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Graphical cutaway representation of the flu virus, including the surface proteins hemagglutinin (HA) and neuraminidase (NA), shown in light and dark blue, respectively, and the internal ribonucleoprotein (light blue coils). Credit: Pixnio public domain

Making a smarter flu vaccine

Sandhya Subramanian

Posted on Jan 24th, 2018


It’s winter, and most likely you remembered some time back in the fall that you needed to get your flu shot—again. Who comes up with these vaccines, why do we need one every year, and why is the 2017-2018 flu outbreak worse than in the past few years?

Like having multiple agencies and emergency responders prepare for hurricanes, fighting the flu requires a large coordinated effort that is sustained throughout the year [1,2].

Behind the scenes: the flu vaccine

Each year three or four flu virus strains are predicted to be the most likely to make people sick for the coming flu season. Public health advisors and scientists around the world review the past year’s data [3], such as which flu strains are worldwide prevalent or which vaccines were most effective. They, including the WHO, then make a recommendation early in the year on which strains are the top candidates for developing the upcoming northern hemisphere flu season vaccines. Pharmaceutical companies need the next four to six months to make the vaccines in time for fall so we can get our shots.

H1N1 flu virus

Why do we need a new flu vaccine each year?

Because the flu virus changes its RNA sequence, or mutates, very rapidly, this identification and manufacturing process has to happen anew every year. In years that the predictions are more accurate, we may have a mild flu season; but sometimes the breaking flu strains have mutated to the point that the antibodies our immune system generates from the vaccines are not effective against this “new” version of the flu. That’s what happened with the flu virus for the 2017-2018 flu season.

Image at right: A 3D image of the H1N1 flu virus, commonly known as swine flu. Credit: Flickr


Structural genomics for a better flu vaccine

In hopes of speeding up the process to create the vaccine and to make it more effective, one of the centers housed under CID Research teamed up with a pharmaceutical company and another partner to pool knowledge and resources.

The project is called STRIVE, the STRucture-guided Influenza Vaccine initiativE, and the partners include the faculty-led Seattle Structural Genomics Center for Infectious Disease (SSGCID); their counterpart, the Center for Structural Genomics of Infectious Diseases (CSGID) with a research arm at Washington University in St. Louis; and Sanofi Pasteur, one of the companies that makes millions of doses of flu vaccine every year. By working together, these organizations are finding ways to make better flu vaccines by utilizing the protein structures revealed through the work of SSGCID and CSGID.

Sanofi’s vaccine development expertise is complemented by the experience of both the SSGCID and the CSGID in determining protein structures – creating a three-dimensional atomic model of a protein. Having the 3D shape of a protein helps with vaccine improvement by allowing us to see at a minute level the conformation of specific sites on the pathogen proteins that make them susceptible to our immune responses. The parts of the vaccine that trigger our immune response can then be re-engineered to mimic these sites more closely.

Above: The molecular structure of an influenza HA protein is shown above in cyan, with part of a human antibody that binds to it shown in gray. Antibodies are stimulated by vaccines, and recognize very specific sites on the surface of a virus. The box shows a close-up view of the interaction between the antibody and HA. By solving structures of different HA proteins, we will learn which sites are shared among many different influenza strains, which will help us to design better vaccines that target the shared sites. (This figure was generated based on the published structure with PDB code 4FQR.)


In the case of the flu, the protein hemagglutinin (HA) sits on the outer surface of the flu virus and helps it bind to proteins on the outer surface of our cells. This binding allows the virus to then enter and infect our cells. It is also one of the best proteins for triggering our immune responses so is used in vaccine design [4].

The main goal of STRIVE is to use 3D protein structures of HA from different strains to help optimize flu vaccine development and manufacturing, with a goal of reducing the time it takes to have a new vaccine responsive to a newly mutated flu strain. The STRIVE project was kicked off in May 2017; in September the SSGCID started work on HA proteins from 25 different flu strains, while the CSGID group focuses on HA proteins from 25 different H3 flu strains. The first HA structure was solved at the beginning of November and the first H3 HA structure was determined right after that. Many more structures are expected to be solved this year to further fine-tune future flu vaccines.

While flu seasons, just like hurricanes, will happen every year, scientists in research and industry, public health officials and many others around the world are constantly working on predicting where the outbreaks will hit and how best to fight the virus and protect people from the flu.

The SSGCID and CSGID are funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under Contract Nos.: HHSN272201700059C and HHSN272201700060C, respectively.


References

1. This Is How Scientists Decide What Goes In Your Flu Shot - Tonic. Available at: https://tonic.vice.com/en_us/article/bj7bqv/how-scientists-decide-what-goes-in-your-flu-shot.

2. Flu vaccines: a mixture of hard science and good fortune | Science | The Guardian. Available at: https://www.theguardian.com/science/2015/jan/18/flu-strain-vaccine-experts-influenza.

3. WHO | Global Influenza Surveillance and Response System (GISRS). WHO (2017).

4. Lee, P. S. & Wilson, I. A. Structural characterization of viral epitopes recognized by broadly cross-reactive antibodies. Curr. Top. Microbiol. Immunol. 386, 323–41 (2015).

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