How asymmetry could make better vaccines

A group of researchers have found a way to make vaccines 25% more effective – using an old chemical trick.

They’ve developed a substance that, at least in a lab-based study, significantly boosts an immune response.

The discovery revolves around the concept of chirality. Chiral things are asymmetrical in a way that means they can be physically identical, but visually different.

Your hands are the most obvious example of chirality: while your left and right hands are functionally made of the same things, connected in the same way, they’re mirror images of each other. If you try to shake someone’s left hand with your right hand, the difference in your hands becomes obvious immediately.

Molecules, like hands, can be chiral. Nature is an expert at making and distinguishing chiral molecules, but – because molecules are (mostly) too small to see – scientists are much worse at it.

Chemical structure of the stereoisomers of thalidomide
Left: S-thalidomide, which has teratogenic effects. Right R-thalidomide, which has sedative effects. Credit: Creative Commons

“Everything alive on Earth is chiral. Chiral molecules can have entirely different properties depending on whether they’re left- or right-handed. The two chiral forms of the same molecule are known as enantiomers,” says André Farias de Moura, a professor in the chemistry department at the Federal University of São Carlos, Brazil.

“A tragic example is thalidomide, a drug prescribed to pregnant women for morning sickness in the late 1950s and 1960s. It caused babies to be born with a range of malformations. One of the enantiomers in the substance had the expected therapeutic effect, but the other atrophied the limbs of the foetus.”

Chirality has plagued drug developers for years, as it’s much harder for chemists to make specific enantiomers than it is for nature. But Moura and colleagues have found a hidden advantage.

The researchers were looking for new adjuvants: things that boost an immune response to a vaccine. Adjuvants aren’t usually vaccine-specific – the same substance might make an equally good adjuvant in an influenza vaccine as a COVID vaccine. Gold nanoparticles – gold-based materials, a few billionths of a metre in size – have been drawing attention as potential adjuvants from researchers recently.

“We began with gold nanoparticles, which are symmetrical and lack chirality. They’re achiral,” says Moura.

The researchers then reacted the nanoparticles with two chiral molecules: both amino acids, which are key building blocks of our proteins.

“We first induced chirality in them by having them interact with the amino acid cysteine, and then intensified the induced chirality by exposing them to polarised light, using the amino acid phenylalanine as a light-harvesting antenna,” says Moura.

Space-filling molecular model showing lots of gold atoms
A computer-generated model of the left-handed, vaccine-boosting gold nanoparticle. Credit: André Farias de Moura

Eventually, the researchers had three nanoparticles: the original symmetrical version, a right-handed enantiomer and a left-handed enantiomer. They tested each of these substances on an influenza virus in the lab.

“We found that the enantiomers greatly enhanced the efficacy of the vaccine,” says Moura.

“Specifically, the left-handed enantiomer caused a 25.8% increase in efficacy compared with the right-handed enantiomer, and an even greater increase compared with the achiral nanoparticle.”

The researchers say that their trick potentially opens up a new field in vaccine research.

“It can be used by any producer of any type of vaccine, including vaccines for novel variants of SARS-CoV-2 or influenza,” says Moura.

“We aren’t vaccine developers, but we’re offering this basic knowledge as a novel technological platform for those who are.”

A paper describing the research is published in Nature.

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