There’s never been a drug as eagerly anticipated as a coronavirus vaccine. And ever since China released the genome sequence of the novel coronavirus in January, pharma companies have been in a mad dash to meet the world’s expectation of producing one.
In just a few months, the field has gotten increasingly crowded and over 110 candidates are now in the works. Yet, as companies like to point out, they’re not racing each other, they’re racing the virus. And they’re hoping to clock a record that’s never been set in pharma before.
Of course, the path of drug development is rarely a smooth, straight line and there are massive hurdles ahead. If history is any indicator, many of these vaccines will ultimately falter. And even if a candidate is approved, the greater imminent challenge of scaling up production remains.
“Let’s be honest. To make [these vaccines] at scale, rather than just a few million doses, is where the real complexity will be,” Sanofi’s CEO, Paul Hudson, said on a conference call with reporters in late April.
News of manufacturing deals between industry heavyweights are now being announced regularly, as pharma companies prepare at-risk investments that will have production capacity ready to go right away, should their vaccine candidate win approval. And for most of the major pharma players in the hunt —including Moderna, Sanofi, Novavax and Johnson & Johnson — the ambitious annual capacity target for 2021 is the same: 1 billion doses.
President Trump wants enough doses for Americans even sooner. On May 1, the White House announced a project called “Operation Warp Speed,” which aims to have hundreds of millions of doses of a vaccine manufactured by this January. The White House offered few additional details about which pharma companies it is working with to meet that goal, or how the vaccines would be produced.
In fact, despite all of the impressive feats generating confidence in the sudden bustling market for a SARS-CoV-2 vaccine, the situation is also riddled with unanswered questions, best guesses and doubt.
Can pharma quickly make enough vaccines to put an ultimate end to the pandemic? Or, as some analyst naysayers have suggested, are companies being overly confident in their development and production estimates? Here’s what the industry is up against.
The vaccine landscape
Within the emerging saga of the coronavirus vaccine race lies the story of two upstart drug technologies looking to prove they can go the distance alongside their competitors.
For more than a decade, biotechs have been touting gene-based platforms that use DNA and mRNA as a way to rapidly generate vaccines. By leveraging DNA and mRNA platform technologies, companies are able to take viral sequences and design vaccines quicker than ever. Inovio Pharmaceuticals claims it took less than three hours to download the coronavirus sequence and generate its DNA coronavirus vaccine candidate. Moderna’s mRNA-based coronavirus vaccine ultimately became the first candidate ready for clinical trials in late February.
Like all vaccines, gene-based vaccines work by triggering the immune system to produce antibody proteins before it comes into contact with a pathogen. But the process is streamlined for gene-based options.
Traditionally, vaccines are made by growing an inert version of the virus in a cell culture and then purifying it into an antigen that is designed to generate targeted antibodies once injected into the body. However, vaccines such as mRNA involve synthesized RNA encapsulated in lipid nanoparticles that instructs cells to produce antigens in vitro — essentially turning the body’s muscles into the workhorses that generate antibodies.
“There are many timeline advantages to DNA and mRNA vaccines,” says Vitaly Glozman, partner, Pharma and Life Sciences at PwC. “If you tried to develop a traditional vaccine, it would likely take much longer.”
Major organizations investing in vaccine development
The Coalition for Epidemic Preparedness (CEPI) — Launched in 2017, the goal of CEPI is to create a coordinated and intergovernmental plan to develop and deploy new vaccines to prevent pandemics. Its coronavirus vaccine investments include:
- Novavax ($368 million)
- Inovio Pharmaceuticals ($9 million)
- CureVac ($8.3 million)
- Institute Pasteur ($4.9 million)
- Clover Biopharmaceuticals Australia ($3.5 million)
The Biomedical Advanced Research and Development Authority (BARDA) — As part of the U.S. Department of Health and Human Services, BARDA acts sort of like a capital investment firm for the U.S. government, doling out grants to companies working to protect the country from chemical, biological, nuclear or other threats. Its SARS-CoV-2 vaccine investments include:
- Johnson & Johnson ($456 million)
- Moderna ($483 million)
- Sanofi ($30 million)
The Bill & Melinda Gates Foundation — As the most prominent non-profit aimed at fighting viruses, the Gates Foundation has promised to devote billions to scaling up manufacturing of a coronavirus vaccine. Although it has not named which vaccine programs will receive manufacturing funding, the Gates Foundation has a $40 billion endowment and has already committed up to $60 million to fund the development of vaccines, including financial support for Moderna, Inovio, and University of Oxford.
