In the spring of 2009, the first flu pandemic in four decades began. Caused by an H1N1 virus that emerged from pigs, likely in Mexico, it spread quickly around the globe.
The world got lucky in 2009. Doubly so. The “swine flu” virus was distinct enough from previous H1N1 viruses that it could cause a pandemic, but it had enough genetic similarities to viruses that had circulated for decades that many people had some immune defenses, which blunted its severity.
The other truly lucky break was that multiple flu vaccines targeting H1N1 were already licensed in the U.S., so the Food and Drug Administration could fast-track approval of pandemic vaccines. That tool, used regularly when seasonal flu shots require updating, sidestepped the need to run a series of clinical trials that could have added as much as a year to the race to get vaccines into arms.
Emergency response planners in the federal government have long hoped to use the same approach if the dangerous H5N1 bird flu virus ever triggers a pandemic. But news that the Trump administration is reconsidering a government-funded study of an experimental H5N1 vaccine is generating fears that it may be on the chopping block, and that could take the fast-track option off the table, at least for one of the manufacturers of messenger RNA vaccines — the fastest vaccines to make and the easiest to mass produce.
At a time of elevated concerns about the potential for an H5N1 pandemic, the Department of Health and Human Services has confirmed that it is re-evaluating a nearly $600 million contract issued to Cambridge, Mass.-based Moderna by the Biomedical Advanced Research and Development Authority, a division of HHS. The contract, signed in the final days of the Biden administration, is designed to help Moderna develop and test the safety and efficacy of vaccines to protect against five subtypes of influenza that could prompt pandemics, including H5N1. The review of the contract was first reported by Bloomberg News.
“While it is crucial that the U.S. Department and Health and Human Services support pandemic preparedness, four years of the Biden administration’s failed oversight have made it necessary to review agreements for vaccine production,” Andrew Nixon, the HHS director of communications, said in an email when asked about the decision.
The swipe at the previous administration aside, there has been no specific rationale disclosed for the re-evaluation. While it is common for new administrations to review some of the spending plans of their predecessors, HHS Secretary Robert F. Kennedy Jr.’s distrust of vaccines and the companies that make them has sparked concerns this could be a prelude for cancelling a contract experts believe is critical to the country’s efforts to be ready for a bird flu pandemic.
“I think the government’s investment in alternative vaccine technologies that could be brought to bear rapidly in a major public health emergency is very important,” said Jesse Goodman, a former head of the FDA division that regulates vaccines, the Center for Biologics Evaluation and Research, and later the agency’s chief scientist. “I think funding those large-scale studies was a really wise decision.”
Most flu vaccines are currently made using a decades-old approach where viruses are grown in hen’s eggs, then inactivated — a process that can sometimes result in mutations that undermine the vaccines’ effectiveness. Production is slow and reliant on huge quantities of eggs — the supply of which could be threatened by outbreaks of H5N1 or other bird flu viruses, as is happening now. Wide-scale outbreaks of H5N1 in poultry are occurring in multiple parts of the country, forcing the culling of flocks and driving egg costs to historic highs.
Goodman said developing flu vaccines made with approaches other than eggs is key to being able to mount a rapid response when the next influenza pandemic occurs. “I would say the biggest priority would be to get an approved alternative technology flu vaccine to use in the pandemic. We need that.”
With the current modes of production, there isn’t sufficient capacity to rapidly produce enough doses to meet global demand in a pandemic. “So that’s why the need for alternative technologies and mRNA is one of them,” said Goodman, who is now director of the Center on Medical Product Access, Safety and Stewardship at Georgetown University.
Studies have shown that vaccines made to protect against H5N1 do not trigger a strong immune response, unless the dose of vaccine used is very high, or an adjuvant — a compound that amplifies the response to the vaccine — is used. Even then, each person would require at least two doses of vaccine, complicating the job of getting as many people vaccinated as quickly as possible in what could be a devastating event.
The Covid-19 pandemic showed the importance of the mRNA vaccine platform, which had never before been used. Pfizer and its partner BioNTech, and Moderna were able to develop, test, scale, and deliver vaccines within 11 months of the posting of the genetic sequence of the virus, using the mRNA platform. Though public distrust of this type of vaccine has grown, fueled by baseless rumors questioning mRNA’s safety, the fact remains that the production speed this platform offers will be needed again, if H5N1 succeeds in transitioning from a bird virus that occasionally infects humans to one that spreads easily among us.
