By Tomas Weber

Drawings depict the torsos of two male figures, shirtess and wearing boxing gloves. One figure has a virus shape instead of a head and the other has a syringe.

The worst pandemic in the last century was caused by a coronavirus, which came as a surprise to many. Influenza was long thought to pose a greater risk. “Before 2020,” said Scott Hensley, PhD, a professor of Microbiology at the Perelman School of Medicine, “if you had asked any virologist what virus they worried about the most, the answer would have been almost exclusively flu.”

It would have been a reasonable assessment. Flu is a devious killer. Globally, it causes around 400,000 deaths each year. While we have decades of experience creating vaccines against the influenza virus, flu, ever-shifting, still catches us on the back foot each season. Year after year, it ducks and weaves to evade human ingenuity.

The viral strains responsible for pandemic outbreaks are generally new ones that first infected humans from an animal host—and these jumps can be hard to predict. Still, every year, we rush to make a new flu vaccine against strains that are already known to be circulating in human populations. Most flu vaccine components are produced in fertilized chicken eggs. The process takes between six to eight months—so slow that it relies on some guesswork about which of the circulating strains might dominate during the upcoming flu season. Representative strains are chosen and injected into fertilized eggs, where the viruses multiply, and are then extracted, inactivated, and purified. The vaccine must then be tested, packed, and distributed.

At the culmination of these annual formulations, over half of all adult Americans get a new flu vaccine every season.

Scott Hensley, PhD
Scott Hensley, PhD

Why, though, do we have to repeatedly protect ourselves against new variants of a familiar virus? From just a handful of shots in early childhood, we have managed to beat back other viruses, including polio, hepatitis, measles, and rubella. Whether we received flu vaccines in childhood or not, most of us caught flu at an early age, and we mounted very good antibody responses to the virus.

The same relatively unusual pattern of annual vaccination may become the norm with SARS-CoV-2, the virus that causes COVID-19. Earlier this year, officials in the Centers for Disease Control and Prevention recommended that updated booster vaccines be given each year, particularly to high-risk groups. (Compared with flu, though, the manufacturing process is likely nimbler, given the greater flexibility of the mRNA platform.) Still, only about 20% of U.S. adults have received the 2022 bivalent booster shot against the Omicron variant, with an updated formulation expected for fall 2023 to help manage COVID-19 as an endemic disease. Why do new viral variants keep dodging our blows? Why can’t we seem to land a knockout punch, taking care of flu and COVID-19 once and for all?

Why Do We Need an Annual Flu Shot and COVID Booster Year After Year?

One common explanation for why we need repeated annual flu vaccines, and why we may need periodic boosters against COVID-19, is that these viruses mutate rapidly. And it’s true: They are “master shapeshifters,” said Hensley. As they replicate, the viruses acquire genetic changes that trigger alterations to their proteins. But the slippery, fast-evolving nature of flu and coronaviruses, Hensley said, is not enough to explain how they keep managing to fight off our assaults. 

Other viruses mutate quickly, too, but pose much less of a threat. The measles virus, for instance, is constantly acquiring random changes, but its mutations do not usually permit it to get past the defenses most of us have from the MMR vaccine. With flu, though, and potentially also with COVID-19, we are constantly being reinfected. What explains it?

The answer, Hensley said, is that flu and coronaviruses seem to be very tolerant of change. For a virus to change and still be capable of infecting a host population, the virus must maintain critical functions such as attaching to host cells. A high rate of change must be combined with great tolerance for transformation. Most viruses aren’t like that at all. 

A drawing of syringes filled with green liquid that appear to be facing off in a boxing match with a human boxer who has a virus for a head.

“With many viruses, when mutations crop up, they just kill the virus, and that’s the end of the show,” Hensley said. Not so with flu and coronaviruses. “Flu and SARS-CoV-2 have this uncanny ability to acquire mutations and still be able to replicate efficiently,” he said. “These viruses evolve to avoid human immunity while maintaining functions critical for viral replication.”

It's natural selection at work: Certain mutations help the virus to gain a stronger foothold, enabling it to better replicate and spread, evading the immunity human populations had previously picked up from exposure to older varieties and vaccines designed for other strains. But there is another reason why evolution can knock back our best efforts to fight these viruses. Vaccines are designed to protect us from pathogens that we already know about and that are circulating in humans. They don’t usually protect us from brand-new strains that come from animal populations.

