Recombinant polio virus vaccine (Istari Oncology)

The polio vaccine. Surgical treatment for macular degeneration. The potential of paraplegics to walk again. Treatment for Parkinson’s disease. Antivirals to treat or prevent HIV. Covid-19 vaccines. Each of these lifesaving medical advancements is rooted in research involving nonhuman primates, most often monkeys. Yet scientists conducting this critical work have faced harassment and threats. We endure calls for primate research to be limited or even banned, which would have dire scientific consequences. These voices are few, but they are loud, and the potential costs of listening to them are high. Nonhuman primates will be critical to our efforts to understand the long-term effects of Covid-19. Estimates suggest that 10-30% of individuals may experience long Covid following initial recovery. The National Institutes of Health must fund research that seeks to explain the neurological impacts of long Covid, and this needs to include projects using nonhuman primate models. In the frightening early days of the pandemic, infectious disease experts turned to primate research to understand how the disease attacked the body and then to develop the Covid-19 vaccine. As early as May 2020, studies were published showing primates could develop immunity against Covid-19, establishing in a record-setting time that vaccines could be an effective tool to control the spread of SARS-CoV2. More than a dozen vaccine candidates were tested on monkeys to determine their safety and effectiveness, critically, scientists drew on previous research that showed an mRNA vaccine provided primates protection from Zika virus. This past experience helped lay the foundation for the development of Covid-19 mRNA vaccines, the fastest vaccines ever created. Going forward, primate research will help us understand if specific groups, such as the elderly, are more prone to develop long Covid. My team and others have early research suggesting the virus can travel to the brain through a person’s nose and potentially cause lasting neurological issues, such as brain fog, lost or distorted senses of smell, anxiety, depression, difficulty focusing and headaches, as has been reported in patients. Even more concerning is the risk that the pandemic will lead to a surge in cases of Alzheimer’s or Parkinson’s. Powerful monkey models of Covid-19 will be required to sort out such a potential link. We’re only at the very beginning of understanding long Covid, and we need to put all our tools — including increased federal funding — to work to unlock its mysteries. Providing additional federal funding for nonhuman primate research will help to speed up this critical research, getting us much-needed answers about long Covid faster. My colleagues and I are committed to conducting our research ethically and humanely. In the four decades I’ve been conducting research on primates, our protocols have continually evolved to improve the monkeys’ well-being. They live in social housing conditions, except in the rare occasions when scientific protocol demands isolation. We take care to respect and sustain the colonies’ natural hierarchies. We provide them dietary supplements and dental and eye care, and we work to keep their stress levels down. Furthermore, before any research on nonhuman primates can occur, it must be approved by an Institutional Animal Care and Utilization Committee, a committee of veterinarians, scientists and lay members of the community. What hasn’t changed since I started my career in primate research? Monkeys’ similarities to humans continue to make them essential partners in our quest for new discoveries of direct relevance to human health. More than 100,000 Parkinson’s patients have benefited from deep brain stimulation, a therapy developed through research on monkeys. Furthermore, researchers have even implanted electrodes in the brains and spines of paralyzed monkeys, allowing them to walk again. This research is already being applied to humans, potentially allowing paraplegics to walk. What was once thought of as impossible might become a standard medical procedure. For us to achieve that bright future, we need to recruit the best young scientists to join the field, and not fear they will be vilified for conducting vital research. We need the support of lawmakers who rightly herald medical advances that save lives every day. Anything else risks missing out on lifesaving advances that could benefit millions of people worldwide.

