Helen Branswell , 2025-05-03 20:13:00
When word broke this week that the Department of Health and Human Services was investing half-a-billion dollars on a National Institutes of Health project to develop a vaccine platform for pathogens that could trigger pandemics, a number of scientists who work in the field of vaccinology had decidedly mixed feelings.
That HHS and NIH are going to continue to invest in efforts to make vaccines that could reduce the impact of future pandemics was good news, many thought. But why spend so much money on using whole killed viruses — an approach pioneered in the last century — as the basis of the vaccines?
“I was confused by the messaging, because it is a 70-year-old technology,” said one scientist who works in vaccine development, noting this was the method used by Jonas Salk to create the world’s first polio vaccine in the early 1950s.
Another scientist familiar with the scope of research that is being done to try to develop a so-called universal flu vaccine to protect against a range of dangerous strains — like H5N1 bird flu — was blunt. “There is incredible work going on. This is not it.”
These and a number of other scientists STAT interviewed for this article spoke on condition they not be identified, fearing they or their institutions might suffer retribution for criticizing the plan. The NIH is the world’s largest funder of scientific research.
Many raised concerns about investing so much in a way to make vaccines that has been overtaken by newer, more nimble production processes. One likened it to turning back the clock. Veteran vaccines researcher Arnold Monto said this approach “is not a eureka moment.”
The press release announcing the project does not mention how much has been committed for the work, but a Wall Street Journal article that broke the news put the figure at $500 million, citing emails shared with the newspaper.
A number of scientists also questioned the way the funding was awarded. Because the project is led by in-house scientists — one who is now the NIH’s principal deputy director, Matthew Memoli, the other his frequent co-author and now acting director of the National Institute for Allergy and Infectious Diseases, Jeffery Taubenberger — it did not have to go through the lengthy and rigorous peer-reviewed appraisal process that scientists at academic institutions must endure when they are seeking NIH funding. “It’s really quite incestuous,” one scientist noted.
Stanley Plotkin, co-developer of the vaccines that protect against rubella and rotavirus, expressed concerns about how well vetted the project was, and whether the amount set aside for it was appropriate.
“Yes, we need a better influenza vaccine. Is this project going to do that, without examining it in detail? I cannot really say, and I would hope that the project has been reviewed by some knowledgeable people,” said Plotkin, a professor emeritus at the University of Pennsylvania.
Several scientists who reviewed initial results from a Phase 1 trial of the NIH group’s universal flu vaccine — which only targets four subtypes of flu — were underwhelmed by the data posted to the website ClinicalTrials.gov. An injected version of the vaccine appeared to generate moderate rises in antibodies, but an intranasal version of the vaccine didn’t perform as well.
Monto, co-director of the Michigan Center for Respiratory Virus Research and Response and a professor emeritus of epidemiology at the University of Michigan, cautioned that a Phase 1 study is designed to see if the vaccine is safe to use; determining immunogenicity isn’t its primary function. And Phase 1 trials are always small; this one included 45 people, divided into three groups, one of which only received a placebo. “When you have 15 in a group, you really can’t say a whole lot about it,” he said.
Dubbed Generation Gold Standard, the project aims to develop a vaccine platform using whole but inactivated or killed viruses. The HHS release suggests the platform could be a way to protect against “pandemic-prone viruses.”
In the early days of vaccine production, making vaccines using whole killed viruses was common; early flu vaccines were made this way. Though the press release suggested that whole killed virus vaccines offer long-lasting protection, when flu vaccines were made using this method they were updated and given annually — like contemporary flu shots — because influenza viruses evolve to evade human immunity.
Over the years, vaccine design has evolved too, with newer approaches that allow for faster production, induce fewer side effects, or trigger stronger immune responses. The whole killed virus approach has largely fallen out of favor, though some vaccines — the rabies vaccine is one — are still made this way. “The rabies vaccine is not a great vaccine,” one critic of the plan said. “We could do better with newer technologies.”
In the statement announcing the project, Director Jay Bhattacharya called it “a paradigm shift.”
“It extends vaccine protection beyond strain-specific limits and prepares for flu viral threats — not just today’s, but tomorrow’s as well — using traditional vaccine technology brought into the 21st century,” he said.
The statement projects that the approach could deliver a flu vaccine that would protect against multiple strains of influenza, another that could protect against a variety of coronaviruses, and eventually other disease threats as well. It boldly predicted that a universal flu vaccine, a complex challenge that multiple research groups around the world have been trying to crack for years, could be approved as early as 2029.
“Clearly the press release was written by somebody who does not understand the difficulties of science,” Plotkin said.
Funding for the work has been reallocated from monies that the Biomedical Advanced Research and Development Authority, the HHS’s agency tasked with preparing for biological and bioterrorism threats, had awarded for development of next-generation countermeasures for Covid-19 — new vaccines, drugs, and assays. Several biotech companies have been informed in recent weeks that they are losing their funding under that program, which was called Project NextGen.
