Fall is officially in full swing, which means it’s time to break out those recipes for pumpkin pie, apple crisp—and flu shots. But not all ingredients stand the test of time. The ever-changing flu vaccine unfortunately tends to be a shot in the dark: Not everyone is eligible to receive it, and many of the millions who do still fall ill. During the 2017-2018 season, influenza resulted in nearly one million hospitalizations and killed almost 80,000 people in the United States alone.
Today, in the journal Science, researchers unveil new technology that may break our longstanding stalemate with these viral villains: A versatile, synthetic immune molecule that’s highly active against the many faces of flu. If the technology is eventually cleared for use in humans, such treatments may confer long-lasting, near-universal protection in the many patients currently unable to benefit from vaccination—and give researchers a leg up against some of the most important viral strains that plague us today.
“The threat of influenza is a very chronic problem, and this may be a great new method for prevention,” says Akiko Iwasaki, an immunologist at Yale University who studies immune responses to influenza, but did not participate in the latest find. “If the technique works [beyond mice],” she adds, “this could be revolutionary for pandemics.”
The majority of vaccines operate under one basic principle: Teach the immune system to recognize a threat before it attacks. Oftentimes, vaccines involve injecting a neutered or chopped up version of a pathogen into the body, allowing immune cells to study the invader’s ways—the molecular equivalent of passing around the mugshot of a criminal on the loose. That way, if the body’s barriers are ever breached by the real thing, the immune system can rapidly deploy a swarm of immune molecules already primed to finger the fugitive.
But influenza has managed to find a few loopholes. While we tend to generalize “flu” as a single entity, a dizzying array of variants exists. There are multiple types of influenza (such as A or B), within which there may be subtypes (such as H1N1 or H3N2). These can be even further subdivided into strains that arise when subtypes mutate from year to year. Exposure to one strain doesn’t guarantee that the immune system will recognize another strain, making it challenging to design vaccines with broad coverage.
Because of the viruses’ shapeshifting ability, a vaccine modeled on a particular subtype in 2018 may be completely ineffective as early as the following winter. Each year, researchers scramble to retool the vaccine recipe to keep pace. But the vaccine isn’t suitable for everyone: a significant fraction of the population responds poorly to vaccination or can’t be vaccinated at all due to their age, immune status, or sensitivity to vaccine ingredients.
To build our arsenal of flu-fighting weapons, scientists have embarked on several complementary paths. Some tinker with current flu vaccines to buoy their efficacy. Others, however, are cutting out the middleman entirely by generating synthetic immune molecules—the same ones that a vaccine would otherwise elicit—which can be transferred directly into a patient.
It was this latter strategy that intrigued study authors Joost Kolkman of the Janssen Infectious Diseases in Belgium and Ian Wilson of the Scripps Research Institute. To expand the options for flu-fighting coverage, the pair led a team of international researchers to design an immune molecule that could target influenza viruses of all shapes and sizes.
Previous efforts in this vein have leveraged the power of antibodies—immune molecules that home in on the unfamiliar surface molecules that speckle the surface of viruses and other threats. Ideally, when exposed to a viral infection, a person’s body will raise an armada of antibodies and other immune molecules that, together, recognize and neutralize the invasion.
Individual antibodies can latch on to specific viral appendages with incredible precision, but are easily flummoxed by even the slightest of viral costume changes. Tethering many different antibodies together, the researchers reasoned, might make for a powerful, multi-functional molecule. But such a complex could prove unwieldy: Its size alone could hamper the molecule’s ability to bind a virus in the first place. Traditional antibodies, it seemed, were not the answer.
Enter the llama. These wool-swaddled wonders, along with their camel and alpaca relatives, are capable of producing a specific type of antibody that’s much smaller than the ones found in humans. So-called “nanobodies” are diminutive enough to squeeze into little crevices on the surface of viruses. Such intimate encounters often detect subtle viral traits that bigger antibodies often miss, making nanobodies powerful allies in disease detection. But nanobodies’ petite packaging could serve an even more promising purpose: allowing them to be strung together into a flu-fighting Swiss army knife.