“Most novel viruses that emerge in human populations are zoonotic,” meaning transmitted from animals, said Louise Moncla, PhD, an assistant professor of Pathobiology at the Penn School of Veterinary Medicine, whose research is focused on understanding what characteristics of avian flu strains affect their potential to infect humans.

Major flu pandemics, including the 1918 pandemic and 2009’s H1N1 outbreak, have been caused by cross-species transmission. Coronaviruses, too, are common in other animal species and sometimes spill over to humans, as was the case with SARS-CoV-2. But it is not easy for a zoonotic virus to successfully infect humans and transmit among us, Moncla explained. The factors which may cause it to do so are poorly understood, making cross-species transmission perilously hard to predict—meaning it’s difficult to plan ahead for human vaccines against these animal viruses. 

A Trick of the Immune System Memory in Vaccinations and Infections

There is another reason why flu is so good at sneaking around our defenses when it so often mutates. Immunologists call it “original antigenic sin,” and scientists at Penn are helping to deliver us from it. 

Our immune systems have a long memory. Our earliest childhood infections provide us with memory B and T cells that stick with us for life. This is a good thing. It allows us to retain immunity over an entire lifespan. But our immunological memory can also cause serious problems when the opponent our immune system encounters looks a little bit different than the one it is primed to remember.  

Our immune systems are shaped by the very first flu variant we were exposed to as children. “Viruses circulating in the late 1970s, when I was born,” said Hensley, “are quite different from viruses that were circulating about a decade ago, when my kids were born. So my kids have different immune memory than me.” 

Our immunological memory continues to influence our responses to fresh variants, in the form of either vaccines or live viruses. The immune responses of different individuals, then, might target different parts of the virus. “My kids and I might mount the same number of antibodies against this year’s flu vaccine strain. But my antibodies likely target a different region of that vaccine compared to my kid’s.”

A drawing of a boxer punching a floating red virus shape

The immune system targets those regions of the antigen that were imprinted at the time of the original exposure. Immune responses, then, can be dangerously narrow. With all your eggs in one basket, Hensley said, “you may be one [viral] mutation away from becoming susceptible again.”

Original antigenic sin also affects our response to COVID-19. Our first exposure to SARS-CoV-2, or to a COVID-19 vaccine designed to mimic the original pandemic strain, could potentially make it harder to pivot to new strains. Although Omicron-targeted booster vaccines offer strong protection, there is some evidence that immune imprinting may have reduced their effectiveness.

To shed light on how susceptibility differs across individuals, Hensley is working closely with Laurel J. Glaser, MD, PhD, an assistant professor of Clinical Pathology and Laboratory Medicine at the Perelman School of Medicine. For the last few years, Glaser and Hensley have been collecting virus and serum samples from flu-infected patients at the Hospital of the University of Pennsylvania (HUP). 

They are completing studies to determine if influenza viruses are evolving to evade antibody responses that are unique to each individual. “The question,” Hensley said, “is simple. If I get infected with the flu virus and show up at HUP, do I have an antibody response that is unique to me, that has allowed that infection?”

This work is uncovering how individuals respond to different flu variants in distinct ways, and they have discovered a similar pattern with COVID-19. Evidence is emerging that different people have specific susceptibilities to new variants of SARSCoV2 due to immune imprinting. “Specificity,” said Hensley, “means everything when it comes down to a virus that is rapidly changing.”

Armed with knowledge of different antibody specificities, Hensley anticipates that in the future it may be possible to predict an individual's susceptibility to emerging variants based on their year of birth and their immune history. Different people may even get different vaccines, he said, “to fill the immunological gaps each of us may have.”

But personalized vaccines, though a real possibility, are not the ultimate goal for Hensley and other Penn Medicine scientists. Their vision? A single, universal flu vaccine, offering equal protection against all variants, regardless of an individual’s immune history. And a single coronavirus vaccine, not just for new variants of COVID-19, but for future zoonotic strains that have yet to emerge. These dreams are edging closer to reality. 

Can We Get One-Time, Universal Vaccines for Flu and Coronaviruses?

The promise of a universal flu vaccine has its roots in earlier, ground-breaking work by scientists at Penn Medicine. In 2005, Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research and director of Vaccine Research at Penn Medicine, and Katalin Karikó, PhD, an adjunct professor of Neurosurgery, made a discovery that would go on to save millions of lives.

Karikó and Weissman found that messenger ribonucleic acid (mRNA), the molecule that carries sequences for synthesizing proteins, could be modified and successfully delivered via vaccination to elicit an immune response. Fifteen years later, as a new virus, SARS-CoV-2, was spreading around the world, Weisman and Kariko’s mRNA technology, which turns cells into powerful factories for building proteins to stimulate the immune system, was licensed by Moderna and Pfizer-BioNTech for use in their COVID-19 vaccines.

