Science‘s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.
As the world is transfixed by the high-stakes race to develop a COVID-19 vaccine, an equally crucial competition heats up to produce targeted antibodies that could provide an immediate boost in immunity to the virus. Clinical trials of these monoclonal antibodies, which could both prevent and treat the disease, are already underway and may show signs of effectiveness in the coming months, possibly before vaccine trials. “If you were to deposit your money, you’d bet you get the answer with the monoclonal before you get the answer with a vaccine,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID).
“Antibodies have the potential to be an important bridge until the vaccine is available,” says Ajay Nirula, vice president of Eli Lilly, one of the many large companies investing in them. Probably more effective than currently available reused drugs, such as remdesivir and dexamethasone, the antibodies could protect healthcare workers most at risk from infection while reducing the severity of COVID-19 illness in hospitalized patients . But making monoclonal drugs involves growing anti-manufacturing B cell lines in bioreactors, raising concerns that they could be rare and expensive. On July 15, Lilly, AbCellera, AstraZeneca, GlaxoSmithKline, Genentech and Amgen jointly asked the United States Department of Justice (DOJ) if they could share information about the manufacture of their monoclonal drugs without violating antitrust laws, “to extend and speed up production ”.
Shortly after the onset of the pandemic, researchers from industry and academia began to identify, design, refine, and perform laboratory testing of monoclonal antibodies against SARS-CoV-2, the virus responsible for COVID-19. Most work by binding and “neutralizing” the viral surface protein, or spike, that starts an infection. On May 29, Lilly, working with AbCellera, launched the first human study of a monoclonal antibody – a phase I trial testing its safety and tolerability in hospitalized COVID-19 patients. Further safety trials followed, with Lilly’s Chinese partner Junshi Biosciences and Regeneron, who developed a three-monoclonal cocktail that works against Ebola.
Regeneron is currently testing the effectiveness of its COVID-19 cocktail, which combines a spike antibody from a person who has recovered and one from a mouse who received the spike protein, in three large-scale, placebo-controlled trials. A prevention trial conducted in coordination with NIAID’s COVID-19 Prevention Trials Network (CoVPN), a branch of the Trump administration’s Operation Warp Speed, will recruit 2,000 people who live in a home with a confirmed case of COVID-19. One treatment study the company is running aims to recruit nearly 2,600 people hospitalized with severe COVID-19, while another, about half that size, will test for antibodies in infected people with mild or moderate symptoms. Lilly has started its own trials, including a placebo-controlled Phase III study of 2,400 residents or staff of long-term care facilities, conducted with assistance from the CoVPN.
“We should be able to see a signal of effectiveness very quickly” from these trials, says Amy Jenkins, who heads the Pandemic Prevention Platform (P3) program at the Defense Advanced Research Projects Agency, which for the past 2 years has invested in accelerating the development of monoclonal antibodies for pandemics. Although Jenkins is reluctant to make a firm prediction, she says the November to December period is “realistic and conservative.” This is likely before any vaccine is proven to be safe and effective, researchers say. “I would be reluctant to say [that] would be sooner than the end of the year, ”Fauci said at a press conference on the launch of NIAID’s first COVID-19 vaccine trial on July 27.
Regeneron’s Christos Kyratsous notes that vaccine trials must wait a few weeks for a person’s immune system to develop appropriate responses to injections and additional weeks for the “event” – incidental exposure to SARS-CoV-2. This means that these tests require time and many people. In contrast, for antibody treatment trials, “your event has already happened,” Kyratsous says. And in prevention studies, household contacts of COVID-19 cases will be much more likely to be exposed than people who typically participate in a vaccine study.
Immunologist Dennis Burton, whose Scripps Research group has isolated very potent monoclonal antibodies to SARS-CoV-2 that they hope to pass into human studies, says he’s optimistic the monoclonal will protect people get the infection for months with just one hit. “It’s much easier to deal with a few incoming virus particles than it is to try to resolve or cure an ongoing infection.” The same logic goes for processing. “Hit the virus hard and early,” says Burton.
Kyratsous says that even if monoclonal antibodies don’t beat vaccines to the finish line, they could still have a role to play against COVID-19. “We’re going to need both approaches in the long term,” Kyratsous says. Vaccines are rarely 100% effective, and many people may decline a vaccine or not skip the vaccination for other reasons. In addition, he notes, the elderly or those who are immunocompromised may not develop robust immune responses after being vaccinated.
Monoclonal antibody supplies may be limited, however, in part due to modest investment. Operation Warp Speed, for example, committed $ 8 billion for six different COVID-19 vaccines; for monoclonal drugs, the government has invested around $ 750 million, much of it in Regeneron, which will produce between 70,000 and 300,000 doses before even having efficacy data. Lilly says she will have 100,000 doses by the end of the year.
If the antibodies work, a study from the Duke University Margolis Center for Health Policy estimates that the United States alone could require nearly 40 million doses next year. But no one knows how far those doses might extend, says Janet Woodcock, who is on leave from the Food and Drug Administration’s directorate of drug review and research division to lead the therapeutic effort of Warp Speed. “Unlike vaccines, it’s hard to predict how many treatments will be available,” says Woodcock. Prevention, which would be a single intramuscular injection, requires less product than the intravenous infusions used in treatment, she notes, but the amount needed depends on a person’s weight.
Although the prioritization of vaccine distribution has already sparked extensive debate, no such discussion has yet taken place on monoclonal antibodies. But the DOJ acknowledged the supply issues on July 23, giving the six companies that asked it the green light to share production information.
Regeneron is not in that group, but Kyratsous is optimistic that the need will be met. “The advantage of some of these organic products is that you can increase production quite quickly,” he says. Nirula agrees. “If we are successful in these clinical trials, we will have a lot of drugs available,” he says.
The cost of monoclonal drugs, especially for the higher doses needed for treatment, could divide the world between the haves and have-nots. “This treatment is unlikely to drop back to a price point in the near future that would be easily affordable globally,” says Seth Berkley, who heads Gavi, the Vaccine Alliance, and is also leading an effort international COVID-19 vaccination.
Jenkins says one of the main goals of Project P3, which provided four groups with $ 96 million in seed money, was to develop monoclonal antibodies that can be made by the body itself, rather than in large fermentation tanks. The idea, which has yet to be tested in humans, is to inject people with DNA or messenger RNA that encodes a desired antibody, allowing their own cells to make it. “We think we can lower the cost of monoclonal antibodies,” Jenkins says.
Regardless of the cost, proof that monoclonal drugs work as preventative agents could benefit everyone by giving vaccinators a clear sign that antibodies to the SARS-CoV-2 surface protein are sufficient to protect a person. This, in turn, could provide a strong indicator to assess the value of a candidate vaccine short of actual efficacy data. “This is going to revolutionize the field of vaccines in a positive way,” says Myron Cohen of the University of North Carolina, Chapel Hill, who leads monoclonal antibody testing for CoVPN. “It offers a thousand possibilities to move faster.”