“If we talk about a measles virus vaccine, a mumps virus vaccine, we are using the same vaccine which was developed in the 1950s, because the virus has not changed; otherwise, the vaccine wouldn’t work today. With influenza, we have a continuing change from year to year.”
The change happens on the surface of the flu virus, which is studded with proteins resembling mushrooms. The body’s immune system targets the mushroom head, which changes every year.
“The head is 10 times more variable,” Palese explained, “so we want to make a vaccine where the immune system is directed against the stalk.” Such a vaccine would protect more broadly against different flu strains, making multi-season protection possible.
Know Your Enemy
Flu-related illnesses kill up to 49,000 Americans annually, according to the Centers for Disease Control and Prevention, and cost the U.S. economy about $87 billion. The World Health Organization estimates that, worldwide, between 250,000 and 500,000 people die each year from flu-related ailments.
The flu virus carries its genetic material (RNA) inside a fatty membrane, but lacks its own cellular structure or metabolism. It can replicate only by invading a living cell, plundering it to make multiple copies of itself and then escaping the devastated host.
Meanwhile, the virus can shuffle its genes with those pillaged from both human and animal hosts. This abrupt re-assortment is called antigenic shift.
Antigens are proteins on the surface of the flu virus. When these antigens—antibody generators—enter the body, the immune system deploys antibodies, warrior molecules, to fight back.
But if the immune system doesn’t recognize a new flu antigen, it may get overwhelmed.
Palese (l) speaks with attendees at a reception in the NIH Library after his talk
Photos: Bill Branson
“The [viral] RNA segments are like mini-chromosomes,” said Palese. “If you have two of these viruses that infect the same cells, one can get an exchange of these RNA segments…There’s a lot of genetic exchange possible and that is giving rise to what we refer to as pandemic influenza viruses.”
Such an antigenic shift occurred in the spring of 2009, when a flu virus with a new combination of genes emerged and quickly spread, causing a pandemic (worldwide epidemic).
The flu virus can also make less ominous changes continually over time (“antigenic drift”), affording scientists time to track these mutations and then update annual vaccines. This is why people who want to be protected need a flu shot every year.
Lessons of History
Two flu virus antigens control its infectivity: hemagglutinin (H) and neuraminidase (N). Palese outlined the genetic subtypes and an overview of influenza viruses, both human and animal.
He included the 1918 virus, “based on Jeffery’s sequence, which he obtained by very elegantly sequencing material from patients who died at that time.” (Dr. Jeffery Taubenberger of NIAID was present in the audience.)
“In collaboration,” Palese continued, “we were able to actually reconstruct in the laboratory such a virus. So this virus is extinct, but the H1N1 from 1918 has given us a lot of information why the pandemic virus was so bad. This is sort of a hallmark…up to 100 million people died in this 1918-1919 pandemic.
“By learning about what the 1918 virus was, we’re in a much better position now to be prepared if something else of that ilk would happen.”
A New Approach
Current flu vaccines are based on inactivated viruses containing H proteins from the virus’s “mushroom” head, which changes year to year. When we receive a flu shot, our immune system creates antibodies to fight these specific antigens. This approach is effective, especially when the vaccine strain closely matches the circulating virus.
Palese’s new strategy redirects the immune response away from the H in the head toward the H and N in the stalk, where they remain more constant over time.
Employing animal models, Palese and his team used experimental vaccine strains with chimeric (lab-engineered) H proteins never encountered by humans under natural conditions. These constructed antigens stimulated both mouse and ferret immune systems to remember H and N proteins found in the stalk and offered good protection against potential pandemic viruses like H5N1 and H7N9.
The goal is to create a human vaccine with broad spectrum protection against a variety of antigenic drift and shift strains.
Palese reminded the audience that “this is not yet a vaccine…It has to go first to phase I, phase II, phase III [clinical trials].
“So clearly, the idea of a universal vaccine is that we don’t have to vaccinate every year. We would hope that based on the change which we’ve seen in the stalk, we would love to suggest it would last 20 years, or even for a lifetime.”