NIAID Researchers Move Closer to Universal Flu Vaccine
Flu viruses mutate from year to year—sometimes gradually, sometimes suddenly. By mutating, they make it harder for the immune system to eliminate them. Two NIAID scientists are attempting to learn more about how the viruses function so they can develop better vaccines. They reviewed their findings at a Clinical Center Grand Rounds lecture in Lipsett Amphitheater recently.
Dr. Matthew Memoli, director of the clinical studies unit in the Laboratory of Infectious Diseases, described work in his lab to understand how the flu virus causes disease. Dr. Jeffery Taubenberger, chief of the viral pathogenesis and evolution section in LID, reviewed efforts to develop a vaccine that protects against multiple flu strains.
Memoli observes how healthy volunteers respond to type A flu infections in his lab. The viruses were created in the lab, but “are genetically identical to the types of flu you could catch walking around on the street.” He then studies how volunteers respond to the infection. These are called challenge studies.
Challenge studies allow Memoli to gather precise information that he couldn’t obtain by studying people who come down with the flu by natural means. He can, for example, control who gets infected and with what type of virus. This allows determination of the minimum viral dose to produce illness, when participants are contagious, how long they are sick and when they develop an immune response to overcome the virus.
In natural settings, it’s difficult to study a single strain of the virus because flu viruses often change every year, he added. The only down side to challenge studies is that the “route of inoculation is unnatural.”
Memoli explained that there are two proteins on the surface of flu viruses: hemagglutinin (HA) and neuraminidase (NA). HA helps the virus bind and enter red blood cells found in the respiratory system. NA is essential for viral reproduction.
Flu vaccines on the market today spur the production of antibodies targeting HA. The goal of the vaccine is to increase antibody levels, which provide protection, above a certain threshold level. Memoli’s research suggests that a vaccine that induces the production of both HA and NA may be more effective.
In one recent study, Memoli infected two groups of volunteers with the flu to learn more precisely what a protective level of antibodies really is. One group had low levels of HA antibodies while the other had high levels of HA antibodies. The patients with higher HA antibodies had developed them because they either had the flu or received a vaccination.
The group with higher levels of HA antibodies had a lower chance of developing mild to moderate symptoms and of spreading the virus to others. Patients with higher NA antibody levels didn’t get severe symptoms, suggesting NA antibodies might better predict the severity of flu-like symptoms and reduce symptoms.
Memoli said his findings are just the “tip of the challenge iceberg.” He hopes to find more information—on the genes involved in responding to the flu and on how the immune system responds to flu viruses—that will lead to the development of vaccines that protect against many strains.
Next, Taubenberger described progress toward a universal flu vaccine, one that “would provide broader protection than a vaccine against a particular flu strain.”
He said influenza A viruses originate in wild birds. The viruses can spill over and “permanently adapt” to wild and domestic animals. He compared predicting the strain that will cause the next pandemic to the complexity and uncertainty involved in picking the winner of the NCAA basketball tournament.
“Pandemics are very unpredictable,” in terms of when they appear, the strains involved and the routes by which they spread. There have been 4 pandemics in the last 100 years, Taubenberger added. “All these viruses share some genetic relationship to an ancestry from the 1918 virus,” which killed at least 50 million people worldwide.
Instead of attempting to guess the next pandemic or seasonal flu virus, Taubenberger tried something different. His laboratory created a virus-like particle (VLP) vaccine cocktail that contains the HA proteins of four strains of flu: H1, H3, H5 and H7. Over the past 10 years, these strains have “caused significant outbreaks,” in people and animals. Made up of characteristic molecules from viruses, VLP vaccines stimulate an immune system response but don’t cause an infection.
They vaccinated mice with the cocktail, which targets HA, and then infected them with lethal strains of flu not tailored to the cocktail.
“We’ve shown, amazingly, we get some very broad protection in animal studies,” he said. In one study, “we were able to get 94 percent survival with lethal challenge with 8 different subtypes, including a variety of subtypes not in the vaccine.”
The vaccine was effective for at least 6 months and in older mice. While the results are encouraging, more testing must be done. Right now, Taubenberger is testing the vaccine in ferrets. If the results are successful, the cocktail could be subsequently tested in Memoli’s clinical challenge studies.