The U.S. government has tens of millions of unused doses of messenger RNA (mRNA) COVID-19 vaccines, regularly trashing shots as they pass their expiration dates. It’s a dismal reflection on recent vaccine uptake, but it’s also a serious roadblock for scientists testing and developing vaccines that could protect against future variants of SARS-CoV-2—and the next pandemic. Developers need existing vaccines as a benchmark to compare with new candidates. But government contracts with the vaccinemakers, and the companies’ own policies, prohibit the use of the vaccines for research purposes.
“At this stage of the game, with millions of vaccines on the verge of being thrown away, this seems crazy,” says Nicole Lurie, U.S. director of the Coalition for Epidemic Preparedness Innovations (CEPI). The situation is so dire that one startup has created mimics of the mRNA vaccines in use to help researchers improve their formulations.
Most researchers working on next-generation vaccines hope to create products that stimulate broader immunity to protect people from all sarbecoviruses, a group that includes variants of SARS-CoV-2, SARS-CoV-1, and related viruses found in bats and other wild animals that might spill over to humans. As part of the development process, researchers want to compare their candidates in animal models to the proven Moderna and Pfizer mRNA vaccines. They want to see how immune responses to the candidates stack up to the responses generated by current shots. They also want to give animals the existing and experimental vaccines and “challenge” them with different SARS-CoV-2 variants.
CEPI, which aims to speed the development of vaccines, has invested $230 million in 13 such vaccine candidates. The National Institute of Allergy and Infectious Disease (NIAID) has committed nearly $60 million to seven other academic teams working on what’s called pancoronavirus vaccine development, which has similar goals. Four groups receiving support from either CEPI or NIAID told Science that long-existing difficulties obtaining comparator vaccines has slowed their progress. “The acquisition of those direct comparators has been very difficult and challenging,” says In-Kyu Yoon, a CEPI director.
Neither NIAID nor the Biomedical Advanced Research and Development Authority, which purchased and distributes the Pfizer and Moderna vaccines, responded to Science’s questions.
The original efficacy trials of the Pfizer and Moderna mRNA vaccines compared those vaccines to placebo shots. But when those products received emergency use authorizations in December 2020, they became the standard of comparison in any future efficacy trials. The initial push for comparators came from developers who had COVID-19 vaccine candidates based on technologies other than mRNA, such as viral vectors or nasal delivery.
Now, researchers who are aiming for more broadly protective vaccines need the comparators to improve the design of their own candidates. The Pfizer and Moderna vaccines today have full approval from the Food and Drug Administration (FDA), a status that usually would allow researchers to purchase and study them. But because of the emergency pandemic response, the U.S. government owns all the product and, by contract with the companies, cannot provide it for research purposes. The contracts specify that the vaccines can only be used for immunizing humans and violations in theory could create liability issues for the companies.
The original doses of the Pfizer and Modern vaccines, which contain the surface protein from the initial strain of SARS-CoV-2, are of limited value as comparators: The two companies now make “bivalent” products that mix in a surface protein from the Omicron variant. But they, too, are locked up under the government purchase agreements.
The companies could make their vaccines available. But Pfizer and Moderna would not discuss the issue with Science, although Pfizer did confirm that its vaccine is not for sale in any private market. “We are not currently providing it directly to other research organizations, with the exception of certain government-funded research organizations, outside of our own targeted clinical development program,” the company stated.
Philip Krause, who for 11 years was deputy director of the FDA division that oversees vaccines, says he can understand why a company with vaccines on the market might look askance at sharing them with a potential competitor. “But obviously, it’s something that works substantially against public health,” says Krause, who left FDA in 2021 and now is a vaccine consultant. “If they’re throwing doses away, or if those doses can’t really be given to anyone anymore, that’s all the worse.”
PrEP4All, a nonprofit that advocates for improved public health responses to the COVID-19 pandemic, in April published a sharply critical report based on a 6-month investigation that involved many stakeholders and reviewing government contracts. “This an eminently solvable issue that must be addressed now—before [a] new crisis,” concludes the report, titled Science Held Hostage.
Some have taken to workarounds. Duane Wesemann, an immunologist at Brigham and Women’s Hospital who has one of the NIAID multiyear grants to develop a pan-sarbecovirus vaccine, says that “after many requests were denied on many fronts for many months” for comparators to use in mouse studies, his group resorted to using expired Pfizer mRNA vaccines. “It’s not ideal, but in mice the vaccine works very well,” Wesemann says.
In another compromise, Helix Biotech has helped frustrated pancoronavirus researchers by creating generic versions of the Pfizer and Moderna vaccines using publicly available formulas. Helix’s clients include NIAID, which provides the comparators to researchers it funds. Graham Taylor, who started Helix Biotech last year, says labs have shown that their mimics trigger similar immune responses to the real McCoy.
The Helix products cannot serve as comparators to help pan-sarbecovirus vaccines win FDA approval. That will require the real thing. Krause says regulators might be satisfied if human trials showed a pan-sarbecovirus vaccine triggered immune responses similar to those elicited by the best available approved products, a concept known as immunobridging. Or they might require developers to stage head-to-head clinical trials that use reduction in mild COVID-19 disease as the endpoint. Either way, Moderna or Pfizer would have to allow the use of their bivalent vaccines.
Although animal studies could test the breadth of a pan-sarbecovirus vaccine’s protection, delivering on their promise would require exposure to new variants or even new coronaviruses. That could only happen in real-world effective studies that take place after a new virus starts to spread.
The boxes of unused COVID-19 vaccine now sitting in freezers point to one more hurdle for pan-sarbecovirus vaccines, Krause says: “Who will believe they need them?