Every year, starting in September, public health officials in the U.S. start prodding you to get this year’s flu shot. But even if you do get one, it is not a guarantee against getting sick.

Why is the common illness so difficult to prevent, and what technologies might change this yearly struggle?  

Seasonal flu is caused by influenza viruses, which can mutate as they spread from person to person, meaning every year brings a new strain of virus. Any antibodies your body produced after getting sick or in response to a flu shot may not work a year later.

Furthermore, each flu season is dominated by several different strains of the virus, and health officials must try to predict which ones to combat because it takes months to produce the vaccine. Every February, the World Health Organization recommends which three viruses should be included in the next season’s vaccines for the Northern Hemisphere (the WHO makes a similar recommendation for the Southern Hemisphere each September), and in the U.S., the Food and Drug Administration typically recommends that those three strains be included in the coming season’s vaccine. While this process carries the risk that the vaccine will not match the dominant strains in the next season, it is necessary.

A new way of making flu vaccines could reduce this long timeline and make it possible to react to unexpected outbreaks. Currently, flu vaccine production starts with chicken eggs. A live virus is injected into eggs, where it replicates. Manufacturers then crack open the eggs, harvest and purify the viruses, and kill the pathogens and chop them into smaller pieces. The inactivated pieces from the three chosen strains are then mixed into a flu vaccine, which trains the body’s immune system to respond to the actual virus.

Next year’s vaccine production could be different, as some manufacturers may replace this time-consuming process with a new approach. In November, the FDA approved a new vaccine from Novartis, which is produced in cultured dog kidney cells. And earlier this month, the agency approved a vaccine made by ProteinsSciences in cultured insect cells. The methods “offer the potential for faster start-up of the manufacturing process than traditional egg-based vaccine methods,” says a spokesperson for the FDA. Additionally, they may help people with egg allergies safely get flu vaccines.

Public and private researchers are also working to develop so-called universal flu vaccines that would preclude the need to get a new vaccine every year. When you get the flu or a typical flu shot, your body responds by making antibodies that glom onto a protein in the virus called hemagglutinin. This protein allows the virus to enter cells, and antibodies against it will prevent that entry. However, this protein also mutates quickly, so that the antibodies your body produces this year may not recognize the protein next year.

Ian Wilson’s group at the Scripps Research Institute in La Jolla, California, has been studying the rare antibodies produced in some people that bind to other parts of the virus. Because they bind to regions of the protein that do not change as quickly as the typical targets, the hope is that these antibodies will be able to recognize many different strains of the virus. Over the last few years, different research groups have shown that such antibodies can recognize multiple flu strains, and a study from Wilson’s group and the Crucell Vaccine Institute in September 2012 showed that one antibody can recognize strains from both major subtypes of seasonal influenza, more than had been previously shown.

“A universal vaccine was something that people always talked about, but until recently, there was no evidence for much hope of that,” says Wilson. “But now, it has been demonstrated that gives the desired type of immune response,” he says.   

The challenge now is to develop a vaccine that will elicit such a powerful and effective response and to find a way to test it. “A lot of these more universal antibodies don’t work in the standard tests for antibody efficacy,” says Wilson. This means that manufacturers and regulators like the FDA will have to develop new assay systems. “Even if we had the perfect vaccine in hand today, we wouldn’t have a good and approved way to test it,” says Wilson.

Pennsylvania-based biotech Inovio is taking a different approach to developing a universal vaccine. Instead of inoculating people with an inactivated virus fragment or protein, the company is developing a DNA-based vaccine. To make it protective against multiple flu strains, the company combines DNA sequences from existing virus strains into a single dose. The DNA pieces are delivered by a shot combined with the company’s proprietary delivery system. A handheld device that looks like a pen delivers a small electric field which temporarily opens up cell membranes to allow the DNA vaccine to enter cells, says Inovio CEO Joseph Kim. Once inside cells, the DNA is read by the cell’s own machinery to build viral proteins which will activate the body’ immune system. The result is that the body creates antibodies against a diversity of flu strains.

The company is currently testing the vaccine in people 65 and older as a combination treatment along with existing flu vaccines. The elderly are the most at risk when it comes to flu and are the least protected by current immunizations. Every year, some 35,000 people die because of the flu and “90 percent of the deaths are in people who are 65 and older,” says Kim. “But the seasonal flu vaccine only protects about 10 to 20 percent of the elderly.”

Inovio’s clinical trial has shown that combining the seasonal flu vaccine with the company’s experimental universal vaccine has doubled the number of elderly protected from the flu.   

“It is hard to predict the future, but if we can have a universal vaccine that can protect against all known dominant strains, the likelihood of protecting against future unknown is much higher,” says Kim. “If we are correct, we can change the flu paradigm into one more like what we do with other vaccinations.”