To assemble their nanobody building blocks, the researchers first injected llamas with bits of flu particles from different subtypes. This prompted the llama immune systems to churn out an assortment of nanobodies active against different lineages of virus. After subjecting the nanobodies to a battery of tests to find the most potent candidates, the researchers fused two nanobodies active against influenza A with two that target influenza B.
Next, the researchers put their new formulation, named MD3606, into action. To their excitement, injecting the hybrid immune complex into mice protected them from a variety of flu viruses spanning several types, subtypes, and strains, ultimately outperforming traditional antibodies designed for the same purpose. The nanobody fusion even fought off strains that the individual nanobodies had been powerless against, showing that the new molecule was more than the sum of its parts.
In the world of immunity, MD3606 is a first: Prior to this finding, no known antibody could, on its own, neutralize both influenza A and influenza B. “We’ve focused on getting the broadest possible protection,” Wilson explains. “And that was achieved.”
Unfortunately, antibodies don’t come with a lifetime warranty, making the immunization a bit ephemeral. To extend the treatment’s staying power, the researchers packaged a set of instructions coding for MD3606 into a benign viral vehicle called adeno-associated virus. Then, they puffed this infectious Trojan horse into the noses of their whiskered patients. In theory, once adeno-associated virus settled into a mouse’s body, it would function as a slow-release nanobody factory, pumping out immune molecules over several months at a time (potentially enough to cover an entire flu season). Once again, the mice were protected against a fleet of flus—even, in the case of H1N1 (commonly known as swine flu), when dosed with the virally-delivered nanobodies weeks in advance.
Fighting virus with virus comes with baggage, however. While the researchers’ viral chauffeur has already been used in clinical trials against other diseases, it’s still technically an infectious agent. The virus wrapper could still elicit an immune response in some patients, explains Jeffrey Ravetch, an immunologist and antibody expert at Rockefeller University who was not involved in the research. If the human body’s immune system shoots the viral messenger, the unwarranted assault could prevent the necessary nanobodies from being delivered—and induce symptoms of sickness to boot. And, because the technique introduces foreign DNA into the human body, it could be viewed as “gene therapy for flu prevention,” Iwasaki says, which could raise its own set of ethical issues.
Though they have their perks, nanobodies don’t recapitulate the protective power of vaccination. For one, nanobody-based treatments would still need to occur relatively close to viral exposure—meaning one needs a priori knowledge of an outbreak, explains Jason Nguyen, an immunologist developing nanobodies to counteract viruses like Ebola at the Massachusetts Institute of Technology. Many vaccines, on the other hand, can be administered decades in advance of infection, without the need for far-flung forecasts.
What’s more, simply injecting these MD3606 skips straight to the punchline, freely supplying the antibodies that a vaccine would otherwise teach the body to produce itself—effectively giving a man a fish, rather than showing him how to reel in his line. Additionally, antibodies comprise only a fraction of the body’s natural immune response, which typically rouses a legion of diverse and powerful cells to ward off disease.
There are a few situations in which MD3606 could still shine: in patients for whom vaccination is an unsuitable option, or in the event of an unanticipated influenza pandemic for which no vaccine yet exists.
“Vaccination is very effective in healthy, young individuals,” Kolkman says. “But it’s not very effective in the elderly or immunocompromised, for instance. Some of the biggest potential is in those people who don’t currently benefit from vaccination.”
Illustrating that multiple strains of flu can be tackled with a single tool tells us that broad protection is possible—and such technology could have big implications for other therapeutics. Coverage across viral types and subtypes could not only improve protection within a flu season, but also across flu seasons in the future, Wilson explains. In fact, one of the most powerful aspects about flu-fighting nanobodies is their ability to interact with viral surfaces that are critical to the pathogen’s viability. These regions are less prone to mutating year to year, which means a nanobody-based solution could have quite a bit of longevity going forward.
The trek from llama to lab was long, the researchers caution, and the path ahead may be just as woolly as they attempt to repeat their findings in other animals. Eventually, however, the researchers hope to make the technology a realistic option for people—and someday ease our anxiety about that annoying annual vaccine.