There’s good reason to believe the timeline for delivery of mRNA pandemic flu vaccine would be shorter still, if the makers of mRNA vaccines can license H5N1 vaccines before a pandemic. That’s because all the trials to determine if the vaccine triggered an adequate immune response and to generate the safety data the FDA would want to see would be done in advance.
“I suspect because mRNA flu vaccines are a relatively new technology, that for a pandemic strain type like H5 … they’d probably want to see a substantial safety database,” Goodman said.
Laying that groundwork would mean that if an H5N1 pandemic started, manufacturers could quickly update the version of the virus the vaccine targeted and get expedited authorization under the same FDA rule manufacturers use when they update seasonal shots.
“It’s a question of preparation,” said Phil Krause, a virologist and a former deputy director of the FDA’s Office of Vaccines Research and Review. “By creating that advanced safety data, we can give this vaccine with more confidence to people initially.”
Doing the preparatory work doesn’t mean safety studies wouldn’t be needed as the vaccines were being used, “but it gives you that head start,” Krause said. Among other things, it would allow regulators to make decisions based on safety data from thousands of recipients of mRNA influenza vaccines, Goodman noted.
“Do you want to go into an emergency where you’ve had thousands of people who’ve gotten the vaccine, so you have that degree of confidence? I would think RFK Jr. would want that,” he said.
In addition to broadening the number of potential suppliers of pandemic vaccines, having one or more mRNA options would be a hedge against unforeseen outcomes — for instance, if the egg-based vaccines did not work as well as expected, or a safety signal arose about possible side effects associated with their use, Krause said.
“Understanding how mRNA vaccines can be used in this setting is very important,” he said, adding “if we don’t have this additional option … all of our eggs are basically in one basket of egg-produced vaccines.”
Doing this advance work could help assuage concerns some people might have if they were again presented with a new vaccine that was perceived to have been developed in a hurry, said Luciana Borio, a former director for medical and biodefense preparedness policy at the National Security Council.
“We don’t want to be in a situation where we’re in a data-free zone and having to make educated guesses when it involves the health of so many people. We don’t want to be in a situation where people don’t have confidence in a vaccine that is forced through because we haven’t done the work ahead of time,” said Borio,
who is now a partner at ARCH Venture Partners and a senior fellow for global health at the Council on Foreign Relations.
Borio, alluding to Kennedy’s promise to bring “radical transparency” to the operation of HHS, said it is important that the department explain “exactly what the rationale is” for reviewing the Moderna contract, to “make sure that it’s not just because there is this belief that vaccines are not important or that vaccines can be made in real time” from a standing start.
Using the fast-track approval process requires there to be a licensed vaccine for that specific subtype of flu. At this point, there are no licensed mRNA flu vaccines of any type. True, both Pfizer and Moderna have been working on seasonal flu shots. But breaking into the seasonal flu market poses challenges for both these companies — there are already established manufacturers who produce adequate supply for the seasonal market demand, which has been declining in the post-Covid era.
The BARDA funding that is currently in suspended animation is to help Moderna do the advanced studies that would be required to license an H5N1 vaccine. It’s work that the company would be unlikely to be willing or even able to do without federal help, given that there is no guarantee there will ever be a need for H5N1 vaccine.
“They can’t make things that may not be used,” said Kathryn Edwards, a retired pediatrician who has studied vaccines for decades.
There are currently three licensed H5N1 vaccines on the books, made by GSK, CSL Seqirus, and Sanofi. The GSK and Sanofi vaccines are made in eggs; the CSL vaccine, Audenz, is produced using viruses grown in cell culture. While this platform doesn’t rely on eggs, the requirement to grow large amounts of virus means its production time isn’t as quick as mRNA vaccines, which do not require growing viruses.
All three companies have received substantial BARDA assistance in their H5N1 work. The vaccines they have tested and licensed are not commercially available, though the U.S. government has some supplies in the National Pre-pandemic Influenza Vaccine Stockpile.
Some other countries have also bought doses for stockpiling, or to vaccinate at-risk agricultural workers. Last year Finland bought some H5N1 vaccine to offer to workers on fur farms that have experienced outbreaks of the virus. Earlier this month, Canada announced it was purchasing a half-million doses of H5N1 vaccine for a similar purpose.
Stimulating the preparatory work to develop the medical tools that would be needed in emergencies — pandemics, outbreaks of rare diseases, or possible bioterror attacks — is the reason BARDA was created, Edwards said.
“BARDA is there to prepare us for pandemics, so that … pilot lots can be made … these vaccines can be tested and made and then they can be scaled up and licensed,” she said, adding that if the Moderna contract is canceled “it could be a very big blow.”