STAT requested an interview with Memoli, but did not receive a response to the request.
STAT did receive a comment — “attributable to the NIH” — that offered a defense of the funding decision. It signaled, however, a lack of clarity about what the project is aiming to achieve, saying vaccines made using the platform “could provide broad, long-lasting protection against all influenza viral pathogens, including influenza and coronaviruses, with the added potential to block transmission and stop outbreaks at the source.” Coronaviruses are not “influenza viral pathogens.”
Some of the scientists who raised concerns about the project worried that support for this vaccine development method might signal a move away from using messenger RNA vaccines for pandemic preparedness. One of the leading candidates in the efforts to develop a universal flu vaccine uses mRNA to target 20 different subtypes of influenza A and B, the full range of known flu threats to humans. The prototype being tested by the NIH team currently targets only four subtypes of influenza A.
Scott Hensley, a professor of microbiology at the University of Pennsylvania’s Perelman School of Medicine who is leading the work on the mRNA-based universal flu vaccine, welcomed the news that the NIH was funding the project. But he stressed other approaches need to be pursued.
“It is exciting to see funding for multivalent inactivated influenza vaccines, but it will be important to continue funding other promising platforms as well, like mRNA vaccines that can simultaneously deliver dozens of influenza vaccine antigens,” Hensley said via email.
Monto agreed. “There are a lot of other technologies and they all need to be considered.”
But mRNA vaccines, so critical in the response to the Covid pandemic, are unpopular with Health Secretary Robert F. Kennedy Jr.’s political base. In late February the administration served notice it was reviewing a BARDA award of nearly $600 million to one of the mRNA vaccine manufacturers, Moderna, which was contracted to make, test, and license vaccines for four avian influenza viruses, including H5N1, that might one day start a pandemic. The status of that review is unknown.
The mRNA platform produces vaccines much more rapidly than many traditional methods, including whole killed virus vaccines. The latter involve growing large amounts of viruses, sometimes in hen’s eggs, sometimes in cell culture — a step that is both time consuming and difficult to scale up in an emergency, when supply will exceed manufacturers’ capacity, which is matched to seasonal market demand. The country and the world saw the dangers of relying on such a slow production approach during the 2009 H1N1 flu pandemic. By the time vaccine doses were ready for distribution in the United States, the surge of cases was well past its peak. (The problem is clear in figure 6.1 on page 48 of this report.)
Existing flu vaccines don’t target the whole virus, they train the immune system to recognize only the hemagglutinin, the protein on the exterior of flu viruses that latches on to cells in the respiratory tract. Using whole viruses would cut down on production time slightly as compared to current production methods, but it wouldn’t be as fast as mRNA vaccine production, Monto said.
Kennedy, who was briefed on the whole virus platform proposal, a source told STAT, recently confounded vaccine experts by declaring that it is an established fact that vaccines for respiratory pathogens that target only a single antigen, or part of the target pathogen, do not work.
Monto noted that more needs to be known about how the vaccines produced using this platform might be deployed. If the idea is to develop a pre-pandemic vaccine — something that could be used to prime the immune systems of health care workers, say, so they would have some protection if a pandemic started that was caused by one of the strains in the vaccine — production speed would be less of a concern than if the plan was to make vaccines once a pandemic had started.
Whole killed pathogen vaccines can provide better immunity in some cases, but that benefit can come with a downside, said Adolfo Garcia-Sastre, a microbiologist and director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai in New York. Garcia-Sastre too is working with colleagues to develop a universal flu vaccine approach to protect people against the myriad flu viruses that don’t circulate in people but could at some point cause a pandemic.
The downside is that vaccines made this way can be more reactogenic, triggering unpleasant side effects. The United States switched the type of vaccine it uses against pertussis, a dangerous bacterial illness also known as whooping cough that can kill young children, because the original whole pathogen vaccine caused upsetting reactions in babies. The newer version of the vaccine, made a different way, is not as protective as the former whole cell version, but it doesn’t cause the rates of high fever, febrile seizures, prolonged crying, and injection site reactions seen with the previous version.
“They are more immunogenic, they are much better, probably, to protect,” Garcia-Sastre said. “But too much immunogenicity may lead to some adverse events in some proportion of people.”
One of the approaches the Generation Gold Standard team is exploring are intranasal vaccines developed using whole viruses. Garcia-Sastre said the approach will have to be carefully watched for adverse events such as Bell’s palsy, partial paralysis of facial muscles that is generally temporary. The condition has been linked to use of at least one intranasal influenza vaccine, a product that is no longer on the market. (It was not made with whole killed viruses.) “I think the intranasal approach with something reactogenic needs to be evaluated very carefully with respect to safety,” Garcia-Sastre said.