As concerns rise around the J&J and AstraZeneca vaccines, global attention is increasingly turning to the little, 33-year-old, productless, bankruptcy-flirting biotech that could: Novavax. In the now 16-month race to develop and deploy Covid-19 vaccines, Novavax has at times seemed like the pandemic’s most unsuspecting frontrunner and at times like an overhyped also-ran. Although they started the pandemic with only enough cash to last 6 months, they leveraged old connections and believers into $2 billion and emerged last summer with data experts said surpassed Pfizer and Moderna. They unveiled plans to quickly scale to 2 billion doses. Then they couldn’t even make enough material to run their US trial and watched four other companies beat them to the finish line. Two of those companies, though, J&J and AstraZeneca, are facing big questions about the future of their vaccines. While the US, UK and Europe jumped to the front of the queue for mRNA vaccines, much of the world relied on the two Big Pharmas and the over 4 billion doses they promised to produce in 2021. But both have faced persistent, occasionally bewildering, production delays. And now experts fear that concerns over a rare but serious blood clot associated with the two vaccines could prompt countries to suspend them or deter people around the globe from taking them. Steve Morrison “People are extremely nervous about whether the [clots] are going to throw J&J and AstraZeneca into a retracted suspension,” says Steve Morrison, director of the global health policy center at the Center for Strategic and International studies. “It’s too difficult, it’s too early to judge. But people are very, very frightened about that.” That, Morrison adds, now makes the tiny Maryland-based biotech and their quixotic vaccine quest all the more essential for vaccinating the world. “People are going to be putting a lot more of a spotlight on Novavax,” he says. Novavax shares some of the same attributes that led experts to talk about AstraZeneca and J&J as global vaccines. Based on more traditional technology than mRNA, the shot is easier to manufacture, can be stored at normal refrigeration temperatures and delivered to remote and under-resourced regions. AstraZeneca provided the backbone for COVAX, the WHO-Gavi initiative to supply vaccines to poorer countries, promising 550 million doses, including virtually all of the shots they’ve shipped thus far. Novavax pledged double that: 1.1 billion doses — each of which now looms larger as many of the AstraZeneca vaccines COVAX shipped sit on refrigerator shelves, unused, around the world. Andrea Taylor “There was some concern that it might just hit the market too late and be unnecessary. But I think that’s no longer a concern,” Andrea Taylor, a researcher at Duke University’s Global Health Institute who has been tracking vaccine purchasing agreements, says of Novavax’s shot. “It will be really important.” Novavax, though, isn’t quite yet ready to shine. If the past few months have given the world a crash course in vaccine manufacturing, Novavax has provided the most interesting case study. In 2019, after a setback on their RSV vaccine, the company sold off their only factory. They have since tried to pull off one of the most herculean feats in the history of industry: to go from a little-known, barely solvent company with no approved products and no manufacturing facilities to a biotech that could annually churn out 2 billion doses of the world’s most sought after product. Amazingly, it’s largely been a success. Factories on three different continents are now churning out or preparing to churn out different components of Novavax’s vaccine, NVX-CoV2373. And the data that have come back are strong: In a 15,000-person UK study, the vaccine appeared as effective as the Pfizer-BioNTech and Moderna shots: 96% effective against the original SARS-CoV-2 virus and 86% effective against the variant now common in the country. “Everything about it that’s in the public domain looks promising,” says John Moore, an immunologist at Cornell, who was so impressed by the early results that he signed up for their Phase III trial. “The question is when is it going to get approved, and timelines seem to be getting pushed back and it’s not obvious why.” At a time when governments and public health officials are urging vaccine manufacturers to scale, Novavax has come up against the limits of what the world or any single company can handle. Virtually overnight, they set up a network of outside manufacturers more ambitious than one outside executive said he’s ever seen, but they struggled at times to transfer their technology there amid pandemic travel restrictions. They were kicked out of one factory by the same government that’s bankrolled their effort. Competing with larger competitors, they’ve found themselves short on raw materials as diverse as Chilean tree bark and bioreactor bags. They signed a deal with India’s Serum Institute to produce many of their COVAX doses but now face the realistic chance that even when Serum gets to full capacity — and they are behind — India’s government, dealing with the world’s worst active outbreak, won’t let the shots leave the country. Novavax has said they will read out on their US trial and file for authorization in the US and Europe this quarter, but they have refused to say how many doses they have on hand if they get a regulatory OK. CEO Stanley Erck first claimed last summer they could start producing vaccines at a rate of 2 billion doses per year “very shortly.” They’ve pushed that target to Q3, although Taylor doubts they will hit it. They’re trying as hard as they can, but so is everyone else. “There continues to be a lot of concern that supply isn’t being increased fast enough,” says Rajeev Venkayya, head of vaccines at Takeda, which has partnered to produce Novavax’s shot. “People need to understand that this is not something that is easily scalable to begin with, it’s already been scaled to a greater degree and faster than has ever been done before. And to do more just places greater risk on the entire system.” Takeda’s pandemic influenza plant in Hikari, Japan, where the company is trying to manufacture Novavax doses