Katalin Karikó, PhD and Drew Weissman, MD, PhD
Katalin Karikó and Drew Weissman

“It turns out it’s very potent,” said Weissman, of their mRNA technology. mRNA produces proteins over a long period of time, which is necessary for a strong antibody response. Plus, the delivery vehicles for mRNA, lipid nanoparticles, act as adjuvants, meaning they stimulate the immune response in a way that makes the vaccine more effective. 

“You combine those two things together, and it becomes an incredibly potent vaccine,” Weissman said. And, compared with seasonal flu vaccines, “it's very easy to make, and very inexpensive.”

Towards the end of 2020, as the trials of the mRNA COVID-19 vaccines were showing a high level of protection, Karikó and Weissman did not take a break to celebrate. In the battle against diseases from malaria and HIV to genital herpes and norovirus there was not a moment to spare. 

“Their discovery really transformed vaccinology,” Hensley said. “The mRNA platform opens doors to areas that we really struggled with in the past.” And one of those entrances led straight to universal vaccines against variable viruses.

Three years before the COVID-19 pandemic, Hensley had a thought. Maybe Weissman and Karikó’s mRNA technology could be harnessed to make a vaccine against all 20 known influenza subtypes and lineages. “Wouldn't it be neat,” Hensley remembers writing in an email to Weissman, “if we could make a vaccine against all 20 of those components?” 

Weissman, in a response sent within 10 minutes, agreed, and the two scientists decided to join their labs together to work on a universal flu vaccine. With funding from the National Institutes of Health, their goal was to devise a new vaccine that would offer protection against newly evolved flu strains, as well as new zoonotic variants. “We were trying to make pan-influenza vaccines that can tolerate mutations and new viruses,” Weissman said. 

Hensley and Weissman’s teams injected mice and ferrets with an mRNA vaccine that encoded antigens from the 20 subtypes and lineages. This caused their cells to make copies of hemagglutinin, an important surface protein of the flu virus, corresponding to each variant. 

When COVID-19 struck, the team had to put the project on the backburner as their laboratories turned their attention to SARS-CoV-2. But last year, they published their results in a paper in Science. The vaccine worked.

The mRNA caused the animals to produce antibodies which remained detectable for at least four months. It reduced symptoms of disease and provided a high protection against death across all the different strains. Plus, the results seemed unaffected by previous flu infection, indicating that Hensley and Weissman may have solved a problem arising from original antigenic sin.

Clinical trials are due to start within the next two years. If successful, Weissman anticipates the vaccine would be most effective when delivered to young children. “That way, they would have protection starting from the beginning of their lives” he said. “If you immunize kids and you make them resistant to flu, you’ve saved them a potentially lifelong history of influenza infections.” 

The elderly, too, would benefit. Compared with other vaccines, mRNA works very well in the oldest sections of the population. And eventually, said Weissman, “everybody in the world would be vaccinated, making flu much less of an issue.”

Weissman’s lab has also already helped to produce a pan-coronavirus vaccine which has been shown to be effective against several different coronaviruses in monkeys. The team is currently applying for funding for clinical trials. As well as helping us beat back existing, frequently mutating viruses like SARS-CoV-2, a pan-coronavirus vaccine would also be a powerful weapon to stop the next zoonotic pandemic in its tracks. 

Even if the trials go well, some hurdles will remain for universal vaccines. Ensuring everybody has access to the vaccine, wherever in the world they live, will be a challenge. “The fear,” Weissman said, “is it’ll be available in the U.S. and Europe and other high-income countries, but not in low- and middle-income countries.” 

Ensuring worldwide access to vaccines has long been one of Weissman’s passions. He has spent years developing mRNA vaccine factories across the globe which make and distribute vaccines locally. “We currently have 18 production sites, either running or being built, across the world.” Among them is a site in Ukraine which, Weissman noted, “is pretty incredible.”

One pressing question is whether new universal flu and coronavirus vaccines would replace the seasonal or annual vaccines we currently use. Or would they just complement them? And would we have to get boosters? 

“It depends how well they work,” Weissman said. Ultimately, though, Weissman is optimistic that their universal flu vaccine will offer a high degree of protection against future mutations and pandemic strains. “In theory, it could be a replacement,” he said. “If the vaccine works, you won’t need yearly injections.”

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