universal flu vaccine

New mRNA universal flu vaccine against all known subtypes takes promising first steps

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The vaccine provided protection for mouse and ferret models.

A new mRNA flu vaccine provides “broad protection” from lethal challenges by a variety of flu viruses, researchers have announced.

The animal study, published in Science, represents yet another step towards vaccinology’s holy grail: a universal flu vaccine.

A new mRNA flu vaccine provides “broad protection” from a variety of flu viruses in mice and ferrets, a step towards vaccinology’s holy grail: a universal flu vaccine.

One vaccine that provides protection against a wide array of flu strains could potentially save thousands or, over the long-run, potentially millions of lives. It could take the guesswork out of picking strains for the flu shot, provide longer-lasting protection, and even reduce the risk from a new pandemic flu virus.

“The idea here is to have a vaccine that will give people a baseline level of immune memory to diverse flu strains, so that there will be far less disease and death when the next flu pandemic occurs,” Scott Hensley, professor of microbiology at UPenn’s Perelman School of Medicine and study senior author, said.

Aiming a broadside: The new universal flu vaccine candidate uses the mRNA platform to get the body to produce “immunogens” — an immune-response stimulating molecule — from every influenza subtype currently known.

There are four different types of influenza viruses, named — with refreshing simplicity for these kinds of things — A, B, C, and D. Of those four main types, A and B are known to cause disease in humans, with A viruses in particular having pandemic potential.

After those major groupings, the viruses get broken down more specifically. The A viruses are separated into numerous subtypes based on the spiky proteins on their surfaces, while the Bs get split into two different lineages, B/Victoria and B/Yamagata.

A universal flu vaccine could take the guesswork out of picking strains for the flu shot, provide longer-lasting protection, and even reduce the risk from a new pandemic flu virus, potentially saving millions of lives over the long-run.

The proteins that determine the A subtypes are called neuraminidase (N) and hemagglutinin (HA). Similar to SARS-CoV-2, influenza viruses use these proteins during their replication cycle. To really oversimplify it, the virus uses HA to help get into your cells, and N to help get out.

But even within each subtype, the “head” of the HA protein — a common vaccine target — also mutates. A lot.

Some universal flu vaccines are looking to get around that problem but taking aim at targets on the virus that mutate less, like the “stalk” or the “anchor.” But that approach has some drawbacks, Jennifer Nayak, a University of Rochester researcher who studies the immune response to influenza, told CNN.

There just aren’t too many places shared by multiple strains of viruses, Nayak, who was not involved with the study, said. And they aren’t generally “immunodominant,” or what the immune system really reacts to on the virus. 

“Instead of trying to find something that’s shared, let’s just put all of the 20 different HA proteins – let’s put the mRNAs from all of them into this vaccine,” Nayak said. And then let the immune system figure out the best way to deal with them.

Enter mRNA: To build their mRNA vaccine, the researchers first tested all of the different targets individually, CNN reported, making sure each one produced an immune response.

After ensuring they worked individually, they packed them together into one mRNA-delivered package. 

In a Science companion piece, University of Saskatchewan researchers Alyson A Kelvin and Darryl Fallzarano noted that mRNA’s flexibility, ability to use multiple targets, and the speed and economics of its production make it a platform suited for pandemics.

The vaccine mRNA platform to get the body to produce “immunogens” — an immune-response stimulating molecule — from every influenza subtype currently known.

“For a conventional vaccine, immunizing against all these subtypes would be a major challenge, but with mRNA technology it’s relatively easy,” Hensley said.

When the team tested their vaccine in mice and ferrets — ferrets being a gold-standard animal model for flu — they found that it created a high level of antibodies, reacting to all 20 subtypes and maintaining antibody levels for four months. 

“What we found is that these vaccines elicit very high levels of antibodies against all 20 subtypes,” Hensley told CNN. The vaccine antibodies reacted not only to the head portions of HA, but the stalk as well.

Mice that were given a placebo mRNA vaccine, which carried the code for an enzyme that had nothing to do with the flu, died after being exposed to the flu — a lethal challenge — while vaccinated animals survived their bout with the virus.

The team does not expect their vaccine to completely prevent infection. Instead, it would lay down the groundwork for a quick immune response to a wide array of viruses, reducing the risk of severe infection and death.

While a promising proof-of-concpet, further research will be needed to see if the vaccine works in people.

Next steps: While the results are a promising proof-of-concept, they are also, well… a promising proof-of-concept.