Click on the image to see the full-sized version When Novavax CBO John Trizzino called up an old colleague at Emergent BioSolutions in February of 2020, he wasn’t looking to produce billions of doses. Only a handful of coronavirus cases — it wasn’t yet called Covid-19 — had been confirmed in the US, and Trizzino just needed someone to build a few lots of the construct his research team had made. Emergent’s Baltimore plant was just a short drive from Novavax’s headquarters and the two had worked on projects together before. John Trizzino It would turn into the first strange twist in their manufacturing effort. Although Emergent produced material for the company’s successful Phase I/II trial, the federal government notified Novavax over the summer that they would have to move. Although the US was backing Novavax’s shot, they deemed J&J a higher priority and installed them at Emergent’s facilities, pushing the smaller company to Fujifilm-run plants in North Carolina and Texas. It seemed like a significant setback when The Washington Post reported the move, one that pushed back their Phase III trial and cost them in the vaccine race. But then this month word got out that Emergent had to destroy 15 million doses of J&J’s vaccine after mixing up ingredients, the beginning of a scandal that led the FDA to shut down the whole plant this week. Suddenly the calculus looked a bit different. “It’s like the old foxhole theory,” says Trizzino, who praised Emergent as a professional organization that hit a snag trying to scale rapidly. “You’re just glad it wasn’t you.” By March, Novavax’s ambitions had grown. Erck, invited to the Donald Trump vaccine summit at the White House, told the president that they wanted to get to one billion doses. “Frankly, we need money,” he said. “We need money to get scale.” Novavax would soon get that money, earning $388 million from Coalition for Epidemic Preparedness in May and a $1.6 billion contract from the Trump Administration’s Operation Warp Speed in June, the largest contract each entity had given out to that point. A Trump official told reporters the size matched the assistance Novavax, as a smaller company, needed in manufacturing. The CEPI funding allowed Novavax to acquire an old, 150,000-foot facility in the Czech Republic that the Serum Institute had been using to make polio vaccines before the Czech government decided that the polio vaccine — a weakened, live virus that can on rare occasions mutate back into pathogenic polio — was not something they wanted made in their borders. The deal came with 150 employees and capacity, the company said, to make 1 billion doses. Trizzino said the money accelerated talks that had already begun. Behind the scenes, Novavax had already been laying the groundwork for a major expansion that, after they got funding, came to include 10 different partners on three continents. Mark Womack “Just the nature of how they put all of this together,” says Mark Womack, CBO of the CDMO AGC Biologics. “I don’t think anyone’s ever seen anything like it.” In early April, Womack checked LinkedIn to find a message waiting for him. It was from Tim Hahn, a former Novavax CMC executive who the company had rehired to help figure out how to scale their vaccine. Hahn explained that he’d been urgently trying to get in touch and that he had to call him now. Novavax’s shot consists of two components. There’s the antigen, a synthetic copy of the coronavirus spike protein. Grown in insect cell lines, it provides the core part of the vaccine, training the immune system to recognize and neutralize the virus. The Czech facility and the US Fujifilm facilities are producing that component. The second part is one of the oldest tools in vaccination, one the other leading Covid-19 candidates don’t use: an adjuvant, an extra ingredient meant to boost the body’s innate immune response. Novavax specifically relies on an extract from Chilean tree bark, which is then packaged into a fat particle 40 billionths of a meter in diameter — a product they call Matrix-M. If Novavax wanted to make 2 billion doses of vaccine, they would also need to make 2 billion of Matrix-M. And AGC had the facilities to do it. Over four days, Womack said, the pair hammered an agreement that would normally take months. Formally announced on June 4, the deal saw AGC repurpose a line in their Copenhagen facility to make 2 billion doses of Matrix-M. Two months later, after Novavax won federal backing, they added another 1 billion doses at a new building in Seattle. In both cases, AGC reshuffled plans they had to use the facilities for a motley of other biological products. “They needed us to move at a speed that maybe no CDMO, in the history of our industry, ever had,” Womack said. That meant doing other things differently than just writing an agreement in four days. AGC generally acquired its own ingredients. Now they would rely in part on ingredients from Novavax, and they would move forward on buying new equipment and hiring dozens of new staff members without assurance they had been secured — which they sometimes weren’t. The Chilean tree extract, saponin, is a scarce commodity and they didn’t always have a steady supply. Still, the companies eventually managed to resolve those and both the Seattle and Copenhagen plants are churning at full speed, encasing the extract in fat to build two particles, and sending them off to the company’s North American and European fill-finish sites to be combined with the protein and injected into vials. An overview of Novavax’s Covid-19 supply chain. “Just the nature of how they put all of this together,” says Mark Womack, CBO of the CDMO AGC Biologics. “I don’t think anyone’s ever seen anything like it.” Click on the image to see the full-sized version Not every facility Novavax enlisted is now on track. The company has been limited both by the quantity of select raw materials that the world has never before needed in such quantities, and the speed at which they could conduct tech transfer. Tech transfer, one of many once-obscure words that officials are now becoming familiar with, simply refers to the process of one company setting up its production process at another company’s facilities. For