Experimental Flu Vaccine Seen as Potential Game Changer

aExperimental influenza vaccines developed using messenger RNA technology appear to be able to induce protective immune responses against all known influenza subtypes, at least in animals. If the research translates to humans, it could turn out to be a version of the long-coveted universal vaccine.

This is not a vaccine that blocks all influenza infections, nor does it replace the need for annual influenza vaccination. Instead, it prepares the immune system to respond better to new flu viruses, lowering the risk of hospitalization, death, and social disruption.

Influenza pandemics would be virtually preventable.

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Michael Worobey, a professor of evolutionary biology at the University of Arizona, has long been interested in how the immune system responds to the flu. He hailed the production as a potential game changer.

“I think this is some of the most exciting work in vaccinology in a long time,” Worobey, who was not involved in the study, told STAT.

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the study It was published Thursday in the journal Science. Senior author is his Scott Hensley, professor of microbiology at the University of Pennsylvania. The vaccine tested was created by Penn immunologist Drew Weissman, one of his pioneers in mRNA vaccines.

In an interview, Hensley explained how he hopes the vaccine will work in people.

“If there’s an H7 pandemic tomorrow, we’re all vaccinated with this,” he said, referring specifically to vaccines that target H7 influenza subtypes. against serious illness and death. ”

“Imagine that the world population is primed against all subtypes of influenza. It is possible to prevent severe illness and death from new strains of influenza that we may encounter in the future. Isn’t there?” Hensley asked.

The search for a so-called universal flu vaccine has been underway for years, with different groups using different approaches to try to train the human immune system to recognize a dastardly shapeshifting adversary. Two types of influenza A viruses, H1N1 and H3N2, and two strains of influenza B viruses circulate among people, causing hundreds of millions of illnesses each year. The World Health Organization estimates that worldwide he kills 290,000 to 650,000 people from the flu during a typical flu season.

However, countless other influenza viruses exist in nature and infect a wide variety of mammals. Occasionally, at unpredictable intervals, new viruses emerge from nature and begin circulating in people, causing pandemics. Some people are brutal. The 1918 pandemic killed an estimated 50 million people worldwide, while 1957 and he in 1968 killed millions more. His latest, his H1N1 pandemic in 2009, was on the opposite end of the severity spectrum, killing an estimated 250,000 people.

Hensley and colleagues worked to develop a vaccine that targets all 18 known types of hemagglutinin, a protein on the surface of the influenza virus that attaches to cells and initiates infection. They are numbered from H1 to H18. The vaccine also targeted his two strains of influenza B, named Victoria and Yamagata.

The group performed a series of experiments on the resulting vaccine in mice and ferrets, which are the best models of influenza disease in humans. I did. Antibody levels in vaccinated mice remained virtually constant over the relatively long follow-up period of four months in the mouse’s lifespan, Hensley said.

This work was performed in naïve mice with no previous influenza infection or vaccination. But few people have never had the flu. By the age of two, most people will have at least one infection of hers. So the team also had to test the vaccine on animals that had been exposed to the flu in the past to see if it would work under conditions that more closely mimic the human immune experience with the flu.

Specifically, researchers wanted to see if vaccines could reverse a phenomenon known as original antigenic sin. imprinting.

Your first exposure to influenza shapes the experience of a lifetime with this virus family. For example, people who were first infected with her H3N2 virus in childhood were more likely to become seriously ill during her H1N1 pandemic in 2009. And the H3N2-dominant flu season hits hard on older people whose first flu infection was the H1N1 virus. Imprinting also influences our response to conventional influenza vaccines. You get a better response to the first virus you encounter than to a virus that comes later.

To see if imprinting prevents the development of antibodies to other strains of influenza, Hensley and his colleagues administered the vaccine to mice that had previously been infected with the H1 influenza virus. Other strains were genetically distant from vaccine targets. In both cases, her H1 antibody levels in mice were boosted. Importantly, however, animals also developed strong antibody responses to other targets of the vaccine.

“Thus, the 20-HA … vaccine induces high levels of antibodies against all 20 encoded HAs in mice with or without prior exposure to influenza virus,” the researchers wrote.

Vaccinated mice were exposed to H1 virus 28 days after vaccination. Mice infected with the H1 strain identical to that contained in the vaccine showed few signs of illness and all survived, while mice infected with distantly related her H1 viruses showed more signs of illness, some did not survive. This indicates that if a vaccine were to be developed using this approach, the degree of disease mitigation could vary depending on how closely the vaccine strain was matched. to disease-causing strains.

This group also performed an experiment on ferrets and received two doses of the vaccine. The animals were then infected with an H1 influenza virus that had a poor match to the virus contained in the vaccine. All the unvaccinated ferrets in that study lost a significant amount of weight. This is a common reaction to infection in ferrets. Half of them died. Vaccinated ferrets lost about half the weight of unvaccinated animals. and no one died.

Henry said the study shows that the vaccine imprints the immune system of children who have not yet been exposed to the flu with all the flu viruses they may face in their lifetime, negating the imprinting problem that exists in adults. “I like to think of this vaccine as an exemption from the original antigenic sin in adults,” he said.

He and his team hope to begin human trials soon with a modified version of the vaccine that targets five hemagglutinins.

However, there is a big hurdle ahead.

The first concerns the mRNA platform, especially how well it is tolerated. In vaccinology terms, they are reactogenic. Sarah Covey, a professor of viral ecology and evolution at the University of Chicago, says that while it induces adequate protection in people against all 20 targets, finding doses that are tolerable to ingest would be difficult. Coby, who was not involved in , has collaborated with Hensley on other studies.

“Reactogenicity is in some ways the Achilles heel of mRNA vaccines right now, and there are many concerns about potential trade-offs between immunogenicity and reactogenicity,” Coby said.

Hensley agreed that the dosage required for people could be an issue. To put it in context, that’s the size of a Moderna Covid booster that targets two Covid strains.The Pfizer-BioNTech bivalent booster contains 30 micrograms of antigen.

“How low can you go? We haven’t done that kind of careful experimentation, and that’s exactly what we’re doing in the lab right now,” Hensley said.

Finding a way to obtain regulatory approval will also be a major challenge if clinical trials show that the vaccine is safe and potentially effective.

New vaccines entering the market usually have to show that they block some of the infections. This vaccine may struggle to cross that hurdle. Vaccines that significantly reduce hospitalizations and deaths would be valuable, but trials to show their impact are impractically large. Similarly, other than measuring antibody levels or conducting challenge studies in which vaccinated volunteers are exposed to a weakened version of a particular virus, there are currently circulating populations. There is no way to demonstrate vaccine protection against non-strains.

“The road to licensure doesn’t look easy to me,” admitted Cobey.

Worobey also suggested that regulators may want evidence that vaccine use does not interfere with the immune response generated by seasonal flu vaccination. Ultimately, though, regulators will develop vaccines for broader preventive flu, if the world can have the tools to blunt the impact of future flu pandemics. I said I need to figure out how.

“Would you like to adopt something that actually very strongly suggests that you can prevent the worst-case scenario? Worst-case scenarios are expected to happen at any time, but you can’t study those problems for decades. “So without knowing all the possible implications, I think we should try to move this forward if it’s as promising as it looks.”

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