Designing a universal flu vaccine by refocusing the immune system

A universal flu vaccine that can protect people against any influenza strain is considered a holy grail of flu research because it could spare scientists from the often inaccurate process of predicting the circulating strains each year and redesigning the vaccine to match them.

Now, a group of researchers at the Massachusetts Institute of Technology, the Ragon Institute and Bristol Myers Squibb has shed light on a possible strategy for developing a universal flu vaccine by targeting a more stable region of the influenza virus that’s normally not targeted by the immune system.

In mice, a vaccine that uses nanoparticles to carry flu proteins triggered an antibody response to the desired segment of the virus, suggesting the vaccine could be broadly effective against any flu strain. The team reported the findings in the journal Cell Systems.

“The reason we're excited about this work is that it is a small step toward developing a flu shot that you just take once, or a few times, and the resulting antibody response is likely to protect against seasonal flu strains and pandemic strains as well,” Arup Chakraborty, Ph.D., the study’s senior author, said in a statement

Influenza virus coats itself with a protein called hemagglutinin (HA), which is crucial for its ability to infect human cells. HA consists of two parts: a globular head region and a stem or stalk region. The head region often mutates and varies across different strains of influenza viruses. In contrast, the stem or stalk region rarely mutates, making it a great target for a universal vaccine.

However, the immune system is almost always drawn to the highly variable head region, producing antibodies that can only recognize a few virus subtypes rather than what are known as broadly neutralizing antibodies.

In the new study, the researchers used computational modeling to determine why the immune system is inclined to target the HA head, and then to find ways to refocus the immune response to the stem.

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It’s been shown that the head region is much more accessible than the stem, so the researchers hypothesized the surface geometry of the virus could be key to its ability to hide the stem from antibodies.

They modeled a process called antibody affinity maturation, in which antibody-producing B cells gradually evolve, leaving only those that can bind tightly to the HA protein. “As time goes on, after infection, the antibodies get better and better at targeting this particular antigen,” Chakraborty explained.

In a typical flu vaccine, the body doesn’t favor B cells that bind to the HA stem because they can’t reach and bind to their targets as easily as their counterparts that target the HA head, the researchers found.

The researchers also used the model to simulate the maturation process of a nanoparticle universal vaccine developed at the National Institutes of Health (NIH), which is already being tested in a clinical trial. As the HA stem proteins in that shot are more loosely spaced, they become more accessible to antibodies and therefore eventually survive the maturation process, the simulations found.

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Because previous immunization or infection could leave behind memory B cells that can immediately launch an attack once the same target shows up, it could be difficult for a universal vaccine using components from the same strain of virus to overcome existing immunity.

Using mice with human immune cells, the researchers tested whether vaccination with HA-like proteins from one flu strain could induce broadly neutralizing antibodies. They first immunized the animals against the 2009 H1N1 pandemic strain, which according to the researchers has “reset” much of the human B-cell memory population and remains a major immunodominant antigen in current memory recall responses in humans. Then they used a nanoparticle vaccine of the HA stem protein from a different H1N1 strain. They found that this approach was much more effective at inducing broadly neutralizing antibodies than other methods they tried.

Outside of HA, scientists have also been looking at antibodies against neuraminidase, which is also targeted by Roche’s popular flu drug Tamiflu. A neuraminidase-inhibiting antibody that scientists from the Icahn School of Medicine at Mount Sinai, the Washington University School of Medicine and Scripps Research isolated from a flu patient was found to protect mice from all 12 strains of influenza virus tested.

Researchers at the NIH’s National Institute of Allergy and Infectious Diseases found an antibody they developed to recognize HA stem was also able to inhibit neuraminidase. Combining that antibody with Tamiflu helped mice survive a lethal viral challenge.

Chakraborty and colleagues believe their findings suggest sequential exposure to variants of an immunodominant antigen can refocus the immune system’s attention onto the conserved HA stem region as a universal vaccine target.