As nutrition experts often say, some fats are good. But taking this phrase to the plane of the new generation of vaccines that scientists are studying, means a possible advance of this material to gain in efficacy and safety of innovative developments against various diseases.
For example, we can mention the little balls of fat found in two of the most widely used COVID-19 vaccines in the world. Known as lipid nanoparticles (LNPs), these tiny bubbles of fat enclose messenger RNA (mRNA) that encodes a viral protein, helping to transport it into cells and protect it from destructive enzymes. This technology, which was a few years old, was perfected in 2020 for the development and subsequent success of Moderna and Pfizer-BioNTech’s COVID-19 vaccines. But despite how beneficial these fats are, experts say there is still much room for improvement, and that new vaccines could be more efficient and have fewer side effects on the body.
A) Yes, Nanoparticles are a major source of unwanted side effects as they spread through the body, triggering the pain and inflammation that many people experience after vaccination. They do a poor job of unloading their cargo once inside cells, a necessary step for the protein-making machinery to convert mRNA sequences into immune priming signals. And because they tend to fall apart when heated, they must be stored at low temperatures, limiting their global use.
A new generation of LNPs with higher potency, fewer side effects, greater stability, and more precise tissue-targeting properties is now in development at large pharmaceutical and biotech companies. Big money is at stake: These improved nanoparticles could lead to better mRNA vaccines for COVID-19 and other diseases. They could also help the mRNA fulfill its promise as a therapeutic tool to treat diseases. “There are delivery innovations that could certainly change the game“, he claimed Philip Santangeloa biomedical engineer at the Georgia Institute of Technology who has collaborated with several mRNA companies.
the biochemist Pieter Cullis of the University of British Columbia (UBC), Vancouver, along with colleagues, developed the first LNPs about 20 years ago to deliver gene-silencing drugs into cells. Later, he and others adapted the four lipid components of LNPs to deliver disease-correcting mRNA to defective cells. “Now that they’re being put to a new use, in vaccines, there’s still a lot of optimization and development to do,” explained UBC bioengineer Anna Blakney, co-founder of RNA vaccine company VaxEquity. And when it comes to understanding how cells interact with nanoparticles, “it’s just this big question mark,” she adds.
A clue emerged earlier this year when Genentech scientists showed how nanoparticles activate a particular inflammatory pathway the interleukin-1 axis, which is critical for generating protective immune responses, but can also cause side effects. Among the LNPs tested, one made with SM-102, an “ionizable” lipid that helps bind and package mRNA into LNPs, proved to be an especially strong instigator of this pathway. That could help explain why Moderna’s shot, which is based on SM-102, is highly effective and prone to making people feel creepy.
The Genentech team did not test the comparable lipid found in the Pfizer-BioNtech vaccine. But Mohamad-Gabriel Alameh and colleagues at the University of Pennsylvania Perelman School of Medicine tested a closely related one and found that it triggered a wide range of inflammatory molecules, both wanted and not. “The goal now is to design ionizable lipids that activate favorable immune pathways without overstimulating harmful ones”said Alameh, who co-founded AexeRNA Therapeutics with bioengineer Michael Buschmann of George Mason University and others. “It is very simple? No,” says Alameh, but it should be possible.
Before his death in March, Buschmann led a team that in 2021 showed how the electrical charge of the LNPs is essential for the success of the vaccine . A negative charge makes the particle less likely to remain in the muscle and lymph nodes of injected mice, where it could elicit beneficial immune responses; instead, it tends to spread widely, increasing the risk of fever, chills, and other adverse reactions.
To make a nanoparticle with less negative charge, the researchers modified the chemistry of the ionizable lipid. When formulated into an mRNA vaccine for COVID-19, the new carrier of LNP prompted the mice to produce more protective antibodies than standard delivery systems and had fewer side effects, according to data published last year in preprint form and now under review in Nature Communications.
Dan Peer, a biochemist at Tel Aviv University and co-founder of the vaccine delivery startup NeoVac, has also developed libraries of novel ionizable lipids with atypical structures. In unpublished experiments, they appear to allow better mRNA vaccines with fewer side effects and also extend their storage stability at room temperature. Other improvements could come from boosting the uptake of LNP into cells and then improving their ability to be released from sacs in the cell membrane, known as endosomes, that transport them inside. The vast majority of LNPs get trapped in these receptacles and are then destroyed or expelled without delivering their vaccine payloads, meaning “there is a lot of RNA that is not being used,” says Gaurav Sahay, a bioengineer at the Oregon Health and Science University.
The shape of ionizable lipids affects an LNP’s ability to alter an endosome, as does cholesterol, one of the other fats in LNPs. Along with Moderna scientists, Sahay and his colleagues reported in 2020 that using different forms of cholesterol can improve escape rates of LNP from endosomal trapping . He has founded a company called Enterx Biosciences to commercialize his discoveries.
Sanofi has started evaluating some of its customized LNPs in human trials. In a study released in 2021, for example, the company has evaluated two LNP options to deliver an mRNA flu vaccine it is developing. According to preliminary data, a formulation of lipids proved much better at boosting immunity against influenza announced Frank DeRosa, head of research and biomarkers at Sanofi’s mRNA Center of Excellence, at an investor event in December 2021. But the same LNP also caused more frequent side effects at higher doses.
Other companies, including BioNTech and Arcturus Therapeutics, have begun exploring ways to remove polyethylene glycol, a compound that helps stabilize LNPs, but has also been linked to some types of bad reactions to vaccines. Meanwhile, many more companies are focused on optimizing lipids to deliver mRNA to treat disease rather than prevent it. This requires delivering mRNAs encoding disease-correcting proteins to the precise cells and tissues where they are needed, not just the liver, where current LNP formulations tend to end up after infusion.
“Delivery of LNP will be key to really expanding the reach of mRNA” beyond preventative vaccines, says Dominik Witzigmann, co-founder and CEO of startup NanoVation Therapeutics, founded by Cullis.