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Lipid Adjuvants in Vaccines

Research Article Adjuvants are added to vaccines to boost their efficiency, but the underlying molecular mechanisms used to be poorly understood.

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Henri Deda
Communications Officer

Henri Deda holds a degree in Molecular Bioengineering. He is spirited to discover what scientists are interested in and to provide concise answers.

Resources


Activation of the endoplasmic reticulum…

Givord et al. | npj Vaccines (2018)


An automated shotgun lipidomics platform…

Surma et al. | EJLT (2015)


Systematic screening for novel lipids by…

Papan et al. | Anal. Chem. (2014)


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Summary

• Lipidomics revealed mode of action of vaccine components
• Oil-in-water adjuvants are potent immunostimulatory agents
• Lipid metabolism results pave the way to novel adjuvants

THE measles, the flu, or the world-gripping COVID-19 – ever changing pathogens are constantly threatening mankind. Pharma research is permanently challenged to find a cure or even a protection in order to make the world a safer place. They look back on a tremendous track record, having developed vaccines against polio or smallpox for example. But they are also under constant attack by critics that fear possible side-effects of the injections.

A graphic representation of how vaccines work from introducing safe amounts of antigens to the body to developing antibodies for future infections.

Vaccines train the immune system to recognize pathogens. To achieve that, they introduce antigens to the body to trigger an immune response. Vaccine development can count on agents that enhance the impact of the antigens in the human body by triggering a stronger immune reaction with fewer antigen.

These vaccine components are called adjuvants, they are the magic sauce of modern vaccines. Some of them boost antibody production or activate T-cells, thus minimizing the needed amount of injected material – all while having little to very limited pharmaceutical effect themselves. Adjuvants are the key component to ensure even the smallest doses and the fewest pathogen particles trigger a long-term immune response in the body.

QUOTE

Science looks back on a history of a hundred years of adjuvant research and might now witness a breakthrough in the development of novel adjuvants from the lipid spectrum.

Prof. Dr. Kai Simons
Prof. Dr. Kai Simons
Emeritus Director of the MPI-CBG and founder of Lipotype

One of the few approved adjuvants is the lipid-based Adjuvant System 03 (AS03). It is an oil-in water emulsion believed to induce a local inflammatory response that triggers the desired stronger reaction in the innate immune system.

Lipid-based adjuvants are believed to play an important role in the efficiency of vaccines, yet the molecular mechanisms behind their triggering effect had not been illuminated yet. By applying lipidomics, researchers have been able to shine a light on AS03’s effect on lipid metabolism and changes in lipid composition triggered by the adjuvant.

After injection, AS03 is transported to nearby lymph nodes where it rapidly alters gene expression. Pathway analysis of the altered expression profile highlighted a cluster of down-regulated genes related to lipid metabolism enzymes in lymph nodes. To research the consequences of AS03 injection on molecular level, a global lipidomics analysis of macrophages, a type of white blood cells of the immune system that digest pathogens and defective cells, was applied.

Scientific images showing AS03 inducing the rapid formation of lipid droplets in macrophages and thereby activating the endoplasmic reticulum stress sensor IRE1α contributing to immunostimulatory properties.

AS03 induces the rapid formation of lipid droplets in macrophages: Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties.
Charlotte Givord et al., npj Vaccines (2018), doi: 10.1038/s41541-018-0058-4

The lipidomics analysis demonstrated that AS03 affects cholesterol and fatty acid metabolism of macrophage cells in lymph nodes, showing a decrease of cholesterol but an increase of phosphatidylcholine lipids, a class of phospholipids which is mainly synthesized in the endoplasmic reticulum (ER).

Dysregulation of phospholipid metabolism in the ER can lead to ER stress that disrupts the ER in its vital role in protein folding. This causes accumulation of misfolded proteins that are not biologically functional. The unfolded protein response (UPR) evolved to protect the cell from ER stress and comprises three highly specific signaling pathways. One of these is the ER stress sensor kinase IRE1α, which is also investigated as a therapeutic target for breast cancer. Once operating, the signaling pathway IRE1α activates inflammatory genes.

The lipid metabolism remodeling initiated by AS03 leads to ER stress, thus activating IRE1α and resulting in an upregulation of genes related to inflammation. Ultimately, this increases cytokine production and induces a protective immune response, the reason for the immuno-stimulatory properties of the lipid-based adjuvant AS03. These findings pave the way for the development of new lipid-based adjuvants in vaccines.

Lipids might be the key to modern immunology, drug design, and drug delivery. A better understanding of the little-known mode of action of adjuvants and other lipids in the human body will help design better drugs and vaccines. Researching the paths and secrets of the lipid metabolism with Lipotype Shotgun Lipidomics analysis provides access to new dimensions for vaccine researchers and pharma.

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The Institute for Medical Immunology of the Université Libre de Bruxelles aims at delivering new concepts of immuno-intervention for human diseases by integrating basic and clinical research.


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