“Impressively the vaccine was able to induce similar immune responses to all 20” HA proteins despite their similarity, Joshua Blight, the CEO and co-founder of antigen-focused biotech Baseimmune, tells Freethink.

But, crucially, mice and ferrets aren’t people — and we’ve yet to see how the vaccine would work in people, Blight adds; humans have preexisting immune memories of different HA subtypes that may interfere with the vaccine response.

Scientists Use mRNA Technology for Universal Flu Vaccine

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Two years ago, when the first COVID-19 vaccines were administered marked a game-changing moment in the fight against the pandemic. But it also was a significant moment for messenger RNA (mRNA) technology, which up until then had shown promise but had never quite broken through. 

Now, scientists hope to use this technology to develop more vaccines, with those at the University of Pennsylvania hoping to use that technology to pioneer yet another first: a universal flu vaccine that can protect us against all flu types, not just a select few. 

It’s the latest advance in a new age of vaccinology, where vaccines are easier and faster to produce, and more flexible and customizable. 

“It’s all about covering the different flavors of flu in a way the current vaccines cannot do,” says Ofer Levy, MD, PhD, director of the Precision Vaccines Program at Boston Children’s Hospital, who is not involved with the UPenn research. “The mRNA platform is attractive here given its scalability and modularity, where you can mix and match different mRNAs.” 

A paper published in Science reports successful animal tests of the experimental vaccine, which, like the Pfizer-BioNTech and Moderna COVID vaccines, relies on mRNA. But the idea is not to replace the annual flu shot. It’s to develop a primer that could be administered in childhood, readying the body’s B cells and T cells to react quickly if faced with a flu virus. 

It’s all part of a National Institutes of Health-funded effort to develop a universal flu vaccine, with hopes of heading off future flu pandemics. Annual shots protect against flu subtypes known to spread in humans. But many subtypes circulate in animals, like birds and pigs, and occasionally jump to humans, causing pandemics. 

“The current vaccines provide very little protection against these other subtypes,” says lead study author Scott Hensley, PhD, a professor of microbiology at UPenn. “We set out to make a vaccine that would provide some level of immunity against essentially every influenza subtype we know about.” 

That’s 20 subtypes altogether. The unique properties of mRNA vaccines make immune responses against all those antigens possible, Hensley says. 

How Do COVID-19 mRNA Vaccines Work?

Some of the COVID-19 vaccines are known as mRNA shots. How are they different from traditional vaccines? And do they contain the real virus?

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Old-school vaccines introduce a weakened or dead bacteria or virus into the body, but mRNA vaccines use mRNA encoded with a protein from the virus. That’s the “spike” protein for COVID, and for the experimental vaccine, it’s hemagglutinin, the major protein found on the surface of all flu viruses.

Mice and ferrets that had never been exposed to the flu were given the vaccine and produced high levels of antibodies against all 20 flu subtypes. Vaccinated mice exposed to the exact strains in the vaccine stayed pretty healthy, while those exposed to strains not found in the vaccine got sick but recovered quickly and survived. Unvaccinated mice exposed to the flu strain died. 

The vaccine seems to be able to “induce broad immunity against all the different influenza subtypes,” Hensley says, preventing severe illness if not infection overall. 

Whether it could truly stave off a pandemic that hasn’t happened yet is hard to say, Levy cautions. 

“We are going to need to better learn the molecular rules by which these vaccines protect,” he says.

But the UPenn team is forging ahead, with plans to test their vaccine in human adults in 2023 to determine safety, dosing, and antibody response. 

Progress on ‘Universal’ Flu Vaccine

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The United States is in the grip of a tough flu season, and the current influenza vaccine is only partially effective. However, scientists say they’re getting closer to a “universal” flu shot for the leading strain of the illness — a vaccine that wouldn’t need to be redeveloped and readministered each year.

Trials in mice found that the new shot triggered lasting immunity against influenza A virus strains, which are responsible for up to 90 percent of cases this year.

“Vaccination is the most effective way to prevent deaths from influenza virus, but the virus changes very fast and you have to receive a new vaccination each year,” explained lead researcher Dr. Bao-Zhong Wang. He’s associate professor at the Institute for Biomedical Sciences at Georgia State University.

“We’re trying to develop a new vaccine approach that eliminates the need for vaccination every year,” Wang said in a university news release. “We’re developing a universal influenza vaccine. You wouldn’t need to change the vaccine type every year because it’s universal and can protect against any influenza virus.”

