Monoclonal antibody maker sees opportunity as COVID-19 vaccines fall off

As access to COVID-19 vaccines dwindles in the US, one company seems to be positioning its products as an alternative way of preventing the disease.

Invivyd is the manufacturer of pemivibart, a monoclonal antibody sold under the name Pemgarda. The US Food and Drug Administration has authorized Pemgarda for emergency use in adults who are moderately or severely immunocompromised. So far, it’s authorized only as a pre-exposure prophylactic, despite Invivyd’s attempts to get the FDA to OK its use as a treatment.

The agency rebuffed those efforts in February, saying it could not “reasonably conclude that the known and potential benefits of pemivibart . . . outweigh the known and potential risks,” according to a press release from Invivyd.

Nonetheless, Invivyd has pressed forward with a strategy to make monoclonal antibodies part of the COVID-19 arsenal. The Waltham, Massachusetts–based company has another drug candidate waiting in the wings: VYD2311, an antibody that the company describes as having around 99% structural similarity to pemivibart. In press releases and interviews, Invivyd executives describe VYD2311 as a medicine that could eventually provide an alternative to vaccination.

“There has been recent talk about how, where vaccine has been used in the past, it might not be used in the future,” Invivyd chief scientific officer Robert Allen tells C&EN. “In those settings, there is the potential for monoclonal antibody to provide some protection.” He adds that data from additional clinical trials would likely be needed.

In a press release dated Aug. 14, Marc Elia, chair of Invivyd’s board of directors, is more blunt. “We believe monoclonal antibodies such as VYD2311 can serve as a powerful alternative to vaccines for COVID-19 prevention, and represent an important potential paradigm shift to move American medicine beyond the real and perceived limitations of COVID-19 vaccines,” Elia says in the statement. “Amidst declining public trust in vaccines, we want to offer Americans a new, non-vaccine choice.”

In keeping with this stance, the company filed a citizen petition in May encouraging the federal government to switch its focus from vaccines to monoclonal antibodies as a preventive strategy for high-risk groups, writing that the medicines “have several inherent advantages over serial vaccination.”

A few weeks later, when FDA leaders said they’d ask COVID-19 vaccine manufacturers to run placebo-controlled trials for their shots in young people without certain health conditions, Invivyd applauded the decision, even as bioethicists pointed out the pitfalls of giving people a placebo when an effective intervention is available.

What remains to be seen is whether the firm’s efforts will bear fruit. VYD2311 has been tested only in a 40-person Phase 1 clinical trial. Invivyd says the study shows that the antibody has a long half-life, from which it infers that the drug candidate will have a long-term protective effect. Invivyd is planning a Phase 2/3 study that, if it succeeds, would be enough for the FDA to decide whether to approve VYD2311 as a preventive.

But not everyone is convinced by the strategy. Monoclonal antibodies have failed to treat COVID-19 before—many times. By their nature, the drugs target specific viral epitopes, and if SARS-CoV-2, the virus that causes the disease, mutates such that the epitope no longer fits the antibody, the drugs stop working.

“[VYD]2311 is almost certain to be rendered obsolete by the virus as the evolution of the virus continues,” says University of California, San Francisco, immunologist Warner C. Greene. “I view it as a flawed strategy, a weak strategy from the beginning.”

Viral evolution

Invivyd began life as Adagio Therapeutics. Spun offof Adimab in mid-2020, the start-up had a lofty goal of creating antibodies that would be able to “neutralize SARS-CoV-2 and all its known variants,” as founder and then-CEO Tillman Gerngross said at the time. Adagio went public in a stock offering a year later, raising $309 million.

As it turned out, a lot hinged on “known variants.” In 2021, SARS-CoV-2 made its genetic leap to omicron, a new and powerful variant whose descendants still rule the viral landscape 4 years later. Adagio’s lead drug candidate collapsed, no longer able to effectively tackle the newly shaped virus. Gerngross left the company, along with several other executives and laid-off staffers.

The company rebranded in 2022 as Invivyd, and new executives aimed to put Adagio firmly in the rearview mirror, prioritizing discovery and early-stage research instead of rejiggering its earlier antibodies. Those efforts eventually yielded pemivibart, a new antibody that held up well against omicron and its various spinoffs. The FDA issued an emergency use authorization (PDF) for pemivibart in March 2024.

Invivyd says it expects both Pemgarda and VYD2311 to maintain their antiviral activity against new SARS-CoV-2 lineages, including the currently dominating Stratus variant.

“Pemgarda was built on the basis of its ability to bind and neutralize those variants that occurred right at the time of the omicron emergence,” Allen says. “[VYD]2311 was updated against spike antigens that had followed the omicron variant emergence. . . . As time passes, the virus evolves, and what we could consider to be evolutionary drift is occurring. The antibody still maintains activity and binds well to those variants that emerge.”

Pemgarda is currently the only monoclonal antibody on the market for COVID-19 in any capacity. By the end of 2022, the FDA had pulled marketing authorizations for every single other antibody for COVID-19 because they no longer worked.

The last one to fall was AstraZeneca’s Evusheld, which, like Pemgarda, was designed as a preventive for people who are at especially high risk of complications from COVID-19. AstraZeneca attempted to develop a newer version of Evusheld called sipavibart, but it discontinued those efforts in the last year, after resistance emerged in a late-stage trial.

“Invivyd is sort of, in the US, the lone monoclonal antibody company, and they’ve done a great job of tweaking a basic structure that works,” says David Sullivan, an infectious diseases specialist at the Johns Hopkins Bloomberg School of Public Health. He says that Pemgarda could eventually fall by the wayside but that VYD2311 has an opportunity to take its place.

Broad population

According to Allen, Invivyd has “no active plans” to expand the use of its antibodies beyond the immunocompromised population, where the FDA has so far shown a clear path to market. But the company is certainly looking.

“With all the space that is still to be realized within immunocompromised individuals in different stages of development, there’s plenty to prospect on,” Allen says. “In cases where we saw that there was a clear need and a disease burden outside that context, we would at least entertain that.”

It appears that window may be opening. Last week, the FDA approved updated COVID-19 vaccines for the 2025–26 season, but only for select groups: people 65 and older, and people with health conditions that make them susceptible to worse outcomes from COVID-19, which the US Centers for Disease Control and Prevention (CDC) has yet to clearly define. Invivyd raised $57.5 million in a stock offering as confusion about vaccine access began swirling.

Monoclonal antibodies provide a kind of protection different from that of vaccines. Whereas vaccines stimulate the body’s immune system to form its own protective antibodies, a process known as active immunity, monoclonals simply are the antibodies. That approach is called passive immunity. Immunocompromised people don’t get as much active immunity from vaccines because their immune systems are weaker to begin with, but “it’s not a black-and-white issue,” says Johns Hopkins immunologist Arturo Casadevall.

“My advice to the person at high risk is to get vaccinated,” he adds. “I don’t see this as either-or.”

Should monoclonals like Pemgarda and VYD2311 be used as a replacement for COVID-19 vaccines? The answer from infectious disease specialists, so far, is a resounding no.

“There is a role for monoclonals. I’ll leave it at that,” Sullivan says. “Honestly, I do not see monoclonal antibodies replacing vaccines.”

Greene agrees. “I don’t think it’s a great plan to try and introduce this type of passive protection into a normally immune-responsive population,” he says. “I don’t think that would fly.”