How Messenger RNA Made The COVID Vaccines Possible

The following is an excerpt from The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets by Thomas R. Cech.

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On January 10, 2020, Prof. Yong-Zhen Zhang of Fudan University in Shanghai posted the RNA sequence of a new coronavirus on an open- access website. The importance of this community-minded act was not immediately appreciated, because the new virus was generating only limited concern outside China at the time. Yes, it was related to the coro naviruses responsible for two previous outbreaks of severe acute respira- tory syndromes—SARS in 2002 and MERS in 2012—but each of those had been contained, resulting in fewer than 1,000 deaths worldwide. Yet the new coronavirus, soon to be named SARS-CoV-2, had a different destiny. It would be the scourge of the planet.

Somehow, the scientists at the then-obscure biotechnology company Moderna, based in Cambridge, Massachusetts, realized that same month that this new coronavirus posed more of a threat than SARS or MERS. Scientists at the equally obscure company BioNTech in Mainz, Germany, were also reading the reports of the new infections in Wuhan, China, and saw the hallmarks of an incipient pandemic: many infected but asymptomatic individuals who would unwittingly spread the virus and no travel restrictions to contain the outbreak. Both companies had been developing messenger RNA for therapeutic purposes. And both companies thought that the mRNA technology they were developing might be quickly retooled to make a protein that would serve as a vaccine against the new virus.

In many respects, the companies were making a very bold move, considering that the utility of any mRNA vaccine was then unproven But they had all the puzzle pieces they needed lying on the table in front of them. For six decades, scientists had been uncovering the mysteries of mRNA. They had deciphered the genetic code, so anyone could read Yong-Zhen Zhang’s SARS-CoV-2 sequence and understand how to make the Spike protein. They had shown that they could in fact use mRNA to make enough protein to elicit an immune response, central to vaccine development. They had developed a powerhouse technique for copying DNA into gobs of mRNA. They had learned that lipid-RNA combinations helped RNA enter human cells, and they’d developed the tiny greaseballs called lipid nanoparticles. And they’d discovered that the U base of mRNA could be substituted with a modified form to disguise the mRNA so it wouldn’t elicit an unhealthy inflammatory response.

Yet, as any of us who have assembled a jigsaw puzzle know, having all the pieces laid out on the table is only the beginning of the hard work. To illustrate how challenging it was to produce a successful Covid-19 vac- cine, consider that the mRNA vaccines were in a race with more than a dozen other contestants—many using proven technologies that seemed very likely to work once again. These multiple approaches cast a wide net: some used inactivated SARS-CoV-2 viruses, others engineered a harm- less virus to express the Spike protein, still others were DNA vaccines. Some of these approaches—such as the Oxford-AstraZeneca DNA vac- cine that was initially used in the United Kingdom—ended up yielding quite respectable vaccines that simply fell short of the efficacy that would be achieved by the two mRNA vaccines. Other approaches failed to elicit a strong enough immune response in humans and were dropped.

Assembling the mRNA vaccine puzzle required remarkable talent, creativity and fortitude, and some truly remarkable scientists to make it happen. Among these, the story of Ugur Sahin and Özlem Türeci is particularly compelling. Born in Turkey, Ugur Sahin moved to Germany when his father got a job at a Ford automobile factory in Cologne. Özlem Türeci was also of Turkish heritage–her biologist mother and surgeon father had immigrated from Turkey to Germany. Sahin and Türeci met in 2001 when they were both working as physicians at a hospital in the Saarland district of Germany. They married in 2002 and had a daughter. Beyond their home life, their shared passion was to bring novel science to bear on unmet medical needs, particularly in the area of immuno oncology: stimulating the immune system to recognize and destroy tumor cells. In 2008, Sahin and Türeci founded BioNTech with the goal of developing cancer vaccines based on mRNA (more on this later). The work was challenging, but they made progress over the next decade—they had more than a dozen compounds in clinical trials—when the fateful day in January 2020 led them on their new mission.

The Covid-19 vaccine’s target would be the telltale spikes that give the coronavirus its crown-like appearance. The 90 protein spikes protruding from the fatty lipid envelope that surrounds the coronavirus are the first things the immune system encounters that warn of an incoming coronavirus attack. Stimulation of the immune system with the telltale Spike protein, therefore, should be enough to enable the immune system to recognize the real virus right away. Furthermore, because the Spike protein helps the virus enter human cells, antibodies against it-which would work by binding and covering it up -should also help inhibit viral infection.

Knowing the sequence of the new coronavirus RNA was essential to designing an mRNA that would encode this viral Spike protein, but it was only a start. For one thing, the form of the Spike protein was not constant; as the virus fused with a human cell, the spikes of the crown would flip into a different shape. If the Spike protein specified by the mRNA vaccine under went this shapeshifting, the immune system might be trained to be on the lookout for the wrong shape. The antibodies that formed wouldn’t match the coronavirus’s spikes when it had just entered the body and when there was still time to prevent it from infecting us which would render the vaccine useless. The solution was to swap into the Spike protein sequence a pair of particularly inflexible amino acids called prolines- a trick that had been developed for the related MERS virus Spike protein- thereby locking the shape in place.

Sahin and Türeci also had to decide what codons to use to encode the Spike protein. This challenge would arise with any mRNA vaccine, not just Covid-19. Because of the “redundancy” of the genetic code-most amino acids can be specified by several codons- many trillions of possible combinations would encode the same protein. Some sequences, however, would be translated more efficiently than others. Sahin and Türeci’s experience working on mRNA cancer vaccines gave useful guidance, and they settled on 20 mRNA sequences to test.

But there were more questions to answer. How many doses would be required to effectively stimulate the immune system? How should their vaccine be stored, and at what temperature? How could they pos- sibly organize human clinical trials in short order? Here, a phone call to Pfizer’s head of vaccines, Kathrin Jansen, quickly brought Pfizer’s enormous vaccine experience into a partnership, to the benefit of both companies—and the world.

In November 2020, the directors of Pfizer Inc. were waiting in ner- vous anticipation. They were about to hear the results of the clinical trial of the mRNA vaccine they were developing with BioNTech. As the vac- cine’s 95 percent efficacy rate was announced, a collective gasp arose—and then the group erupted with applause and shouts of triumph. The board had been hoping for at least 70 percent efficacy, which would have been a public health success. That would have put the Covid-19 vaccine somewhere between the influenza (flu) vaccine (averaging 40 percent effective, with a year-to-year range of 10 to 60 percent) and the mea- sles vaccine (97 percent effective). Ninety-five percent was beyond most expectations. This conservative pharmaceutical company, which had a reputation for being risk-averse, had taken a bet on this unproven mRNA technology—and it had just paid off.

Similar celebrations were undoubtedly occurring in Mainz, as well as in Cambridge, Massachusetts, because the Moderna vaccine trials read out at about the same time and likewise revealed a 95 percent efficacy rate. Considering that BioNTech/Pfizer and Moderna worked inde- pendently and made many decisions differently-such as which codons to use to encode the Spike protein- it is rather amazing that they arrived at the finish line almost simultaneously and with similarly effective vac- cines. It had taken 30 years for mRNA therapeutics to evolve from being generally disparaged— “too unstable,” “too difficult to get into cells, ‘”t00 immunogenic”—to being heralded as “A shot to save the world.”

Excerpted from “The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets”. Copyright © 2024 by Thomas R. Cech. Used with permission of the publisher, W.W. Norton & Company. All rights reserved.