A Blog by Ed Yong

Better Flu Vaccine Made from Self-Assembling Sculptures

Sculpture is all about deliberation. You painstakingly chip marble from a block, or slowly assemble Lego bricks into a shape, or carefully pile clay upon clay. But we’re now entering a world where people can sculpt with proteins, creating amazingly intricate nano-scale shapes just a few billionths of a metre across. And when it comes to these nano-sculptures, the deliberation lies in selecting your materials in the first place. Once that’s done, you throw them all together and watch them assemble themselves.

Masaru Kanekiyo and Gary Nabel used this approach to create a new breed of flu vaccine that (in animal tests) provides better and broader protection than the ones we currently have. I’ve written more about this over at Nature, so head over there for the details.

Over here, I’m going to lay out exactly how the vaccine is built because it’s just so damn cool.

Flu vaccines are caught in a seemingly endless struggle against an ever-changing enemy. Flu viruses mutate all the time, and every year brings a slightly different set of seasonal strains. Immunising against one strain won’t necessarily protect against the others, so flu vaccines must be re-made every year to protect against the (usually three) strains that are predicted to cause the most problems in the upcoming season.

The traditional vaccine uses actual flu viruses that have been killed or inactivated. The idea is to give the immune system a sneak preview of next year’s likely blockbuster strains, so it can prepare by raising an army of defensive antibodies. Kanekiyo’s vaccine trains the immune system in the same way, but does it much more effectively. And it uses faux-viruses.

It’s made of two proteins. The first—haemagglutinin (HA)—is used by flu viruses to recognise and break into our cells. It studs the outer coat of a flu virus like pins in a pincushion. Each pin is made of three HA molecules, which line up in parallel to form a three-sided cylinder.

The second protein—ferritin—is involved in shuttling and storing iron molecules. It’s completely irrelevant to flu infections; it’s there for its handy ability to assemble into a sphere. Each sphere looks a bit like a volleyball and is made from 24 ferritin molecules.

Here’s the beautiful bit. Kanekiyo fused the two proteins together at just the right point that when he mixed 24 of them together, they automatically assembled into a ferritin sphere surrounded by eight HA spikes. Once he got the components right, they could sculpt themselves.

It gets better. The ferritin sphere has eight small triangular gaps on its surface, which are exactly the same width as the HA spikes—28 nanometres, no more and no less. This means that the HA spikes don’t just attach themselves to the sphere in random places. Instead, they become evenly spaced out in very specific positions. Under the microscope, the finished nanoparticle looks like a jack.

Ferritin sphere made of 24 units (left), and haemagglutinin spike of 3 units (right, end-view)
Ferritin sphere made of 24 units (left), and haemagglutinin spike of 3 units (right, end-view). From Kanekiyo et al, 2013. Nature.

Compared to a traditional vaccine (which, if you’ll remember, are actual viruses)., these nanoparticles raise anywhere from 10 to 40 times more antibodies against flu. And the antibodies work against a far more diverse range of strains.

It’s all in the presentation. A real flu virus has around 450 HA spikes crowding its surface, along with other proteins. The nanoparticles have just 8 HA spikes, which are regularly spaced and have nothing else getting in the way. It screams, “LEARN THIS!” to the immune system and then gives it a really good look.

Nanoparticles built using the HA from one particular strain seem to protect against many others. So, if they prove their worth in human test, the hope is that they won’t need to be updated so regularly, or could better prepare us against future pandemics. (Again, read more over at Nature.)

But for the moment, I’m just in awe of how neatly the numbers work. Twenty-four ferritin molecules make a sphere with eight 28-nanometre-wide gaps. Twenty-four HA molecules make eight spikes that are 28 nanometres wide, and fit onto that sphere in exactly the right places.

It’s a testament to the importance of structural biology—knowing the precise shapes of proteins. That knowledge was the key to designing this new vaccine.

Reference: Kanekiyo, Wei, Yassin, McTamney, Boyington, Whittle, Rao, Kong, Wang & Nabel. 2013. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature http;//dx.doi.org/10.1038/nature12202

3 thoughts on “Better Flu Vaccine Made from Self-Assembling Sculptures

  1. Great post! One small correction: You said the spaces are 28 nanometer (10e-9 meter) wide, but the image says 28 A, that is Angstrom (10e-10 meter). That’s a difference of a factor of 10.

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