Vaccines can be made more than 25% more effective by adding left-handed chiral gold nanoparticles as adjuvants, according to the results of a study by an international research team in China, the United States, and Brazil. In a publication in Nature, the researchers reported the results of tests with their nanoparticles on human immune cells and also in combination with a vaccine against the influenza virus. “The key to understanding the contribution of these nanoparticles is the concept of chirality, which applies to an object or system that can’t be superimposed on its own mirror image,” explained André Farias de Moura, PhD, a professor in the chemistry department at the Federal University of São Carlos (UFSCar).

The team said the new technology and knowledge can now be exploited by vaccine developers. “It can be used by any producer of any type of vaccine, including vaccines for novel variants of SARS-CoV-2 or influenza,” Moura added. We aren’t vaccine developers, but we’re offering this basic knowledge as a novel technological platform for those who are.”

The published paper by Moura and colleagues is titled, “Enantiomer-dependent immunological response to chiral nanoparticles,” in which they concluded, “Here we show that achiral and left- and right-handed gold biomimetic nanoparticles show different in vitro and in vivo immune responses … left-handed nanoparticles show substantially higher (1,258-fold) efficiency compared with their right-handed counterparts as adjuvants for vaccination against the H9N2 influenza virus, opening a path to the use of nanoscale chirality in immunology.”

Moura’s group in Brazil collaborated on the study with researchers affiliated with the University of Michigan in the United States, and with Jiangnan University in China. Moura is also a researcher with the Center for Development of Functional Materials (CDMF), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.

Chirality is a type of asymmetry. The term is derived from kheir, the ancient Greek term for hand. The best example of chirality is, perhaps, the difference between left hand and right hand. When we hold up our hands to a mirror, the hand we see on the right is our left hand and vice-versa.

“Everything alive on Earth is chiral,” Moura said. “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. 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 fetus.”

Research in nanomaterials has advanced sufficiently to enable scientists to separate one enantiomer completely, Moura commented, and the team’s reported study reported in Nature exploited this ability. “We began with gold nanoparticles, which are symmetrical and lack chirality. They’re achiral. 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 polarized light using the amino acid phenylalanine as a light-harvesting antenna,” he further explained.

Chirality is measured in “g-factor” on a scale from minus two (-2) to plus two (+2). The procedure used in the study enabled the scientists to exceed 0.4 and resulted in three nanoparticles: the original achiral gold nanoparticle, the right-handed enantiomer, and the left-handed enantiomer.

“Initially we tested the nanoparticles on human immune cells cultured in vitro and found that the chiral nanoparticles induced production of substances associated with an immune response even in the absence of an antigen—any substance capable of triggering antibody production,” Moura said. “This kind of reaction is exactly what an adjuvant does in a vaccine.”

The team further wrote, “We find that binding of nanoparticles to two proteins from the family of adhesion G-protein-coupled receptors (AGPCRs)—namely cluster-of-differentiation 97 (CD97) and epidermal-growth-factor-like-module receptor 1 (EMR1)—results in the opening of mechanosensitive potassium-efflux channels, the production of immune signaling complexes known as inflammasomes, and the maturation of mouse bone-marrow-derived dendritic cells.”

Testing the L-P+ and D-P nanoparticles with an influenza virus vaccine, in live mice, the team confirmed far greater efficacy with the left-handed nanoparticle. “We found that the enantiomers greatly enhanced the efficacy of the vaccine. 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,” Moura noted.

The authors further reported, “We injected C57BL/6 mice with H9N2 influenza vaccine mixed with different nanoparticles. In agreement with our in vitro and in vivo data … left-handed nanoparticles produced a greater increase in the influenza-specific antibody titer than their right-handed counterparts: after injection of L-P+ nanoparticles, the response was 1,258-fold higher than after D-P nanoparticles, and lasted for as long as 91 days.”

They further concluded, “These findings demonstrate the need for the parametrization of nanoparticle chirality in biomedical and toxicological studies … The described chiral effects also raise the possibility of tailoring immune responses using precisely engineered chiral inorganic nanostructures, leading to a better understanding of their role in biological systems.”

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