Currently, flu vaccines have to be changed every year to match the flu viruses predicted to be the most common in the upcoming flu season. However, the vaccines miss the mark in some flu seasons.

The experimental vaccine against influenza A targets flu viruses in a different way. As the researchers explained, the typical seasonal flu vaccine is engineered to focus on the microscopic head of the virus’s exterior surface protein. But this part of the flu virus mutates easily, so it’s a “moving target” each year.

The new vaccine goes deeper — aiming at the interior “stalk” of the virus, which is much less quick to change.

“This way you’re protected against different viruses because all influenza viruses share this stalk domain,” Wang said.

Using super-small protein “nanoparticles” to help target the stalk, Wang’s group found that the vaccine shielded mice against a wide range of influenza A viruses, including strains H1N1, H3N2, H5N1 and H7N9.

Of course, much more work needs to be done, since experiments that work in animal studies often don’t pan out in humans. The next step is to test the vaccine in ferrets, which are more similar to humans in terms of their respiratory system, Wang’s group said.

Two flu experts said such a shot is desperately needed.

“Any vaccine technology that can potentially result in a ‘universal’ vaccine is welcome news,” said Dr. Sunil Sood, chair of pediatrics at Southside Hospital in Bay Shore, N.Y.

“A layered protein nanoparticle influenza A vaccine, if ultimately tested in humans, could protect against the majority of influenza viruses that circulate yearly, because A viruses almost always predominate,” he said.

Dr. Marta Feldmesser is chief of infectious disease care at Lenox Hill Hospital in New York City. She expressed cautious optimism for the new research.

“While they demonstrate efficacy in mice, whether humans will respond similarly awaits future demonstration,” Feldmesser said.

Source:  Nature Communications.

Big Pharma Has the Flu

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Flu vaccines make pharma companies $3 billion a year and aren’t very effective. Without a Manhattan Project-style initiative to modernize immunizations, things aren’t going to get any better.

A week ago, the Centers for Disease Control and Prevention confirmed what people have been suspecting: This flu season is one of the worst in recent memory. It’s on track to match the 2014-2015 season in which 34 million Americans got the flu, and about 56,000 people—including 148 children—died.

One reason behind the high toll is a mismatch between one of the flu viruses infecting people and one of the viral strains chosen almost a year ago for the global vaccine recipe, which gets rewritten every year. The dominant strain this winter is one called H3N2, which historically causes more severe illness, hospitalizations, and deaths than other strains. When the flu swept through Australia last summer, the effectiveness of the H3N2 component of the vaccine was only about 10 percent. The CDC doesn’t yet have a hard estimate for effectiveness in the United States but thinks it might be near 30 percent.

That mismatch is a bad piece of biological luck. But we should consider it a warning.

We’ve long known that our flu vaccines aren’t built to last, or to tackle every strain. But pharma companies don’t have an incentive to research drugs that will make them less money—not while current vaccines are good enough to make them $3 billion a year. To drive those new vaccines forward, medicine needs a Manhattan Project-style investment, pulling on resources outside the drug industry to force a new generation of vaccines into existence.

It’s well-known inside medicine, and little appreciated outside it, that flu vaccines aren’t as protective as most people assume. In January, the CDC collated data on flu-vaccine effectiveness from 2004 up through last year. There was no flu season in which the vaccine protected more than 60 percent of recipients. In the worst season, 2004-2005, effectiveness sank to 10 percent. That’s very different from childhood vaccines. As Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, lamented at a meeting last summer: “The measles, mumps, and rubella vaccine is 97 percent effective; yellow fever vaccine is 99 percent effective.”

The flu virus itself is to blame. The measles virus that threatens a child today is no different from the one that circulated 50 years ago, so across those 50 years, the same vaccine formula has worked just fine. But flu viruses—and there are always a few around at once—change constantly, and each year vaccine formulators must race to catch up.

The dream is to develop a “universal flu vaccine,” one that could be given once or twice in toddlerhood like an MMR vaccine, or boosted a few times in your life as whooping-cough shots are. That is a substantial scientific challenge because the parts of the flu virus that don’t change from year to year—and thus could evoke long-lasting immunity—are hidden away in the virus, masked by the parts that change all the time.

A handful of academic teams are competing to build such a new shot. They’re tinkering with the proteins that protrude from the virus, trying to take off their ever-changing heads so the immune system can respond to their conserved, unchanging stalks. They’re creating chimeric viruses from several proteins fused together, and they’re emptying out viral envelopes or engineering nanoparticles to provoke immunity in unfamiliar ways. Several of those strategies look promising in animal studies but haven’t been tested in humans. There are substantial hurdles to putting any formula into a human arm—including the fundamental one of figuring out what level of immune reaction signals that a new formula is protective enough.

