Progress on Universal Flu Vaccine That Could Work Against Any Influenza Strain

Using computer models and laboratory experiments, the researchers are working on a strategy for vaccines that can protect against influenza viruses.

Every year the flu vaccine has to be redesigned to account for mutations the virus accumulates, and even then, the vaccine is often not completely protective for everyone.

Researchers at WITH and the Ragon Institute of MIT, MGH and Harvard are currently working on strategies to develop a universal flu vaccine that can work against any strain of flu. In a study published on October 7, 2020 in Cell systemsThey describe a vaccine that elicits an immune response against a segment of influenza protein that rarely mutates but is usually not attacked by the immune system.

The vaccine consists of nanoparticles coated with flu proteins that train the immune system to produce the desired antibodies. In studies on mice with humanized immune systems, the researchers showed that their vaccine can trigger an antibody response that targets this elusive segment of protein, increasing the possibility that the vaccine could be effective against any strain of flu.

“The reason we are excited about this work is that it is a small step in developing a flu shot that you only do once or a few times, and that the resulting antibody response is likely to protect against seasonal strains of flu and pandemic strains well,” says Arup K. Chakraborty, Robert T. Haslam Professor of Chemical Engineering and Professor of Physics and Chemistry at MIT and a member of the MIT Institute for Medical Technology and Science and the Ragon Institute of MGH, MIT and Harvard.

Chakraborty and Daniel Lingwood, assistant professors at Harvard Medical School and group leaders at Ragon Institute, are the lead authors on the study, which appears in today Cell systems. MIT researcher Assaf Amitai is the lead author of the paper.

Targeting flu

Most flu vaccines are made up of inactivated flu viruses. These viruses are coated with a protein called hemagglutinin (HA) that helps them attach to host cells. After vaccination, the immune system creates a series of antibodies that target the HA protein. These antibodies almost always bind to the head of the HA protein, which is the part of the protein that mutates the fastest. Parts of the HA strain mutate very rarely.

‘We don’t get the full picture yet, but for many reasons, the immune system itself is not good at seeing the conserved parts of these proteins, which, if effectively targeted, would trigger an antibody response that would neutralize several types of influenza “says Lingwood.

In their new study, the researchers wanted to investigate why the immune system ultimately targets the HA head rather than the stem, and find ways to bring the immune system’s attention back to the stem. Such a vaccine could produce antibodies known as “largely neutralizing antibodies” that would respond to any strain of flu. In principle, this type of vaccine could end the arms race between vaccine developers and rapidly mutating flu viruses.

One factor that was previously known to contribute to antibody preference for the HA head is that HA proteins are densely clustered on the surface of the virus, making it difficult for antibodies to access the stem region. The head region is much more accessible.

The researchers developed a computational model with which they could further investigate the “immunodominance” of the protein’s head region. “We hypothesized that the surface geometry of the virus could be key to its survivability by protecting its vulnerable parts from antibodies,” says Amitai.

Researchers studied the effects of geometry on immunodominance using a technique called molecular dynamics simulation. They also modeled a process known as antibody affinity maturation. This process, which occurs after B cells encounter a virus (or vaccine), determines which antibodies predominate during the immune response.

Every B-cell has proteins on its surface, so-called B-cell receptors, which bind to various foreign proteins. As soon as a certain B-cell receptor binds strongly to the HA protein, this B-cell is activated and begins to multiply quickly. This process introduces new mutations in the B-cell receptors, some of which bind more strongly. These better binders tend to survive while the weaker binders die. At the end of this process, which takes a week or two, there is a population of B cells that are very good at binding to the HA protein. These B cells secrete antibodies that bind to the HA protein.

“Over time, after infection, the antibodies will target that particular antigen better,” says Chakraborty.

The researchers’ computer simulations of this process showed that B-cell receptors, which bind strongly to the HA strain, while giving a typical flu vaccine during the maturation process, have a competitive disadvantage because they cannot achieve their goals as easily as B. Cell receptors that bind strongly to the HA head.

The researchers also used their computer model to simulate this maturation process with a nanoparticle vaccine developed at the National Institutes of Health and currently in a Phase 1 clinical trial. This particle carries HA parent proteins that are spaced less densely. The model showed that this arrangement makes the proteins more accessible to antibodies that are Y-shaped so that the antibodies can grab the proteins with both arms. The simulations showed that these strain targeting antibodies were predominant at the end of the maturation process.

Re-focused immunity

The researchers also used their computational model to predict the outcome of several possible vaccination strategies. One strategy that appears promising is to immunize with a strain of HA from a virus that is similar, but not identical, to the strains the recipient was previously exposed to. In 2009, many people around the world were either infected with or vaccinated against a novel strain of H1N1. The modeling led the researchers to hypothesize that if they are inoculated with nanoparticles that have HA-like proteins from a strain different from the 2009 version, it should produce the kind of largely neutralizing antibody that should be universal Can confer immunity.

The researchers tested this strategy on mice with human immune cells and first immunized them against the 2009 H1N1 strain, followed by a nanoparticle vaccine that carries the HA parent protein of another H1N1 strain. They found that this approach was much more successful in eliciting largely neutralizing antibodies than any other strategy they tested.

“We found that this particular event in our immune history can actually be used with this particular nanoparticle to bring the immune system’s attention to one of these so-called universal vaccine targets,” says Lingwood. “If there is a refocusing event, it means we can swing the antibody response against that target, which is simply not seen under other conditions. We have shown in previous studies that such a response, if you can trigger it, protects against strains of flu that mimic pandemic threats. ”

Reference: “Defining and manipulating B-cell immunodominance hierarchies in order to elicit largely neutralizing antibody responses against influenza viruses” by Assaf Amitai, Maya Sangesland, Ralston M. Barnes, Daniel Rohrer, Nils Lonberg, Daniel Lingwood and Arup K. Chakraborty, 7 October 2020, Cell systems.
DOI: 10.1016 / j.cels.2020.09.005

The research was funded by the National Institutes of Health, the Harvard University Milton Award, the Gilead Research Scholars Program, and the National Science Foundation Research Fellowship Program.