Seeking a more effective flu vaccine

With a flu season that arrived earlier and more harshly than usual, government health officials have been loudly sounding the call for everyone to be immunized, while more quietly encouraging efforts to develop a better flu vaccine. The vaccines in use today are only about 60 percent effective, last for only a single flu season, and take months to produce—which left Americans initially unprotected in 2009 when the swine flu pandemic arose without much warning.

Incremental progress has been made: Next year, two manufacturers will for the first time produce a quadrivalent vaccine, which contains four strains rather than the three in current vaccines, as a shot and a spray. And the US Food and Drug Administration approved the first gene-based flu vaccine last week, which uses DNA technologies to produce mass quantities of the virus in insect cells instead of in chicken eggs. While that will enable a faster manufacturing process and make more vaccine available to those with egg allergies, it may not increase the effectiveness of the vaccine much.

“From the standard of protection, there’s nothing new here,” said Michael Osterholm, an epidemiologist at the University of Minnesota’s Center for Infectious Disease Research and Policy. In an analysis of flu immunizations published last October, he and his colleagues called for more funding for a universal flu vaccine that would protect against hundreds of flu strains and potentially last for a decade or more. Most important, it would work better than current vaccines for the most vulnerable populations, such as the elderly and patients with weakened immune systems, who get relatively little protection from their seasonal flu shot and have a greater risk of dying from the flu compared with young healthy people.

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Developing such a vaccine and testing it in thousands of people for efficacy and safety will require millions in research funding that’s currently lacking. “The problem we’ve found is that no one is investing a sufficient amount of money to get past the initial work,” Osterholm said. “It might take up to a billion dollars to get a single universal vaccine on to the market.”

The National Institute of Allergy and Infectious Diseases allocated $260 million last year for influenza research, which included vaccine development. “We selectively prioritize influenza research to a point where even when our budget is flat, we make sure to increase it,” said Dr. Anthony Fauci, the institute’s director. “We’ve had this sense of urgency since the threat of bird flu occurred in 2003, and it became clear we had to keep it going with the 2009 pandemic.”

But Fauci estimated that Americans won’t have access to a universal flu vaccine—that would protect against multiple strains and last for several years—for quite some time. “Ten years would be a conservative estimate,” he said, “but if we’re lucky, we can have one in five.”

One of the biggest hurdles rests in the flu virus’s transformational skills. The virus’s DNA mutates constantly, leading to new strains circulating every year. Flu vaccines are designed to get the body to produce an immune response only to specific strains contained within the shot, and that immune response is very temporary, usually lasting less than a year or two.

In 2009, researchers at the Dana-Farber Cancer Institute and elsewhere determined a major reason why flu viruses continuously outwitted the body’s immune defenses, requiring yearly immunizations to thwart infections. The virus has a lollipop-shaped protein, called hemagglutinin, that serves as a key to enter healthy cells and create more flu viruses. The head of the lollipop evolves rapidly and differs from strain to strain, which is why new flu strains that crop up every year can evade the body’s immune defenses.

While traditional vaccines target and destroy the head of the lollipop, a universal vaccine could be designed to work against multiple strains if it aimed for the lollipop’s stem, which tends not to change and looks identical within a group of similar flu viruses.

Such a vaccine would also have the potential to be more potent than current vaccines by generating a stronger and longer-lasting antibody response by the body—though it would undoubtedly be more expensive than the yearly flu shot.

“This finding was the eureka moment,” said Dr. Wayne Marasco, an immunologist at Dana-Farber who co-authored the paper on the research. “We realized if we could destroy this stalk machinery, we could completely disable the flu virus.”

With government and industry funding, researchers have recently begun testing a handful of universal vaccines in small human trials to see whether any are safe enough to test for effectiveness.

“This is an optimistic period in the field of universal flu vaccines,” said Dr. Gary Nabel, chief scientific officer at the Cambridge office of Sanofi, which manufactures influenza vaccines. His firm has been testing several vaccine components capable of boosting antibodies in the body that would aim for the hemagglutinin protein’s stem; these are capable of killing off many kinds of flu strains—at least in mice, rats, and monkeys.

“I would be surprised if we didn’t see some of these candidates moving into human studies within the next year or two,” Nabel said.

Marasco has been researching universal flu protection on two fronts: developing a broader-acting vaccine as well as more potent anti-viral drugs that, unlike oseltamivir (Tamiflu) or zanamivir (Relenza), could be given at any point during an infection, rather than just in the early stages. The drugs are monoclonal antibodies, which mimic the antibodies made by immune cells in response to germs and vaccines, and would be far less likely to lose their effectiveness over time due to flu viruses becoming resistant.

Older anti-viral drugs such as amantadine and rimantadine were ineffective against this year’s flu strains for this reason, and some flu strains have already developed a resistance to oseltamivir and zanamivir.

A drug that Marasco hopes to start testing soon in human trials is a monoclonal antibody called F10. Like a universal flu vaccine, it targets the lollipop protein stem to disable the flu virus, he said, and it’s taken only once a month instead of daily like Tamiflu or Relenza.