As this year’s flu season gathers steam, doctors and pharmacists have a fresh stock of vaccines to offer their patients. The vaccines usually provide strong protection against the virus, but only for a while. Vaccines for other diseases typically work for years or decades. With the flu, though, next fall it will be time to get another dose. “In the history of vaccinology, it’s the only one we update year to year,” said Gary J. Nabel, the director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases.
That has been the case ever since the flu vaccine was introduced in the 1950s. But a flurry of recent studies on the virus has brought some hope for a change. Dr. Nabel and other flu experts foresee a time when seasonal flu shots are a thing of the past, replaced by long-lasting vaccines. “That’s the goal: two shots when you’re young, and then boosters later in life. That’s where we’d like to go,” Dr. Nabel said. He predicted that scientists would reach that goal before long — “in our lifetime, for sure, unless you’re 90 years old,” he said.
Such a vaccine would be a great help in the fight against seasonal flu outbreaks, which kill an estimated 500,000 people a year. But in a review to be published in the journal Influenza and Other Respiratory Viruses, Sarah Gilbert of Oxford University argues that they could potentially have an even greater benefit. Periodically, a radically new type of flu has evolved and rapidly spread around the world. A pandemic in 1918 is estimated to have killed 50 million people. With current technology, scientists would not have a vaccine for a new pandemic strain until the outbreak was well under way. An effective universal flu vaccine would already be able to fight it. “Universal vaccination with universal vaccines would put an end to the threat of global disaster that pandemic influenza can cause,” Dr. Gilbert wrote.
Vaccines work by enhancing the protection the immune system already provides. In the battle against the flu, two sets of immune cells do most of the work. One set, called B cells, makes antibodies that can latch onto free-floating viruses. Burdened by these antibodies, the viruses cannot enter cells. Once flu viruses get into cells, the body resorts to a second line of defense. Infected cells gather some of the virus proteins and stick them on their surface. Immune cells known as T cells crawl past, and if their receptors latch onto the virus proteins, they recognize that the cell is infected; the T cells then release molecules that rip open the cells and kill them.
This defense mechanism works fairly well, allowing many people to fight off the virus without ever feeling sick. But it also has a built-in flaw: The immune system has to encounter a particular kind of flu virus to develop an effective response against it. It takes time for B cells to develop tightfitting antibodies. T cells also need time to adjust their biochemistry to make receptors that can lock quickly onto a particular flu protein. While the immune system educates itself, an unfamiliar flu virus can explode into full-blown disease.
Today’s flu vaccines protect people from the virus by letting them make antibodies in advance. The vaccine contains fragments from the tip of a protein on the surface of the virus, called hemagglutinin. B cells that encounter the vaccine fragments learn how to make antibodies against them. When vaccinated people become infected, the B cells can quickly unleash their antibodies against the viruses. Unfortunately, a traditional flu vaccine can protect against only flu viruses with a matching hemagglutinin protein. If a virus evolves a different shape, the antibodies cannot latch on, and it escapes destruction.
Influenza’s relentless evolution forces scientists to reconfigure the vaccine every year. A few months before flu season, they have to guess which strains will be dominant. Vaccine producers then combine protein fragments from those strains to create a new vaccine. Scientists have long wondered whether they could escape this evolutionary cycle with a vaccine that could work against any type of influenza. This so-called universal flu vaccine would have to attack a part of the virus that changes little from year to year.
Dr. Gilbert and her colleagues at Oxford are trying to build a T cell-based vaccine that could find such a target. When T cells learn to recognize proteins from one kind of virus, the scientists have found, they can attack many other kinds. It appears that the flu proteins that infected cells select to put on display evolve very little.
The scientists are testing a vaccine that prepares T cells to mount a strong attack against flu viruses. They engineered a virus that can infect cells but cannot replicate. As a result, infected cells put proteins on display, but people who receive the vaccine do not get sick. In a clinical trial reported this summer, the scientists found that people who received the vaccine developed a strong response from their T cells. “We can bring them up to much higher levels with a single injection,” said Dr. Gilbert, the lead author of the study. Once the scientists had vaccinated 11 subjects, they exposed them to the flu. Meanwhile, they also exposed 11 unvaccinated volunteers. Two vaccinated people became ill, while five unvaccinated ones did.
While the Oxford researchers focus on T cell vaccines, others are developing vaccines that can generate antibodies that are effective against many flu viruses — or perhaps all of them. The first hint that such antibodies exist emerged in 1993. Japanese researchers infected mice with the flu virus H1N1. They extracted antibodies from the mice and injected them into other mice. The animals that received the antibodies turned out to be protected against a different kind of flu, H2N2. In hindsight, that discovery was hugely important. But at the time no one made much of it. “By and large, people just said, ‘This is an oddity — so what?’ ” said Ian Wilson of the Scripps Research Institute.
Scientists did not appreciate its importance for more than 15 years, until Dr. Wilson and other researchers began isolating the antibodies that provided this kind of broad protection and showed how they worked. The new antibodies turn out to attack different parts of the flu virus from the ones produced by today’s vaccines. Today’s vaccines cause B cells to make antibodies that clamp onto a broad region of the tip of the hemagglutinin protein. Recently, Dr. Wilson and his colleagues discovered a new antibody with a slender tendril. It can snake into a groove in the hemagglutinin tip.
Dr. Wilson and his colleagues found that this tend riled antibody can attach to a wide range of flu viruses. The results hint that the groove — which flu viruses use to attach to host cells — cannot work if its shape changes much. The antibody is also impressively powerful, the scientists found. They infected mice with a lethal dose of the flu and then, after three days, injected the new antibody into them. The antibody stopped the virus so effectively that the mice recovered. The hemagglutinin groove is not the only promising target for antibodies. Dr. Wilson and other scientists are discovering antibodies that attack the base of the protein. Influenza viruses can be broadly categorized into three types — A, B and C. Until now, scientists have found only antibodies that attack different versions of influenza A. Dr. Wilson and colleagues at Scripps and the Crucell Vaccine Institute in the Netherlands recently found a stem-attacking antibody that blocks influenzas A and B. “The whole field is invigorated,” Dr. Wilson said. “It’s a great time.”
Building on these discoveries, Dr. Nabel and other scientists have recently developed vaccines that generate some of the new antibodies in humans. Now they are trying to figure out how to get the body to make a lot of the antibodies. “Once you have an antibody that has all the properties you desire, how do you coax the immune system to make that?” Dr. Nabel said. “That’s the classic problem in immunology.”