The manufacturing process for vaccines like mRNA is also less labor-intensive. And because smaller batches of synthesized mRNA can produce higher yields, these types of vaccines can be made with a smaller manufacturing footprint and thus, reduced costs. For these reasons, gene-based vaccines have generated considerable buzz and have been targeted for potential use against a range of diseases, from viruses to cancer. There’s just one problem — no DNA or mRNA vaccine has ever been approved for human use. Because they’ve only been used in clinical trials, the infrastructure for widespread manufacturing for these vaccines, quite simply, doesn’t exist.
“The challenge is that there are no existing facilities that mass produce cGMP mRNA vaccines,” explains Rob Boulanger, process specialist with CRB, an engineering, architecture and construction firm that works on designing and building biotech facilities.
Company heads involved in the development of DNA or mRNA vaccines have nevertheless expressed confidence in their ability to scale-up production to hundreds of millions of doses.
Johnson & Johnson also leveraged a platform technology for its vaccine candidate, Ad26, an adenoviral vector vaccine. But because of the time it takes to grow stable viral vectors, J&J’s vaccine company, Janssen, doesn’t expect its clinical trials to start until September.
Meanwhile, Sanofi Pasteur, Sanofi’s global vaccines business, is leaning on the same recombinant DNA technology it uses to make its approved flu vaccine, which will be combined with an adjuvant from GlaxoSmithKline to enhance the immune response for dosing. The company also has a second candidate based on mRNA technology that it is developing with Translate Bio.
Across the pond, researchers at the University of Oxford have grabbed headlines in recent weeks for reporting that they could have efficacy data about their candidate, a recombinant adenoviral vector vaccine which is in clinical trials, by mid-June. The Oxford team has reportedly been able to move ahead of the pack because its candidate is based on a vaccine developed for a different coronavirus last year.
With so many technologies in development — from DNA and mRNA to recombinant proteins — which one is the most likely to survive clinical trials? It’s a tough call to make until the candidates get through the first phase of clinical testing.
“Phase 2 sees the highest attrition because that is where vaccines have to show competitive immunogenicity, and depending on the prevalence of the disease/feasibility, also some proof-of-concept efficacy/protection in phase 2b,” says Michael Haydock, senior director of Infectious Diseases at Datamonitor Healthcare.
A study of over 185,000 clinical trials published last year in Biostatistics by Oxford Academic found that overall, infectious disease vaccines had a 33 percent probability of success — a higher rate of approval than all drug development programs combined (13.8 percent), but still a worrying figure when considering what’s at stake with the coronavirus.
When factoring in new technologies, the outlook could be even grimmer. In April, Clarivate, an analytics firm, released a report saying that it had used AI to predict the probability of success for Moderna’s mRNA vaccine candidate. The machine learning tool ultimately gave the new drug a 5 percent probability of success and an estimated time to approval of 5.2 years.
With so much uncertainty around these vaccines, Daniel Chancellor, director or Thought Leadership at Informa Pharma Intelligence, said in a recent CPhI webinar that it’s critical for the industry to take these “multiple shots on goal” if it hopes to score.
Bill Gates tried to warn us. In 2015, the Microsoft co-founder gave a now notorious TED Talk cautioning that when the next viral outbreak came, we wouldn’t be ready. These days, Gates has become one of the most called-upon public figures to give interviews on the response to the coronavirus and what needs to be done to bring a vaccine to fruition. His message has been consistent: We need to prepare manufacturing now.
