If all goes according to plan, the annual flu shot protects about 60 percent of vaccinated people. This year’s inoculation, of course, fell far short of such expectations, safeguarding only one in four vaccinated people who encountered the dominant H3N2 strain. This shortfall injected further momentum into the push to create a universal vaccine that protects against many flu types over time.

Last month Bill Gates announced his foundation will be earmarking up to $12 million to advance such work. Sen. Edward Markey (D–Mass.) introduced a bill in February that would provide $1 billion in government funding for a universal flu vaccine. The National Institute of Allergy and Infectious Diseases (NIAID) called such research a priority and unveiled a strategic plan for it. The White House also gave a nod to the universal flu vaccine; its Office of Science and Technology Policy tweeted in March it is “closer than ever.” Yet the road ahead is littered with obstacles.

“It’s a scientific challenge because there are still so many things we don’t know,” says Anthony Fauci, director of the NIAID. And even if such a vaccine were developed, a perfect inoculation that protects against all flu types, is “unattainable,” he says. Researchers hope to find a vaccine that can provide durable protection for all age groups against multiple influenza strains—including those that might cause a pandemic—but as they study the flu they keep encountering further complications that trip up their plans.

“Influenza research today is a humbling experience. The more we learn the less we understand,” says Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy. Osterholm points to the fact there is much more to making the vaccine work than predicting the correct strains circulating in a given year. A growing body of evidence suggests the standard practice of growing flu virus in chicken eggs, for use in the seasonal flu shot, appears to reduce its effectiveness.

Researchers are also realizing the first flu virus we are exposed to in life may play a larger role in immunity than previously thought, shaping our response to all flu viruses we encounter in the future—a concept often referred to as imprinting. Although the phenomenon is not completely understood, current science strongly suggests, “years later, even when you get exposed to a flu virus or vaccine, you will tend to skew your response back to the original type of influenza you got exposed to,” Fauci notes. As a result, you will have the strongest immune system defense against the first flu strain you encountered.

Moreover, beyond clinical trials and regulatory hurdles there are also a vast array of technical roadblocks ahead, which include making these shots profitable for developers yet affordable for consumers and deciding who should receive these inoculations—and when.

So far, there is not one clear front-runner vaccine but there are multiple candidates. Earlier this month the National Institutes of Health announced one experimental vaccine, M-001, is headed into phase II clinical trials. Investigators will monitor its safety among adults as they assess whether it also appears to help them mount a clear defense against the flu virus. That vaccine is also slated to enter phase III trials in Europe among older adults there (although that population differs from U.S. test subjects because it is uncommon for most healthy Europeans to get annual flu shots).

The experimental inoculation is not built like other flu vaccines. M-001 does not contain a whole inactivated flu virus like the current seasonal flu shot. It is also not an attenuated live virus vaccine (which is another experimental approach that has shown promise in lab animals). Instead, M-001 consists of nine epitopes—short stretches of viral protein—that were carefully selected because they are shared across many different influenza strains. The epitope-laden shot primes the body to recognize sites on flu viral proteins that do not change much across flu strains, so it can theoretically respond more effectively.

There are also other factors that make it different than a seasonal flu shot. For example, the M-001 formulation was chosen because these tiny epitopes spark both T cell and B cell immune responses. That feature means this inoculation would have a leg up on seasonal flu shots, which primarily work by eliciting B cell responses—antibodies that detect enemies by their strain-specific shapes. The addition of T cell firepower would help the body target multiple strains, as these immune system soldiers would be looking for numerous characteristics.

But at this stage of testing volunteers will not just be receiving the M-001 shot. They will also receive the standard seasonal flu shot as a booster—fortifying their defenses against flu strains circulating at the time. Yet the hope is that M-001 might eventually prove a strong stand-alone defense—making the seasonal flu vaccine obsolete. The M-001 vaccine approach is exciting, says Kathleen Sullivan, chief of the Division of Allergy and Immunology at The Children’s Hospital of Philadelphia, who was not involved in the work. “The conceptualization of this vaccine is really innovative.”

In the current phase II trial, which will occur across several U.S. institutions and will be led by Robert Atmar at Baylor College of Medicine, there will be up to 120 healthy adult volunteers randomly placed into two groups. The first group will get a shot of M-001 whereas the other group will get a placebo. Then, several weeks later, the first group will get another shot of M-001 and the second group will get another placebo. Finally, at day 172, both groups will receive a third shot—the seasonal flu vaccine. Blood will be periodically drawn from both groups to evaluate their immune responses to the experimental vaccine (or placebo) and the seasonal vaccine. The researchers plan to have some results within two years.

Yet even if M-001 looks promising, researchers still need to explore how many strains of the flu it might help fight. Moreover, how well it may be able to overcome or complement our early-life flu imprinting remains an open question: An adult with decades of immune responses to various flu strains may not respond as well as an infant to a universal flu vaccine because the adult’s immune system has already been primed to other types of influenza, Fauci notes. With this question in mind, researchers are hoping to launch more studies of our early-life imprinting. NIAID put out a call last month for proposals to enroll pregnant women and their infants in long-term studies to see how flu strains circulating in a given birth year, vaccination status and natural infections influence flu immunity. Eventually, Fauci says, he expects “we will go through universal influenza vaccine 1.0, 2.0 and so on that will protect against different viruses.”