An incredible new study published in the journal Science demonstrates the potential for a single mRNA vaccine to provide protection from all 20 known influenza A and B virus subtypes. It's hoped the vaccine, so far seen to be effective in preclinical animal models, would prevent future flu pandemics by promoting immunity against influenza strains yet to cross over from animals into humans.
Vaccines work by helping teach the immune system to recognize certain parts of a pathogen, so when the real thing strikes our bodies can quickly recall that training and fight back. Our annual flu vaccines generally concentrate on between two and four antigens from the the strains of influenza most likely to be spreading at that time. Our recent COVID-19 vaccines, on the other hand, focus on just one iteration of the infamous SARS-CoV-2 spike protein.
One of the hypothetical strengths of the recently emerged mRNA vaccine technology is its ability to present the body with a wide variety of different antigens at the same time. Older vaccine technology is unable to pack 10 or 20 different antigens into a single shot, but mRNA technology, in theory at least, doesn't face these limitations.
So far, with the introduction of the latest bivalent Omicron mRNA vaccine booster, researchers have incorporated two particular antigens into the one shot. But what if a single vaccine could help teach the immune system how to recognize dozens of different iterations of the same virus?
It is this very idea that researchers at the Perelman School of Medicine at the University of Pennsylvania explored in their landmark study.
We created an mRNA vaccine expressing HAs from all 20 flu types. First, we vaccinated mice and found that this multivalent vaccine elicits robust antibody responses reactive to every HA. 2/n pic.twitter.com/GrZLpfaN0U
— Hensley Lab (@SCOTTeHENSLEY) November 25, 2022
The key antigenic target in influenza vaccines is a molecule called the hemagglutinin protein. It sits on the surface of the virus and is crucial to its infectivity. Each strain of influenza carries its own uniquely shaped hemagglutinin protein. The experimental mRNA vaccine tested in this new research covers 20 different influenza hemagglutinins: all 18 known subtypes of influenza A and two subtypes of influenza B.
The newly published study reported testing the multivalent vaccine in mice and ferrets. As explained by Scott Hensley, senior author on the new study, the big takeaway from these experiments is the animals seemed to develop distinct antibodies against all 20 influenza strains. This shows a single mRNA vaccine can effectively deliver broad protection against a large number of different antigens.
"Our new vaccine does not simply elicit antibodies that cross-react to every known influenza subtype," Hensley explained on Twitter. "Instead, we found that that the vaccine elicits distinct antibody lineages against all 20 different flu HAs [hemagglutinin antigens]."
The idea behind the novel vaccine is not to prevent influenza infection but to reduce the severity of disease that comes with those infections. And the initial animal studies do indicate that could be possible, with the vaccine effectively preventing severe disease in mice exposed to both the specific strains in the vaccine and other strains of influenza distinct from the specific 20 targets.
Perhaps the most unconventional aspect to this vaccine is that it contains antigens from influenza strains that have yet to cross over into humans. Many of the 20 antigenic targets are types of influenza only currently circulating in animals. But according to Hensley, the big goal here is to get ahead of the next pandemic by building a degree of broad immunity in the human population.
"[In mice] the vaccine prevented severe disease and death against viruses that were distinct from the vaccine components," Hensley said on Twitter. "This resembles a pandemic situation. And that is our goal: to elicit a baseline level of immunity in the population that would not necessarily prevent infections with new pandemic strains – but rather prevent severe disease and death caused by new pandemic strains."
This new work is far from the first to explore the potential of mRNA vaccine technology to fight influenza. A number of mRNA flu vaccines are in various stages of being trialed. Most recently a team of researchers demonstrated preclinical efficacy of a mRNA vaccine that targets four specific influenza proteins and is believed to offer universal protection against most strains.
But what is particularly unique, and potentially controversial, about this new 20-strain mRNA vaccine is its targeting of many types of influenza that are not currently a problem in humans. The big hypothesis is that delivering a vaccine like this, particularly to very young children, could help prime their immune memory against all influenza subtypes for their entire life.
"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," said Hensley. "We think this vaccine could significantly reduce the chances of ever getting a severe flu infection."
Adolfo García-Sastre, from Mount Sinai Hospital in New York, called this new research "interesting" and "promising." While he is cautious, suggesting we wait for human clinical trial data before concluding this to be a significant breakthrough, García-Sastre noted if this strategy does work it certainly would help us get ahead of potential future flu pandemics.
"[The study] demonstrates the ability to be able to develop multivalent mRNA vaccines that are able to immunize against 20 or perhaps more different antigens at the same time," García-Sastre said. "In this case, these are influenza virus antigens that encompass all possible influenza virus subtypes and variants, including those with pandemic potential."
It's a bold strategy that delivers on the promise of mRNA technology transforming the way we uses vaccines. But even if it does work it leaves plenty of questions for us all to grapple with. Are regulatory health authorities, or the general population, interested in a vaccine targeting future pandemics instead of immediate threats?
Nevertheless, further preclinical tests are ongoing and Phase 1 human trials are being planned.
The new study was published in the journal Science.
Source: Penn Medicine
