This excellent Nature article explains the long and complex development of mRMA vaccines, including Malone's important contribution of mixing mRNA with a mixture of lipids including a positively charged lipid.
https://www.nature.com/articles/d41586-021-02483-w ... Years later, Malone followed the Harvard team’s tactics to synthesize mRNA for his experiments. But he added a new kind of liposome, one that carried a positive charge, which enhanced the material’s ability to engage with the negatively charged backbone of mRNA. These liposomes were developed by Philip Felgner, a biochemist who now leads the Vaccine Research and Development Center at the University of California, Irvine.
Malone is named as a co-inventor with several other inventors in the patent dating from 1989:
US5703055AGeneration of antibodies throughlipidmediated DNA delivery
Claim 10 defines the positively charged lipid.
Malone's contribution was one step in a very long journey.
The major breakthrough to making a practical vaccine came in 2007 when Katalin Kariko's dogged persistence led to a key discovery:
The same year, a fledgling mRNA start-up called RNARx received a more modest sum: $97,396 in small-business grant funding from the US government. The company’s founders, biochemist Katalin Karikó and immunologist Drew Weissman, both then at the University of Pennsylvania (UPenn) in Philadelphia, had made what some now say is a key finding: that altering part of the mRNA code helps synthetic mRNA to slip past the cell’s innate immune defences.
Karikó had toiled in the lab throughout the 1990s with the goal of transforming mRNA into a drug platform, although grant agencies kept turning down her funding applications. In 1995, after repeated rejections, she was given the choice of leaving UPenn or accepting a demotion and pay cut. She opted to stay and continue her dogged pursuit, making improvements to Malone’s protocols14, and managing to induce cells to produce a large and complex protein of therapeutic relevance15.
In 1997, she began working with Weissman, who had just started a lab at UPenn. Together, they planned to develop an mRNA-based vaccine for HIV/AIDS. But Karikó’s mRNAs set off massive inflammatory reactions when they were injected into mice.
She and Weissman soon worked out why: the synthetic mRNA was arousing16 a series of immune sensors known as Toll-like receptors, which act as first responders to danger signals from pathogens. In 2005, the pair reported that rearranging the chemical bonds on one of mRNA’s nucleotides, uridine, to create an analogue called pseudouridine, seemed to stop the body identifying the mRNA as a foe17.
Moderna tried to license the patents for modified mRNA that UPenn had filed in 2006 for Karikó’s and Weissman’s invention. But it was too late. After failing to come to a licensing agreement with RNARx, UPenn had opted for a quick payout. In February 2010, it granted exclusive patent rights to a small lab-reagents supplier in Madison. Now called Cellscript, the company paid $300,000 in the deal. It would go on to pull in hundreds of millions of dollars in sublicensing fees from Moderna and BioNTech, the originators of the first mRNA vaccines for COVID-19. Both products contain modified mRNA.
So if you are looking for a good bet for the Nobel Prize for Medicine ...