vaccines, it’s a far more important step than sharing patents or intellectual property, but it can be intensive. Moderna CEO Stéphane Bancel has said part of the reason his company has not enlisted more outside partners is that they don’t have enough trained personnel to do so. Novavax had an advantage when it came to tech transfer. Their protein-based technology is similar to vaccines, such as the hepatitis b shot, which is already routinely made around the world. The company, Trizzino said, has relied on a single team of about a dozen people who have flown around the world to build up the vaccine. That might have worked out smoothly for one new facility. But the company is now trying to do it on an unprecedented scale. “The more partnerships you add, you’re spreading this team thinner and thinner, which makes it harder to manage the risk of each of these partnerships,” says Venkayya of Takeda, speaking generally about tech transfer. “This is going to stretch any organization.” Maria Bottazzi Maria Bottazzi, associate dean of the National School for Tropical Medicine at Baylor, noted that Novavax’s technology is not precisely like old-fashioned protein vaccine: They turn the coronavirus into a particle-like shape. That makes it more visible to the immune system but the process involved could make tech transfer more difficult. She says the company may have been a bit too ambitious with its production targets. “The aspiration goal they have is great, but technology transfer is not easy,” says Bottazzi, who is helping develop a more traditional protein-based vaccine. Novavax signed a partnership with Takeda last summer to produce 250 million doses. Takeda opted not to build its own Covid-19 shot as they focused on bringing Dengue vaccine to market, but they had facilities to build someone else’s vaccine. In 2014, they won a Japanese government grant to build 6,000 liters, two-story-high steel bioreactors in their plant in the southern city of Hikari. Novavax’s scientists, though, haven’t been able to fly into Japan to do tech transfer because of government restrictions. Instead, the two manufacturing teams have met remotely, trying to make sure that Takeda got identical equipment and raw materials Novavax used elsewhere, that their team is set up and could follow the exact same process, and they had the right quality tests to make sure the final product is the same. “You have to spend typically months, many months and thousands of person hours,” Venkayya said. “It’s very, very complicated and a lot can go wrong.” Takeda’s Rajeev Venkayya has been trying to set up Novavax’s production in Japan, although neither he nor Novavax’s team can enter the country Click on the image to see the full-sized version Nearly eight months after Takeda and Novavax signed an agreement, the Hikari facility is still not making vaccines. And Venkayya said it may not begin production this year. The problem is the same one that has affiliated the globe: the supply of raw materials. Although Novavax has established a manufacturing network across the globe, they’re missing key components to keep it running. That includes single-use bags that encase the insect cells when they’re inside the bioreactors. To get the Czech facility running, Trizzino says, they also need a filter that’s used throughout the production process, including for purification. Those delays have cost the company. Reuters reported in March that they forced the company to push back contract negotiations with the EU, as the Czech facility couldn’t make enough doses to supply the continent. Matthew Johnson Novavax executives and their partners at the Serum Institute have said the US government is restricting exports, although the reality is a bit more complicated. There’s a shortage of both components globally as supply chains strain under an unprecedented vaccination effort. The companies that make filters, for example, don’t have enough raw materials to make them, says Matthew Johnson, who leads cGMP at the Duke Human Vaccine Institute. The Defense Production Act doesn’t directly stop companies that produce components from exporting them, but it requires them to give the government priority on orders, meaning supply can continue once the US has enough to produce the vaccines it’s ordered but not enough but not until then. “As long as they are fulfilling their contractual agreements with the US, a Defense Production Act priority rating doesn’t impact what they do or how they engage in other business,” a spokesperson for HHS said in an email. “It is our legal obligation to ensure that a company only uses a Defense Production Act priority rating to satisfy U.S. Government orders.” Trizzino said those issues should be resolved by the second half of this year, at which point public health experts hope it will join a continued rollout of J&J and AstraZeneca’s vaccines. The EMA has insisted the benefits of the two vaccines far outweigh the risks, although countries around the world are still deliberating. Novavax may, however, still face a different export ban at that point. The Serum Institute contracted to produce 1 billion doses of Novavax’s vaccine in 2021, many of which are designated for COVAX. They’re already behind, and experts fear that India could keep its export ban on vaccines in place even after production scales up. Still, there are other ways Novavax’s vaccine could get deployed around the world. Although the biotech agreed to give the federal government 100 million doses, Morrison noted that the US will likely have more Covid-19 vaccine than it needs by the time Novavax gets past the FDA. Earlier this month, he authored a report calling among other things for the federal government to donate its excess doses to foreign governments. He pointed to the recent launch event for a new Covax drive, where Gavi CEO Seth Berkley and others stressed the need not only for companies to sell but also for vaccinated countries to donate doses. “Their tone has changed,” Morrison said. “They are desperate for donated shares.” The article has been updated to clarify Novavax’s trial is expected to read out in Q2 For a look at all Endpoints News coronavirus stories, check out our special news channel.