Although the global impact of a novel virus like SARS-CoV-2 has so far reached devastating proportions, it has spurred science at an unprecedented rate with potential vaccines developed under a year now nearing U.S. authorization.

But while some may say the end to this pandemic is in sight, an actual date is blurry at best, as manufacturing and supply capabilities muddy the outlook.

“This is something that will go on for a long time because 600 million vaccinations have never been done before,” said Thomas Warf, an expert consultant with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (HHS; BARDA).

With the U.S. population at about 330 million people and with most advanced vaccines, including Mainz, Germany-based Biontech SE and New York-based Pfizer Inc.’s BNT-162b2, requiring two doses, the ability to manufacture enough to supply the country in a timely manner appears unsurmountable.

Thomas Warf, expert consultant, HHS, BARDA

“I feel relatively confident this will last through this year, through this coming year, and even into the next,” said Warf, who spoke Nov. 12 during a virtual manufacturing briefing, which partially focused on the industry’s response to Operation Warp Speed (OWS) and COVID-19. The briefing was hosted by BioNJ, the life sciences association for New Jersey.

The pandemic’s impact has created, for the first time ever, a situation in which the government has placed a huge bet on vaccine manufacturing prior to receiving complete clinical data. OWS, a partnership between HHS and the U.S. Department of Defense, has already invested about $10 billion in the development and manufacturing of six vaccines for COVID-19. A potential $25 billion more could come with the next government stimulus. But even though the immediate need for manufacturing has created more efficient processes, the pandemic has held up the advancement of late-stage products targeting other diseases.

Peter Marks, director, FDA CBER

“It’s been a challenge,” said Peter Marks, director of the FDA’s Center for Biologics Evaluation & Research (CBER). “If you look at the map, a lot of the U.S. is looking very red, and it’s very challenging for us to do inspections of the facilities.”

The difficulty expands beyond the U.S. borders. Spectrum Pharmaceuticals Inc., of Henderson, Nev., for example, learned in late October that the agency was unable to inspect its manufacturing facility in South Korea, delaying a decision on the company’s biologics license application for Rolontis (eflapegrastim) to treat neutropenia in patients on myelosuppressive cancer drugs.

The agency is looking at a “combination of desk audits and remote inspections knowing the COVID-19 pandemic is probably going to be with us several months more,” Marks said.

The pandemic also has “put the kibosh” on global regulatory harmonization efforts in the field of gene and cell therapies, an area expected to blossom from five approved therapies currently to potentially hundreds in the next several years. Without harmonization between countries, potential treatments will become cost prohibitive. “It means there’s going to be large numbers of people who could be treated who won’t be treated, if there’s not some reciprocity,” Marks said.

Mireli Fino, site head, Sanofi Pasteur Protein Sciences

But for now, the focus remains on COVID-19 vaccines, a world in which Mireli Fino, the site head of Sanofi Pasteur’s Protein Sciences, has been immersed for a “crazy nine months.”

While typical vaccine development from the identification of the target to the time of registration can take between 10 and 15 years with well-defined gating criteria, “we knew a staged approach was not possible” and that eight years of clinical testing was too long for a COVID-19 vaccine, Fino said.

Sanofi SA, of Paris, and partner Glaxosmithkline plc, of London, were awarded about $2.1 billion in July from OWS to support development and large-scale manufacturing of their adjuvanted recombinant protein subunit vaccine, providing the federal government with 100 million doses. The companies also have supply deals with the U.K., Canada and Gavi. A phase I/II study began in September with 440 subjects. First results are expected in December and a pivotal phase III could begin before the end of 2020.

Compressing timelines

To speed the process of vaccine development, Fino said her team looked at compressing timelines by moving through phase I and II trials with a higher number of subjects to determine safety and the first signs of efficacy. A second compression will involve conducting the phase III trial while also scaling up, “producing the clinical materials, but already thinking about how you’re going to do the validation,” she said. While the company typically moves into one manufacturing facility to start, “because it’s the pandemic, we’re looking at how to generate millions of doses at the fastest pace” so multiple facilities are necessary, she said.

Of the four main approaches to COVID-19 vaccines, two already have licensed products, including virus vaccines and protein subunit vaccines. Approved virus vaccines are for the flu, polio, rabies, hepatitis A, mumps, measles, rubella and yellow fever, while approved subunit vaccines include those for hepatitis B, flu and the human papillomavirus. Two other approaches, viral vector vaccines and nucleic acid vaccines, such as mRNA options, do not have licensed products. Biontech/Pfizer’s BNT-162b2, which recently showed 90% efficacy with interim data, is an mRNA vaccine expected to take longer to manufacture.

Sanofi also anticipates starting a phase I/II trial of an mRNA vaccine, MRT-5500, for SARS-CoV-2 sometime in the fourth quarter of 2020. The vaccine is partnered with Translate Bio Inc., of Lexington, Mass.

The Sanofi/GSK vaccine candidate is a protein subunit vaccine. As an established technology, it can likely harness process design and expertise, as well as licensed buildings, raw materials, supply flow and market authorizations.

“The maturity of these platforms are going to have a very specific impact on your timelines,” Fino said, but there is still specific development work to be done in terms of the process and methods used, scale-up, building upgrades, tech-transfer and acquiring raw materials in a fiercely competitive market.

Warf agreed that supply shortages are a major issue for COVID-19 vaccine manufacturing, with sterile single-use bags, filters and media all in critical demand. As things come across the U.S. borders, BARDA has “preset all of the paperwork, so it’s done and (the supply) doesn’t sit on a tarmac for days.”

While the Defense Protection Act of 1950 has spelled out how the government prioritizes manufacturing in the U.S. and would put a company with a COVID-19 vaccine at the front of the line, “we have five or six vaccine lines and more therapeutics lines,” Warf said.

As more people contract the virus and die from it, how to allocate effective vaccines into hot spots may become a sticky situation. “Obviously, every state is going to think that they’re critical and so this will create a little friction as time goes on as to how we distribute the vaccine,” Warf said.

The U.S. Centers for Disease Control and state public health departments are currently determining where freezers to store vaccines are available and how quickly the vaccines can be administered so they do not go to waste.

“People must be lined up,” Warf said.

As of Nov. 12, the World Health Organization had reported 51.85 million confirmed cases of COVID-19 worldwide, including 1.28 million deaths.

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