily retooled to produce large numbers of vaccines because it was designed to support treatment of chronic diseases.

“We were envisioning a significant scale-up to account for chronic dosing of mRNA in patients with rare diseases like cystic fibrosis.”

Ron Renaud, Translate Bio

In September, Translate Bio announced a five-year deal with CMO Albany Molecular Research Inc. (AMRI), which is building the biotech dedicated manufacturing suites and helping it scale up its 100 gram single-batch production process to multiple 250 gram batches per month.

“We were envisioning a significant scale-up to account for chronic dosing of mRNA in patients with rare diseases like cystic fibrosis,” said Renaud.

The company said the COVID-19 crisis had caused interruptions in enrollment and dosing for its ongoing Phase I/II trial of cystic fibrosis candidate MRT5005 -- its lead program.

On March 27, Translate Bio announced it was expanding its three-year vaccine development partnership with the Sanofi Pasteur unit of Sanofi (Euronext:SAN; NASDAQ:SNY) to include a COVID-19 vaccine (see “Sanofi Adds to COVID-19 Pipeline with Translate Deal”).

Under the original 2018 deal, Translate Bio received $45 million up front and was eligible for $760 million in milestones. The biotech hasn’t received additional funds from Sanofi, but Renaud said the partners are in discussions and there is “a lot of government funding” available for COVID-19 programs.

Stacking up mRNA

Translate Bio and Sanofi’s push to make up to 360 million vaccine doses a year puts it in league with other big players with mRNA vaccine candidates for COVID-19.

And Renaud told BioCentury that if Translate Bio’s candidates ultimately failed to show efficacy, it would consider lending its manufacturing firepower to other mRNA vaccines to help address the massive global need.

“It’s going to probably encompass the entire global vaccine capacity that’s out there, and then some,” he said. “It’s a decision we would have to make with our partners at Sanofi Pasteur, but certainly we would want to be part of the solution.”

Collectively, mRNA vaccine makers have projected they could produce billions of doses annually in 2021 and beyond.

Moderna, which is partnered with NIH, said it plans to be able to produce 100 million 50 μg doses of mRNA-1273 annually by year’s end, and expects its manufacturing collaboration with Lonza Group Ltd. (SIX:LONN) will push that up 10-fold to a billion doses per year (see “Lonza to Manufacture Moderna Vaccine”).

Phase III testing of the candidate is slated to begin in July. Moderna reported the first hints of efficacy in humans on Monday (see “What Moderna’s COVID-19 Vaccine Data Does Not Say”).

BioNTech and partner Pfizer Inc. (NYSE:PFE) have said they will produce “millions of vaccine doses increasing to hundreds of millions in 2021.” Its BNT162 vaccine candidate is in Phase I/II testing (see “Pfizer, BioNTech First to Test Vaccine on Two Continents”).

“It’s going to probably encompass the entire global vaccine capacity that’s out there, and then some.”

Ron Renaud, Translate Bio

At least two groups with preclinical mRNA vaccines have also made capacity projections. CureVac AG expects “up to several hundred million doses of bulk RNA material per annum” with its current facility, and is planning to get a new suite running within two years where it can produce a billion doses per year or more.

Arcturus Therapeutics Holdings Inc. (NASDAQ:ARCT) and Catalent Inc. (NYSE:CTLT) have said they can produce millions of mRNA vaccine doses in 2020 and “potentially hundreds of millions of doses annually for worldwide use.” Their candidate LUNAR-COV19, developed with Duke-NUS Medical School, encodes the spike protein.

Other companies that have disclosed preclinical mRNA vaccine programs for COVID-19 include Capricor Therapeutics Inc. (NASDAQ:CAPR), eTheRNA immunotherapies N.V., RNACure Biopharma Co. Ltd., Stemirna Therapeutics Co. Ltd. and Ziphius Therapeutics NV.

Choose your weapon

While Translate Bio’s lead COVID-19 vaccine will use a targeting strategy and route of administration that is similar to other mRNA candidates, the company is exploring different approaches for a next wave of programs.

The first program delivers the full-length SARS-CoV-2 spike protein in its prefusion conformation, a strategy also adopted by Moderna’s mRNA-1273; at least three other sponsors with preclinical mRNA vaccines list the spike protein as their only disclosed antigen. BioNTech’s BNT162 is the only mRNA vaccine with a different disclosed target, the virus’ 3C-like protease.

Renaud said the company is also investigating candidates that encode specific parts of the spike protein, with epitope selection guided by recent electron microscopy studies of the virus. Products encoding shorter sequences are more straightforward to develop and manufacture, he added.

Like the Moderna and BioNTech vaccines, Translate Bio’s candidate will be administered intramuscularly. But future COVID-19 candidates could be inhaled, capitalizing on Translate Bio’s work on inhaled mRNA therapies for pulmonary diseases.

Renaud said the company is considering inhaled delivery of both mRNA vaccines and mRNA-encoded antibodies, a strategy gaining traction during the pandemic (see “COVID-19: Manufacturing mAbs in Patients”).

Renaud said another key source of variation across candidates is the chemistry behind each company’s proprietary mRNA and lipid nanoparticle (LNP) delivery vehicles.

“What sets everybody apart is what they’re using to deliver it, how they’re purifying and constructing the messenger RNA -- modified versus unmodified -- all of those things are differentiating factors,” he said.

But he doesn’t think one mRNA approach will necessarily edge out the others. “There’s a very good chance that we’re going to see many vaccines work here, and that would be probably the best outcome.”

While protein-based vaccine technologies are more established and make up the lion’s share of COVID-19 candidates, the speed and ease of developing nucleic acid vaccines -- along with their greater potential to stimulate T cell responses -- has made them the second-largest category, and the first to enter the clinic (see “COVID-19 Modalities in the Clinic”).

Among nucleic acid modalities, mRNA vaccines have delivery advantages over DNA candidates; the former only needs to cross a cell’s plasma membrane to trigger production of viral antigens, while the latter must cross both the plasma and nuclear membranes.

Targets

SARS-CoV-2 3CLpro (SARS-CoV-2 NSP5; SARS-CoV-2 Mpro; SARS-CoV-2 main protease) - SARS-CoV-2 3C-like protease

SARS-CoV-2 S - SARS-CoV-2 spike protein

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