To that end, the Bill & Melinda Gates Foundation has already funneled tens of millions of dollars into several vaccine trials. The Foundation has also promised to pump “billions” into building out manufacturing capacity for several vaccine candidates. In interviews, Gates says that the Gates Foundation will invest in creating capacity for several promising candidates so that it’s ready to roll once they are approved, and acknowledged that the endeavor may ultimately amount to billions wasted on manufacturing facilities for candidates that fail.
Although the Gates Foundation has yet to announce which candidates it plans to back with manufacturing investments, the industry is clearly on the same page and is soldiering on with its own efforts to create vaccine capacity.
Scale-up deals that have been announced so far
Technology: Four different combinations of mRNA format and target antigen
Development stage: Phase 1/2
Production plans: Pfizer is leveraging three sites in the U.S. and one in Belgium for scale-up
Johnson & Johnson/Catalent/Emergent BioSolutions
Technology: Adenoviral vector
Development stage: Clinical trials expected in September
Production plans: J&J is planning to use its facility in Leiden, Netherlands for clinical trials, and then scale-up with drug substance manufacturing by Emergent, and formulation and fill-finish by Catalent
Development stage: Entering phase 2 trials
Production plans: The companies have signed a 10-year manufacturing deal and will leverage Lonza’s facilities in Switzerland for mass scale-up
University of Oxford/AstraZeneca (AZ)/Serum Institute of India (SII)
Technology: Adenoviral vector
Development stage: Phase 2 trials
Production plans: SII is planning to have 20-40 million doses of Oxford’s vaccine candidate manufactured by this fall, and aims to scale up to 10 million doses per month. Oxford and AZ also have a partnership that makes AZ responsible for worldwide manufacturing and distribution of Oxford’s vaccine.
To get a sense of the average capacity at a vaccine production facility, Boulanger says it’s useful to look at the pandemic response plan that was put in place by the Biomedical Advanced Research and Development Authority (BARDA), to leverage existing facility space.
“What they would target with a typical pandemic, like influenza, is making 50 million doses at a plant within six months,” Boulanger says.
Although far-reaching plans, such as the one being proposed by the Gates Foundation, don’t specify whether new facilities would be built or if production lines in existing plants would be retrofitted to accommodate a coronavirus vaccine, Boulanger says that converting facilities is the much faster way to go.
“To design, build and validate a new plant…you’re talking two years. And we don’t have that kind of time,” he says. “But to convert? Assuming it’s a perfect scenario…you probably need six months.”
As Boulanger points out, however, converting an existing facility is “no trivial task.”
“It’s going to take several months to acquire the raw materials to make a new vaccine,” he says. “Almost all of these products have very specialized raw materials…anyone of these could have a long lead time. So you’d want to be on the phone with whoever makes your growth media, for example, to secure a supply.”
Niranjan Kulkarni, director for Operations Improvement at CRB, says that changing a processing line from one vaccine product to another will also require regulatory scrutiny.
“If changing equipment or process, you need to requalify your equipment and validate the process changes,” he says. “That takes time.”
Bringing a newer type of vaccine to scale, such as mRNA, provides its own unique challenges, even though the technology exists to manufacture them.
“I think there are going to be some steps, such as plasmid manufacturing, that will require additional engineering and development because they will be using different equipment,” Glozman says. “Similar to other vaccines, I think the scale challenge will be in downstream steps like chromatography, purifying and formulation, because that’s where you have to increase the volume of the product.”
Companies will also need to eye solutions for expanding fill-finish capacity.
“Depending on the customization and automation needed, procuring, installing and running filling equipment can go all the way up to two years in lead time,” Kulkarni says. “So you need to find facilities with the right technology tailored to what you’re filling.”
Gates has also warned that the industry could struggle to secure packaging materials such as medical glass to meet widespread demand for a coronavirus vaccine. John Bell, a professor at the University of Oxford, recently told the BBC that there are only 200 million vials left in the world now because so many companies are preparing to manufacture a vaccine.
