Despite annual reminders, fewer than half of Americans get a flu shot each year. While their reasons vary, many feel that the vaccines just don’t work very well. And they’re not entirely wrong: in a given year, the flu vaccine’s effectiveness can range from 10 to 60 percent, according to U.S. Centers for Disease Control and Prevention. That’s not great compared to other vaccines, such as measles (97 percent effective), chicken pox (98 percent effective), or polio (100 percent effective).
Flu is tricky to vaccinate against because the virus mutates extremely quickly. Vaccine manufacturers try to overcome this problem by predicting how the virus will evolve and redesigning the shot every year based on that prediction. But it’s not perfect.
Another reason for existing flu vaccines’ limited efficacy: they don’t generate immunity where it’s needed—namely, the nose. Castle professor of medicine Dan Barouch, his former graduate student Catherine Jacob-Dolan, and colleagues recently described the problem in Science Translational Medicine and detailed their proposed solution: new vaccines that stop infection where it starts, laying the groundwork for a new generation of better flu shots.
“There’s a lot of room for improvement,” said Barouch, who directs the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center. “Many of us have [had] the experience of getting the flu vaccine and then getting infected with the flu, and I think poorly effective vaccines [are] one of many reasons why we have vaccine hesitancy.”
Barouch has been on a decades-long quest to develop better vaccines for a number of diseases, including HIV, Zika, tuberculosis, and COVID-19 (his technology was commercialized by Johnson & Johnson as the vaccine Jcovden). Recently, he turned his attention to influenza.
Like most respiratory viruses, flu enters the body through the mucous membranes (or mucosae) that line the inside of the nasal passages, mouth, throat, and windpipe. These tissues secrete mucus to lubricate and clean surfaces that are in contact with outside air and harbor immune cells that can trigger an immune response against viral invaders. This response is what causes classic flu symptoms, including congestion, runny nose, and sneezing. As the virus migrates down into the lungs, it can cause more severe symptoms, including shortness of breath and body aches.
It makes intuitive sense that the best way to stop a virus that enters through the mucosae is to generate immunity in the very tissues that get infected, so the virus can’t spread. But that hasn’t been a priority for vaccine developers, Barouch said: “The vaccine field is really accustomed to giving intramuscular shots for pretty much everything.”
Most flu vaccines are therefore injected via a shot in the upper arm muscle that introduces dead virus particles to trigger an immune response. There is also a nasal spray that releases a live, weakened virus into the nose, but it’s far less commonly used—in part because it’s no more effective than the shot, despite being delivered to the right tissues.
Barouch has been on a decades-long quest to develop better vaccines.
Barouch and his colleagues set out to study exactly how effective the existing vaccines are at generating immunity in the mucosae and to compare them to two newer vaccine types based on technologies used in COVID-19 vaccines. One is an mRNA-based flu shot, similar to the Pfizer and Moderna COVID vaccines. The other is an adenovirus-based vaccine, similar to the Johnson & Johnson vaccine that Barouch helped develop. Because adenoviruses are naturally stable enough to survive in the nasal passages, the researchers were able to administer that vaccine both as a shot and directly as a liquid to the nose and throat using a pipette.
They performed their experiments in 40 macaques, primates whose immune systems are similar to humans’. After administering a standard flu shot to mimic the exposure that virtually all humans receive, they boosted different groups of macaques with each of the four vaccine types. Then they exposed them to a strain of the H1N1 (swine) flu to see what would happen.
The animals that had been given the clinically available flu shot or nasal spray showed almost no immune response in the mucosae and had nearly the same amount of flu virus in their lungs as animals that had received no booster. This was especially surprising for the nasal spray, which the researchers had expected to work better because it targets the mucosae directly.
The best-performing type was the adenovirus vaccine administered directly to the nose and throat, which—in addition to generating the strongest and longest-lasting mucosal immunity—cleared the virus from the animals’ bodies in as few as two days. Animals that received the currently available vaccines took a week or more to clear the virus.
The mRNA vaccine shots generated moderate amounts of mucosal immunity: they were not quite as strong as the adenovirus vaccines, but significantly better than both commercially available flu vaccines.
The results supported the approach that Barouch has been advocating for years. “If you want to make a better vaccine to protect against infection,” he said, “you’re going to need to have a vaccine that generates mucosal immunity.”
Based on this new flu study, Barouch’s team engaged in early discussions with researchers at the National Institutes of Health’s Vaccine Research Center about testing their promising new vaccines in humans. Those talks have now been suspended due to uncertainty surrounding the proposed cut of nearly 40 percent to the agency’s budget. Barouch’s lab is currently exploring the use of adenovirus and mRNA vaccines against H5N1, a highly contagious strain of bird flu that can be lethal in humans.
Other virology researchers are working to create mRNA vaccines stable enough for delivery via a nasal spray, which could offer another, more effective vaccination option (in addition to the adenovirus-based vaccine). But those studies are also in jeopardy following the U.S. Secretary of Health and Human Services Robert F. Kennedy Jr.’s decision to cancel $500 million in grants supporting mRNA vaccine development.
While the answer to a better flu vaccine might be right under our noses, new shots won’t be available any time soon. Barouch’s recommendation: keep getting your annual flu shot, and stock up on some extra tissues.