And then, of course, there’s the fact that creating a new vaccine is expensive. It includes not just the cost of research and development, clinical trials, and licensing—generally accepted, across the pharma industry, to take 10 to 15 years and about $1 billion—but also the price tag for building a new manufacturing facility, which can top $600 million. Contrast that to the expenses of making the current vaccines, which use equipment and processes not changed in decades. A 2013 World Health Organization analysis pegged each manufacturers’ cost of refreshing the annual vaccine at $5 million to $18 million per year.

Now consider this: Right now, millions of people, roughly 100 million just in the United States, receive the flu vaccine every year. If those shots were converted to once or twice or four times in a lifetime, manufacturers would lose an enormous amount of sales and would need to price a new vaccine much higher per dose to recoup.

“What’s the business model here? Am I going to spend more than $1 billion to make a vaccine when I can only sell $20 million worth of doses?” Michael Osterholm asks.

The founder of the University of Minnesota’s Center for Infectious Disease Research and Policy, and a former adviser to the Secretary of Health and Human Services, Osterholm has been pushing for years to get people to notice that the market structure for the flu vaccine works against innovation. “Think about this,” he told me. “If you get a licensed product, which can take billions of dollars to achieve, how are you going to get a return on investment unless you are able to charge an exorbitant amount?”

This isn’t a hypothetical. Take the case of FluMist: As Osterholm’s CIDRAP group revealed in a 2012 report, The Compelling Need for Game-Changing Influenza Vaccines, the vaccine manufacturer MedImmune expended more than $1 billion to develop the novel nasal-spray flu vaccine. In 2009, its first year on the market, FluMist earned just $145 million. And in 2016 and 2017, a CDC advisory body recommended against using the spray at all, saying its rate of effectiveness had sunk to 3 percent.

Examples such as FluMist, Osterholm’s group wrote in their report, make it unlikely that any manufacturer will embark on a new flu vaccine or that VCs will fund them. “We could find no evidence that any private-sector investment source, including venture capital or other equity investors or current vaccine manufacturers, will be sufficient to carry one, yet alone multiple, potential novel-antigen influenza vaccines across the multiyear expenses of production,” they wrote.

As it happens, another sector of medicine is grappling with a similar problem. Since about 2000, pharma manufacturers have largely abandoned antibiotics because of a similar mismatch between investment and reward. Like vaccines, antibiotics are priced low and used for short amounts of time—unlike the lucrative cardiovascular or cancer drugs you’ll see advertised on TV and in magazines.

One answer to the funding gap has been a public-private research accelerator, CARB-X. It was founded in 2016 to dispense $455 million from the US government and a matching amount from the Wellcome Trust in England to support risky early stage research into new antibiotic compounds. Another proposal, put forward by the British Review on Antimicrobial Resistance but not yet enacted, would give roughly $1 billion in no strings “market entry rewards” to companies that get new compounds all the way through trials to licensure, counting on the cash grant to repay R&D expenses.

Osterholm thinks flu vaccines need research support, market rewards, sales guarantees, and more—a matrix of investment in research, manufacturing, and research leadership that he likens to the Manhattan Project, the all-in federal effort to build atomic bombs to bring an end to World War II. Only governments have the power to organize that scale of project, he thinks, and only private philanthropy, on the scale of the Gates Foundation or the Wellcome Trust, has the resources and the flexibility.

And he may be right. What’s clear is that the current flu vaccine market is broken. It’s important to think about that now, because this flu season marks the 100th anniversary of the worst flu known to history: The world-spanning 1918 influenza, which killed an estimated 100 million people in little more than a year. Flu pandemics arrive irregularly, and no one has been able to predict when the worst of them will come again. It would be smart of us to fix the vaccine problem before it arrives.

Will We Ever See a Universal Flu Vaccine Developed Within our Lifetime?

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More than 150 million Americans have the flu shot each year to try and protect themselves against the dreaded illness. That’s a lot of dosages of medicine and can take as long as six months to produce once the targeted flu strain has been decided upon. The trouble with this is that even the experts get it wrong sometimes which can cause major problems. In 2009, a strain of influenza called H1N1 emerged that the prepared influenza vaccine wasn’t able to beat, and more than 18,000 people died as a result. However, that number is simply a confirmed amount, when the true figure is more likely to be closer to 150,000 deaths. So, will there ever be a “one shot does all” kind of injection for all different types of flu virus?