Overall, it’s a massive puzzle to solve, but pharma has begun mobilizing to make the pieces fit together.
Setting the stage
With notoriously low margins, vaccines are not the pharma industry’s favorite product. According to Duncan Emerton, director of Custom Intelligence and Analytics at Informa Pharma Consulting, about 80 percent of the global vaccines market is dominated by just a handful of companies — Sanofi, Merck & Co., Pfizer, GlaxoSmithKline and to a lesser extent, Janssen.
Without the manufacturing footprint of Big Pharma, contract manufacturers are going to play a major role in the coronavirus vaccine build-out.
“I think a CMO could do the job,” Kulkarni says. “They have the right flexibility and space, and more quickly adapt.”
It’s a direction that major pharma players are clearly headed in. At the end of April, Janssen announced that it has struck a partnership with Catalent Biologics to expand manufacturing capabilities for its coronavirus vaccine, even though clinical trials for its candidate have not begun.
The companies have not disclosed any financial details about the deal, but said it will involve a joint investment to rapidly scale up production capacity. According to Mike Riley, president of Catalent Biologics for North America, Catalent will be involved in drug formulation and fill-finish, and it will leverage a new, segregated space at its facility in Bloomington, Indiana with high-speed filling lines.
Although there’s no word on the exact capacity the new deal will create, Riley says that Catalent is aiming to “meaningfully contribute to J&J’s goal of making 1 billion doses” of a coronavirus vaccine.
Moderna also recently announced that it has found a manufacturing partner for its mRNA vaccine candidate — Lonza. According to the companies, Lonza will build out capacity at facilities in the U.S. and Switzerland with the ultimate goal of cranking out 1 billion shots each year.
AstraZeneca also recently jumped into the fold by partnering with the team at Oxford. Under the agreement, AstraZeneca will be responsible for the development and worldwide manufacturing and distribution of Oxford’s vaccine.
For other major companies in the hunt for a vaccine, the road to building capacity is still being decided. Sanofi, which has received a $30 million grant from BARDA to help fund research and clinical trials for its two potential candidates, has yet to disclose its plans for scale up.
“No option is off the table,” says Clem Lewin, Sanofi Pasteur’s associate vice president head, BARDA Office and NV Stakeholder Engagement.
According to Lewin, the company currently has the capacity for 100-600 million doses of a recombinant vaccine, and is planning to scale up to a 1 billion-dose capacity within the next 12 months. Sanofi is also striving to create capacity for 90-360 million doses of its mRNA candidate by 2021, and further expansion plans are being prepared. But Sanofi is still evaluating the magnitude of demand and its other manufacturing options.
“As an industry, there are different approaches being used. But the one thing that is consistent is that everyone is working as hard as possible to make a vaccine available as quickly as possible,” Lewin says.
When will it be ready?
Although President Trump has expressed confidence that a coronavirus vaccine will be ready by the end of this year, experts are far more skeptical. The general consensus among pharma seems to be that at best, the first batches might be in production by mid- to late-2021. But demand for a drug product has never been higher — and it could take much longer for pharma to catch up, especially if the approved vaccine requires more than one dose.
“No matter how successful we are, demand will outstrip supply by a considerable margin in the near term,” Glozman predicts. “It will probably take substantial time after initial approval and commercial availability before we are manufacturing at scale that is sufficient to address the global demand.”
“I think it depends on how many candidates are successful and then, what the yields are,” Lewin says. “There are so many variables that it is difficult to give an accurate prediction. The key is that the more vaccines we have to go into production, the faster it’s going to go.”
Who gets it first?
While companies around the world scramble to get their vaccines ready, government leaders are signaling their intent to ensure that doses produced on their shores will go to their citizens first.
