For decades, HIV and Ebola have shrugged off humanity's best attempts to design vaccines against them. Now a team at Scripps Research in California thinks it has found a way to catch the viruses with their guard down — by studying them on tiny lipid “discs” that mimic the real thing.
The platform, described this month in Nature Communications, has already revealed hidden weak spots on both viruses. Scientists hope it will speed the design of vaccines for two of the world's most stubborn pathogens.
Why old methods fell short
Viruses break into human cells using proteins that stud their outer surface. Those proteins are what vaccines train the immune system to recognise. The problem is that, in the lab, scientists usually have to chop off the bits of the protein that normally sit anchored in the virus's oily outer membrane — the equivalent of trying to learn how a door works after sawing off the hinges.
“For many years, we've had to rely on versions of viral proteins that are missing important pieces,” said Professor William Schief, co-senior author of the study and executive director of vaccine design at IAVI's Neutralizing Antibody Center. “Our platform lets us study these proteins in a setting that better reflects their natural environment, which is critical if we want to understand how protective antibodies recognize a virus.”
So what is a nanodisc?
In plain English: a nanodisc is a microscopic patch of fatty membrane, held together at the edges by a ring of protein. Drop a viral surface protein into the middle of one and it sits there as if it were still on the surface of a real virus — hinges and all.
That small change has big consequences. Antibodies — the immune system's guided missiles — bind to viral proteins in subtly different ways when those proteins are kept whole. The Scripps team, working with the global vaccine non-profit IAVI and Moderna, was able to capture detailed three-dimensional images of antibodies latching on to HIV and Ebola proteins in this near-native state.
The pictures showed previously invisible interactions right at the base of the proteins, where they meet the membrane. It is precisely this region that some of the most powerful “broadly neutralising” antibodies — the ones that can take down many strains of HIV at once — are known to attack.
A faster road to better vaccines
The platform is not itself a vaccine. It is a research tool — but a strikingly efficient one. Tests that previously took a month can now be done in about a week, the team said, making it far easier to screen multiple vaccine candidates side by side.
“Putting all of these components together into a single, reliable system was the key,” said first author Kimmo Rantalainen, a senior scientist in Schief's lab. “The individual pieces already existed, but making them work together in a way that's reproducible and scalable opens up new possibilities for how vaccines are analyzed and designed.”
The researchers say the same trick should work for influenza and SARS-CoV-2, both of which use similar membrane-bound proteins.
Cautious optimism
HIV still infects an estimated 1.3 million people worldwide every year, and Ebola outbreaks remain a recurring threat in parts of central and west Africa. A working HIV vaccine has eluded researchers for more than 40 years.
There is no overnight breakthrough here — no jab is about to roll off a production line. But by giving scientists a clearer, more honest view of what antibodies actually see when they meet a virus, the nanodisc platform could shorten the long road between lab bench and clinic.
“This gives the field a more realistic, accurate way to test ideas early on,” Schief said. “By improving how we study viral proteins and antibody responses, we hope this platform will help advance next-generation vaccines against some of the world's most challenging viruses.”
The work was funded by the US National Institutes of Health, the Bill and Melinda Gates Foundation, IAVI's Neutralizing Antibody Center, and the Alexander von Humboldt Foundation.
