Science’s COVID-19 reporting is supported by the Pulitzer Center.
Merck, one of the largest pharmaceutical companies in the world, has been conspicuously absent from the race to develop COVID-19 vaccines and drugs. No longer. The company this morning announced it has cut deals to develop and manufacture two different COVID-19 vaccines and a much-discussed experimental antiviral compound that is already in early clinical trials.
Roger Perlmutter, president of Merck Research Laboratories, portrays the company as deliberate rather than a latecomer. And the immunologist believes Merck’s skills and experience can accelerate the progress that other, smaller developers already have made. “Clearly, we have a lot of heft,” says Perlmutter, who declined to disclose how much Merck is investing in each project.
According to the World Health Organization’s latest table of COVID-19 vaccines, 124 candidates are at various stages of development with eight different technologies, or platforms. Merck’s new investments focus on a platform, known as the replicating viral vector, that takes longer to develop than others, but will potentially lead to robust immune responses triggered by a single dose. “Most vaccine projects fail—it’s very difficult to make a vaccine,” Perlmutter says. “So if I’m going to start making a vaccine, I’d like to be thoughtful about which vaccine platforms have the greatest likelihood of success.” Being first hasn’t been the company’s priority. It’s likely that the world will need more than one COVID-19 vaccine to meet demand, Perlmutter says. And different populations like the elderly or children may need different preparations, he adds.
One of the COVID-19 vaccine candidates that Merck decided to back aims to build off the success it had with an Ebola vaccine that came to market last year. That vaccine uses an engineered vesicular stomatitis virus (VSV) to shuttle a gene for the Ebola virus surface protein into a host’s cells. Merck now plans to develop a VSV-based COVID-19 vaccine in partnership with the International AIDS Vaccine Initiative (IAVI), a nonprofit that was originally set up to push forward HIV vaccines but has broadened its portfolio to include vaccines for a wide range of other diseases.
Mark Feinberg, who heads IAVI and previously worked at Merck on the Ebola vaccine project, notes that IAVI scientists have been working with the VSV platform for vaccines against Lassa fever, Marburg virus, and a different Ebola virus. They’ve now stitched into VSV the surface protein, or spike, for SARS-CoV-2, the virus that causes COVID-19. Feinberg says Merck approached IAVI in March about collaborating.
“The multiple shots on goal analogy [for the COVID-19 vaccine pursuit] makes enormous sense here,” Feinberg says. “With 100-some candidates, not all of them are going to advance to the clinic or be able to be produced at scale. There will have to be a rigorous, thoughtful, data-driven process to select the most promising ones.” As part of the deal, the U.S. government has awarded IAVI $38 million through the Biomedical Advanced Research and Development Authority (BARDA).
For the second vaccine project, Merck is acquiring Themis, an Austrian company that licensed a platform based on the established measles vaccine and developed at the Pasteur Institute. The vaccine contains a weakened, safe version of that virus that causes measles, which Pasteur scientists showed could serve as a carrier for genes from a wide range of pathogens, including the coronavirus that causes severe acute respiratory syndrome. Adding the spike gene from SARS-CoV-2 to this attenuated measles virus was a logical next step. Themis, the Pasteur Institute, and the University of Pittsburgh in March received $4.9 million to develop the approach from a nonprofit, the Coalition for Epidemic Preparedness Innovations.
Perlmutter says neither IAVI nor Themis has yet tested whether these vaccine candidates can protect monkeys from SARS-CoV-2 infections or serious COVID-19 symptoms. But he says both platforms have proved themselves in human studies for other diseases and “we have a high confidence” that they can work. The live replicating viruses, he says, have the advantage of stimulating both B cells, which make antibodies, and T cells that clear infected cells. And unlike the many COVID-19 vaccine candidates that use nonreplicating vectors or just engineered versions of the coronavirus surface protein, this approach may only need a single shot because the viruses copy themselves, potentially producing high levels of spike that elicit strong immune responses. “When you start thinking about immunizing billions of people, the idea of having to track people down for boosters is very problematic,” Perlmutter says. “It’s not impossible, but you’d prefer not to do it.”
Lawrence Corey, a vaccine developer at the Fred Hutchinson Cancer Research Center who co-chairs a committee at the National Institutes of Health that aims to speed testing of COVID-19 vaccines, welcomes Merck to the race. “I’m delighted to see them undertake two novel platforms for potential COVID vaccine development,” Corey says.
On the therapy front, Merck has chosen to back development of EIDD-2801, a compound designed to inhibit diverse viruses that use RNA as their genetic material, which includes SARS-CoV-2. Merck is collaborating with Ridgeback Biotherapeutics, which licensed the drug from a nonprofit at Emory University called Drug Innovation Ventures at Emory (DRIVE). Ridgeback recently started a safety trial of the drug in healthy patients in the United Kingdom.
The drug, which inhibits a polymerase enzyme used during viral replication, has been at the center of a controversy involving Ridgeback’s attempt to win BARDA funding. The agency’s former director, Rick Bright, filed a whistleblower complaint that went into great detail about how his bosses allegedly pressured him to fund EIDD-2801’s development, which he worried could present serious toxicities. BARDA did not award the money—which could have totaled $300 million—to Ridgeback or DRIVE.
At least one other pharmaceutical company abandoned development of a compound similar to EIDD-2801 because it has mutagenic properties. Perlmutter agrees that “ordinarily you prefer not to advance a mutagen,” but he says the drug, which can be given as a pill, has been “well tolerated” in the U.K. trial and that they plan to look closely at its cancer-causing potential in reproductive and developmental biology animal studies. Other mutagenic drugs that treat infectious diseases have come to market, he notes.
Perlmutter stresses that there are no easy solutions to the COVID-19 pandemic—particularly when it comes to developing and evaluating vaccines. “One of the things I think is disturbing is I don’t want people to imagine that—not that they would—that Merck is coming in now and it’s all going to get taken care of in 12 months,” Perlmutter says. “It’s not. These things take a long time.”