President Trump’s stated goal for Operation Warp Speed is to have enough doses for American’s population ready by the end of this year. In a press statement about its deal with AstraZeneca, Oxford make a point to say that it is working on global distribution along with “providing the UK access as early as possible if the vaccine candidate is successful.” China’s government is funding the development of its lead candidate. And the chief executive at the world’s largest vaccine producer, the Serum Institute of India, which has stated that it plans to produce up to 60 million doses of a vaccine candidate by the end of this year, has also indicated that any vaccines it manufacturers will go to people in India first.
The growing geo-political positioning of vaccine production has experts worried that pharma will not be able to prioritize giving doses to frontline workers or other higher-risk individuals first, which could be key to slowing the pandemic.
“We have to make sure that those that need this vaccine get it first, and we don’t get into some of the situations we’re seeing with PPE,” says Fatema Rafiqi, the research programme manager for Antimicrobial Resistance Benchmark at the Access to Medicine Foundation, which publishes a biennial index ranking how well pharma companies ensure global access to medicines and vaccines.
Glozman speculates that ensuring a vaccine is equitably given to not just high-risk individuals, but also lower-income countries, could require integrated involvement from government bodies, agencies, and industry to coordinate distribution.
“For example, there could be a joint body that involves leading regulatory agencies that would be responsible for guiding approval,” he contemplates. “And then if countries accept this integrated approval process, they would be able to access a portion of the approved vaccine supply.”
Several world leaders have already signaled their intent to work together. In early May, the European Commission held a virtual summit in response to the WHO’s appeal for global vaccine collaboration. All told, the countries who attended, including EU countries, Saudi Arabia, Japan and others, pledged to devote $8 billion to vaccine development. (The U.S., however, declined to attend.)
To some extent, Rafiqi says the pharma industry will have to be fully engaged in the efforts to distribute vaccines equitably.
“It’s up to pharma companies to take a multi-stakeholder approach to ensure this new treatment is made available,” she says.
How much will it cost?
There are few issues in pharma that are touchier than drug prices. The public pressure is already on to make sure that any approved vaccine doesn’t become a cash cow for the industry.
J&J says it will likely price its vaccine around $10 per dose, which is about the cost of production. Several other companies have indicated that they will also produce the vaccine on a non-profit basis for the duration of the pandemic, and Moderna’s CEO has also stated that its price would not be higher than any other respiratory-virus vaccines.
According to Emerton, $10 per dose falls on the low end of the normal vaccine price range and indicates that companies are not expecting their vaccine endeavors to pay off in any big way.
“Profit? Yes. Profit big? No,” says Emerton. “It would be a significant break in the historic trend for a vaccine manufacturer to make a significant profit from a SARS-CoV-2 vaccine. And there’s too much political sensitivity around the manufacture of a vaccine…so any fumbled attempts to maximize gains from a vaccine are likely to be met with significant resistance.”
U.S. government officials have also said that any vaccine developed with financial backing from a U.S. agency will face increased pricing scrutiny.
Future lessons for the industry
What will it say about pharma if a vaccine is produced — and manufactured — in record time? From the public’s point of view, a vaccine that puts an end to the pandemic could help improve pharma’s reputational standing. But Emerton says it should also prompt some introspection within the industry.
In a recent webinar hosted by CPhI, Emerton pointed out that the industry should ask itself “What if this does work? If it is possible, I’m certain questions will be asked about how the learnings can be applied to others areas of pharma R&D.”
Going forward, the SARS-CoV-2 vaccine rush could provide a new framework for how the industry can speed drug development. Chancellor says the industry should ultimately evaluate the tools it used to develop the vaccines so quickly — such as overlapping clinical trial phases and evaluating surrogate endpoints — to see if they can become new best practices.
The industry is still a long way off from answering those questions, however. For now, pharma companies remain consumed by their push to produce a coronavirus vaccine, unsure of how successful they’ll be. Even though history and probabilities are not necessarily on pharma’s side, Lewin says that doesn’t mean that the industry can’t set a new record for vaccine development and manufacturing.
“It hasn’t been done — but that doesn’t mean it won’t be done,” Lewin says.