A flu vaccine is the best shot at keeping influenza at bay, but it’s far from bulletproof against infection. But researchers have now discovered a potential way to prevent flu transmission that targets the host rather than the virus.
In a study published Jan. 11 in the American Society for Microbiology’s academic journal mBio, scientists from New York University Langone Health and Grossman School of Medicine described how they found that using an enzyme to temporarily remove compounds called sialic acids in the nasal passages of infant mice dramatically cut transmission between them. The study also hinted at why young mice—and human kids—might be more prone to spreading viruses in the first place.
“We wondered if we could inhibit transmission by targeting sialic acids, and in our model, we were able to demonstrate that we can do this,” study lead Mila Ortigoza, M.D., Ph.D., told Fierce Biotech Research. “This was a very proof-of-concept, preclinical study that demonstrated that we can do this if we use this approach.”
Sialic acids are sugars that coat the body’s mucosal surfaces, where they’re involved in many different functions. Viruses, bacteria and other pathogens use sialic acids to hitch a ride through the mucus barrier and infect cells, Ortigoza explained, as well as to exit the body once they reach a certain point in their life cycle in a process known as viral shedding. Two types of sialic acids in particular—alpha 2,3 SA and alpha 2,6 SA—line the respiratory tract, making them the ideal targets for protecting against microbes that would otherwise invade via the nose and mouth.
To prevent the flu virus from using sialic acids to enter and exit the respiratory tract, Ortigoza’s team turned to an enzyme called a neuraminidase, which under normal conditions cleaves sialic acids from the respiratory tract. In the case of flu infection, when virus particles are attached to sialic acids, neuraminidases can sweep them out using the same mechanism.
As a visual aid, Ortigoza compared sialic acids to a lollipop, where the candy part is the sialic acid. Neuraminidases cleave the candy off the end of the stick, she explained.
“If you give the stick part without the candy to the child, the child isn’t going to like it very much, right? This is kind of the same thing,” Ortigoza said. “If we give neuraminidases to a host or a patient—or [in the case of our study], infant mice—the neuraminidases are going to cut that candy part from the lollipop, so then the virus that needs the candy to enter and exit the cells won’t have it.”
If you give the stick part without the candy to the child, the child isn’t going to like it very much, right? This is kind of the same thing." — Mila Ortigoza, M.D., Ph.D.
“The strategy is to cut off all the essential components that the virus needs to enter and exit the cell,” she added. “Instead of attacking the virus itself, we’re basically depleting the host of its essential receptor to enter the cell.”
To put this concept to the test, Ortigoza’s team infected infant mice with influenza, then dosed them with neuraminidases. Why infant mice rather than adults? Well, for starters, adult mice are poor models of flu transmission, likely because they have fewer sialic acids in their noses than infant mice do—a hypothesis backed up by Ortigoza’s team’s findings from an earlier study.
“We noticed that [sialic acid] receptors were present in infants and adults, but that they were present in a larger quantity in infants compared to adults,” Ortigoza explained. Though the studies haven’t been conducted yet, this is likely true in humans too, she added. Children are often the drivers of infectious disease, especially respiratory viruses.
This idea bore out in the new study as well. Transmission between infected baby mice that received one type of broad-acting neuraminidase, ba-NA, and uninfected mice was completely blocked when the treatment was given within two hours of infection. At 24 hours, the rate of inhibition was around 87% when given within 24 hours, and dropped to about 29% when given 72 hours later.
“Collectively, these findings indicate that [sialic acid removal with neuraminidases] lowers…shedding and contact transmission in a time-dependent manner and is most effective within 48 [hours] of…infection,” the researchers wrote in their paper.
Of course, given that sialic acids are crucial for cell function, it’s critical that any treatment that removes them is only transient. At the same time, it must be bioavailable for long enough that transmission is actually inhibited.
The neuraminidases used in the study appear to meet both those criteria, Ortigoza said. The mice tolerated the treatment well. And while her team didn’t include the data in the study, they saw that the sialic acids returned within 72 hours of stopping treatment.
They also checked for the risk of a theoretical threat: susceptibility to infection with the pathogens that cause bacterial pneumonia, which are known to use free-floating sialic acids that aren’t attached to the mucus membranes for growth and replication. Mice that received neuraminidases weren’t any more likely to develop pneumonia than those that weren’t treated.
“It’s reassuring that we didn’t see the adverse effect of bacterial overgrowth in their systems,” Ortigoza said.
While there is much more work to be done before the approach can be tested in humans, the results suggest a path controlling the flu that not only prevents transmission between infected and uninfected hosts—a potential shortcoming of flu vaccines—but may also circumvent the problem of resistance to antiviral drugs like Tamiflu. This is because the strategy targets not the viral proteins, but those within the host.
“In the case of influenza, all antivirals currently available are against viral proteins. A major disadvantage to that is the development of resistance,” Ortigoza said. “We need to develop different options for different proteins, and antivirals toward host proteins or important components of the host that are crucial for the viral lifecycle.”