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In The Midst Of The Vaccine Frenzy, Let’s Not Forget Drugs

Messenger-RNA Vaccines Are The Buzz, But The Real Technology Advance Is The Lipid Mixture That Delivers The mRNA

The back story: Messenger-RNA vaccines have been wildly successful against the coronavirus and are very safe. Expect more of them in the future, even for flu. As exciting as it is to see a simple mRNA sequence generate immunity to a pathogen, it is the less “sexy” lipid, or concoction of fat molecules that makes it possible and has been a bit of a bottleneck in manufacturing the vaccines.

Messenger RNA is a fragile molecule since there are RNA-degrading enzymes called RNases all over the place. Therefore, researchers decided to encapsulate the genetic material inside a protective shell composed of a cocktail of different types of the fatty molecules that, in a solution, will form mini-cells called lipid nanoparticles. These nanoparticles essentially mimic the lipid membrane of your cells so that when, after injection and they bump into a cell, the lipids of the nanoparticle and of the cell membrane fuse, spilling the mRNA into the cells. There, normal cellular machinery can transcribe the mRNA sequence into a viral spike protein that is expressed on the cell surface, stimulating an immune response. There also are RNase enzymes inside cells that digest the mRNA after it has done its business so the vaccine genetic material naturally disappears in a couple of days and cells cease expressing the spike protein.

Some history: Since the 70s, research has been underway into using lipid nanoparticles to deliver large, fragile bio-molecules and drugs to cells. But, but the nanoparticles are notoriously difficult to make and use. Bob Langer, now a Professor of Biological Engineering at MIT has been working with lipid nanoparticles since the 70s when he was a pioneer trying to prove you can capture and transport big, complex molecules like DNA and RNA inside tiny lipid nanoparticles without destroying them. Many people told him it was not possible and he had his first 9 grant applications rejected—and this was a time when research grants were pretty easy to get. He also could not get a faculty position because people did not believe in his research.

But, he did succeed. Today, Professor Langer has a bioengineering lab at MIT bearing his name. The lab is focused on the intersection of biotechnology and materials science. In 2010, Langer branched out and co-founded a small biotech company named Moderna where he’s still on the board. That company, like the German biotech company, BioNTech, has, over the last decade been developing mRNA vaccines for infectious diseases, cancer and rare illnesses. The Moderna mRNA vaccine, developed along with researchers at NIH, is Moderna’s first commercial product.

The lipid nanoparticle field had a watershed moment in 2018, when the FDA approved the first drug delivered via lipid nanoparticles from yet another biotech, Alnylam Pharmaceuticals based in Cambridge, Massachusetts.  Their nanoparticles were used to encapsulate and deliver a drug, Onpattro, to treat a rare genetic disease that causes nerve and heart damage. That meant that before the coronavirus pandemic, regulators already had some familiarity and comfort with using lipid nanoparticles to deliver therapeutic molecules. The technology is not brand new as some vaccine naysayers like to claim.

Another scientist, Thomas Madden, worked for years with Alnylam on developing that pioneering lipid delivery system. However, before the FDA approved Alnylam’s delivery system, Madden had moved on to his own Vancouver-based company, Acuitas Therapeutics, which hoped to develop mRNA therapeutics for different diseases. Madden recalls an epiphany in 2011, when he realized that in order to successfully use mRNA for therapeutic purposes; they needed a better delivery system to protect the mRNA from the ubiquitous RNases that quickly digest any mRNA found circulating outside of cells.

To prevent that from happening, he adapted the lipid-packaging technology developed at Alnylam, thinking that if the mRNA could be packaged inside the artificial lipid membranes it  would protect the fragile genetic mRNA from the ubiquitous RNase enzymes. This became the basis for the technology behind the Pfizer/BioNTech and Moderna mRNA vaccines. The mRNA in Covid shots sits inside a lipid shell composed of four lipids. After protecting the mRNA on its journey into a person’s arm, the nanoparticle gets taken up into a cell and the mRNA is released inside the cells. Once inside the cell, the mRNA instructs the cell to produce copies of the coronavirus spike protein, which is then recognized by the body’s immune system.

Moderna has designed its own lipids used to create the nanoparticles, while Pfizer has licensed the Acuitas lipid delivery technology. Yet another mRNA vaccine is being developed by another biotec, CureVac, which also is using the Acuitas lipid technology. Each of these companies was engaged in early clinical trials of other mRNA therapeutics before the pandemic and CoV-2 burst onto the world stage. They all pivoted their efforts to develop several novel vaccines against the novel coronavirus in record time.

When Covid-19 emerged, Madden, from Acuitis Therapeutis, flew to Germany to talk to regulators and BioNTech officials about how they could most quickly commence clinical trials of mRNA COVID-19 shots. They decided to repurpose the lipid nanoparticle from a very new rabies vaccine recently developed by CureVac, since it had proven effective in people. This gave regulators further confidence on the safety and potential for lipid delivery of the coronavirus spike protein mRNA.

In a nut shell, that is how we got to this point so quickly. An important take-home message is that the mRNA vaccine technology and lipid nanoparticle delivery system are not new concepts. The vaccines are the product of decades of research and trials conducted by several academic and biotechnology labs. The lipid nanoparticle delivery system has proven effective and safe for delivering other vaccines and drugs.

In an earlier blog post, I dubbed this amazing new biology, BioX, after the name of the new and amazing space enterprise known as SpaceX.

New challenges: As Moderna and Pfizer have, almost overnight, greatly ramped up production of their lipid nanoparticle delivery systems, supply chain issues became evident. Soon after getting its mRNA vaccine approved, Pfizer announced it was scaling back the number of doses it would deliver due to difficulty obtaining the raw chemical materials needed to make the necessary lipid compounds. Until a year ago, the German biotech company, BioNTech, that partnered with Pfizer, purchased only a few grams at a time of the needed chemicals to produce its lipids for a cancer vaccine research program. Now the company is tapping huge German chemical conglomerates like Merck and Evonik Industries for barrels of the stuff in order to manufacture 2 billion vaccine doses this year. Moderna also has dramatically scaled up its need for chemicals to produce the lipids that go into its promised one billion vaccine doses. Other mRNA vaccines are also being developed by CureVac NV and Sanofi, both of which will require massive amounts of the raw materials. Lipids have leaped to the top of the world’s health-care supply-chain priority list.

Major drug and chemical makers have taken notice of the new demand for the lipid chemicals. In early February, Germany’s Merck agreed to speed up the supply of lipids to BioNTech while Evonik followed suit a week later. Evonik is repurposing tanks and vessels at two plants in Germany and buying new instruments for the purification process. Typically, in the pharma industry such large-scale manufacturing scale-up takes a year or two, but Evonik plans to do this in a couple of months in order to meet the sudden and immediate demand.

That is the German version of Warp Speed.

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