A new delivery particle developed at MIT could make mRNA vaccines more effective and potentially lower the cost per vaccine dose.In studies in mice, the researchers showed that an mRNA influenza vaccine delivered with their new lipid nanoparticle could generate the same immune response as mRNA delivered by nanoparticles made with FDA-approved materials, but at around 1/100 the dose.“One of the challenges with mRNA vaccines is the cost,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES). “When you think about the cost of making a vaccine that could be distributed widely, it can really add up. Our goal has been to try to make nanoparticles that can give you a safe and effective vaccine response but at a much lower dose.”While the researchers used their particles to deliver a flu vaccine, they could also be used for vaccines for Covid-19 and other infectious diseases, they say.Anderson is the senior author of the study, which appears today in Nature Nanotechnology. The lead authors of the paper are Arnab Rudra, a visiting scientist at the Koch Institute; Akash Gupta, a Koch Institute research scientist; and Kaelan Reed, an MIT graduate student.Efficient deliveryTo protect mRNA vaccines from breaking down in the body after injection, they are packaged inside a lipid nanoparticle, or LNP. These fatty spheres help mRNA get into cells so that it can be translated into a fragment of a protein from a pathogen such as influenza or SARS-CoV-2.In the new study, the MIT team sought to develop particles that can induce an effective immune response, but at a lower dose than the particles now used to deliver Covid-19 mRNA vaccines. That could not only reduce the costs per vaccine dose, but may also help to lessen the potential side effects, the researchers say.LNPs typically consist of five elements: an ionizable lipid, cholesterol, a helper phospholipid, a polyethylene glycol lipid, and mRNA. In this study, the researchers focused on the ionizable lipid, which plays a key role in vaccine strength.Based on their knowledge of chemical structures that might improve delivery efficiency, the researchers designed a library of new ionizable lipids. These contained cyclic structures, which can help enhance mRNA delivery, as well as chemical groups called esters, which the researchers believed could also help improve biodegradability.The researchers then created and screened many combinations of these particle structures in mice to see which could most effectively deliver the gene for luciferase, a bioluminescent protein. Then, they took their top-performing particle and created a library of new variants, which they tested in another round of screening.From these screens, the top LNP that emerged is one that the researchers called AMG1541. One key feature of these new LNPs is that they are more effective in dealing with a major barrier for delivery particles, known as endosomal escape. After LNPs enter cells, they are isolated in cellular compartments called endosomes, which they need to break out of to deliver their mRNA. The new particles did this more effectively than existing LNPs.Another advantage of the new LNPs is that the ester groups in the tails make the particles degradable once they have delivered their cargo. This means they can be cleared from the body quickly, which the researchers believe could reduce side effects from the vaccine.More powerful vaccinesTo demonstrate the potential applications of the AMG1541 LNP, the researchers used it to deliver an mRNA influenza vaccine in mice. They compared this vaccine’s effectiveness to a flu vaccine made with a lipid called SM-102, which is FDA-approved and was used by Moderna in its Covid-19 vaccine.Mice vaccinated with the new particles generated the same antibody response as mice vaccinated with the SM-102 particle, but only 1/100 of the dose was needed to generate that response, the researchers found.“It’s almost a hundredfold lower dose, but you generate the same amount of antibodies, so that can significantly lower the dose. If it translates to humans, it should significantly lower the cost as well,” Rudra says.Further experiments revealed that the new LNPs are better able to deliver their cargo to a critical type of immune cells called antigen-presenting cells. These cells chop up foreign antigens and display them on their surfaces, which signals other immune cells such as B and T cells to become activated against that antigen.The new LNPs are also more likely to accumulate in the lymph nodes, where they encounter many more immune cells.Using these particles to deliver mRNA flu vaccines could allow vaccine developers to better match the strains of flu that circulate each winter, the researchers say. “With traditional flu vaccines, they have to start being manufactured almost a year ahead of time,” Reed says. “With mRNA, you can start producing it much later in the season and get a more accurate guess of what the circulating strains are going to be, and it may help improve the efficacy of flu vaccines.”The particles could also be adapted for vaccines for Covid-19, HIV, or any other infectious disease, the researchers say.“We have found that they work much better than anything that has been reported so far. That’s why, for any intramuscular vaccines, we think that our LNP platforms could be used to develop vaccines for a number of diseases,” Gupta says.The research was funded by Sanofi, the National Institutes of Health, the Marble Center for Cancer Nanomedicine, and the Koch Institute Support (core) Grant from the National Cancer Institute.