With influenza being the cause of most major pandemics over the past century, one would hope so. But then if it were that easy, surely it would have been done by now?  We discovered long ago that infection conferred immunity against disease. For example, those who contracted small pox would not come down with it again, and similarly, those who were immunized against certain diseases would not suffer from them again. So, why do people need to get immunized against influenza each year? It’s not because the flu shot is weak in any way, but because the influenza strain changes so often.

An artist’s rendition of the anatomy of a virus. Anna Tanczos/Wellcome 

Each virus is made up of its own membrane that holds constantly mutating genetic material. Inside the membrane are two types of spikes called hemagglutinin (HA), and neuraminidase (NA) and each has its own head and stem. Typically vaccines will set to work by targeting these molecules through antibodies. But for vaccine developers, it’s tough to always have an adequate flu vaccination available because of how rapidly HA and NA change. Each year epidemiologists still manage to forecast which flu strains will more likely affect which populations.

Scientists have now discovered a process called rational design and are a different, yet effective way to design a vaccine. The end goal is to design an immunogen that can produce sufficient antibodies without being exposed to the virus. If they can master this, it will inevitably change the world of vaccinology as we know it.  But for the moment, it’s unlikely that we will see a “one shot does all” influenza shot and can only hope scientists can stay ahead of the viruses enough to keep us safe for yet another year.

Is a universal flu vaccine on the horizon?

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Every fall, millions of people roll up their sleeves for a flu vaccine, hoping to give their immune system a leg up on influenza. But the flu virus has thousands of strains that mutate and evolve across seasons, and the vaccine can’t guard against all of them. Now, two groups of researchers have independently created vaccines that lay the groundwork for a long-sought shot that could protect against every type of flu.

“This is really cutting-edge technology,” says Antonio Lanzavecchia, an immunologist at the Swiss Federal Institute of Technology in Zurich, who is unaffiliated with both studies. “There is still work to do, but this is a clear step forward and it’s headed in the right direction.”

Scientists develop flu vaccines by predicting the strains most likely to infect a population. They use year-round flu surveillance along with field reports from countries in the Southern Hemisphere to guess which strains are most likely to hit North America at the height of the flu season—December through March. But viral guesswork is a tricky business, and it’s impossible to be 100% right. This uncertainty makes for patchy protection, and as flu strains mutate over the course of the season, vaccines become less and less effective.

Flu vaccines stimulate the production of antibodies against pieces of dead virus. Should the virus return, the antibodies can recognize, attack, and neutralize the threat. But because these vaccines are based on parts of the virus that evolve over the course of a flu season, protection is not guaranteed.

To solve this problem, two teams of researchers independently focused on a protein called hemagglutinin, found on the surface of the flu virus H1N1. It has two major components: the head—the portion of the virus that mutates and changes from strain to strain—and the stem, which is similar across most flu strains. The teams tried to remove the variable head region and keep the stem as the base of their vaccines. But hemagglutinin turns out to be rather feeble. Once beheaded, the stem falls apart, and antibodies can no longer bind to it.

To anchor the headless stem, the teams took different approaches. Researchers writing today in Nature Medicine used a two-step method: They introduced a combination of mutations to stabilize the core of the hemagglutinin stem. Then, they bound a bacteria-derived nanoparticle to the stem, which pulled the subunits of the protein together to hold it in the right position. The other team, writing today in Science, applied a combination of mutations that realigned the subunits of the stem at the top. This was enough to sustain a functional structure for the vaccine.

When the teams vaccinated mice, both groups saw full protection against H5N1, a lethal influenza strain distantly related to H1N1. In both studies, mice that did not receive the stem-derived vaccine died, but vaccinated mice all survived. In further experiments, the nanoparticle-anchoring vaccine showed partial protection in ferrets, whereas the other vaccine showed partial protection in monkeys. Two of the six vaccinated ferrets fell ill and died, compared with a 100% mortality rate for the unvaccinated ferrets. None of the monkeys died, but those that were vaccinated had significantly lower fevers than their nonvaccinated companions.

“The [experimental] designs were different, but the end results were very similar and highly complementary,” says Ian Wilson, co-author on the Science paper and a structural and computational biologist at the Scripps Research Institute in San Diego, California. “It’s a promising first step, and it’s very exciting to see this research come to fruition.” Authors of both studies say the next step is expanding protection to other strains of influenza, namely H3 and H7.