A Shot to Save the World is an interesting book about the development of the vaccines used to combat the COVID-19 pandemic. Although there were plenty of times where I questioned whether the author owned Moderna shares, given the amount of focus and narrative in the book surrounding that company.
The background history was also too long. Zuckerman went all the way back to the original vaccine to give a history of the COVID-19 vaccine. (And dedicated only half, or less than half, of the book to the actual pandemic.) I’m undecided if this was a good thing or not, as I learnt new things about HIV and the likes.
Perhaps it’s also Zuckerman’s WSJ background, but there were plenty of focus around the stock price of these pharmaceutical companies. I guess it’s important somewhat, in terms of resources available for these companies.
I also loved this incredible but scathing review on Goodreads.
Government scientists who followed Heckler to the podium were nearly as sanguine. They had history on their side: Traditionally, vaccines were how most epidemics ended. Indeed, few figures are as revered as those responsible for creating shots capable of wiping out plagues and disease.
Salk tried a different tack: He grew samples of the polio virus in his lab at the University of Pittsburgh and killed, or inactivated, the pathogen by adding formaldehyde, a method that had worked for vaccines for rabies and cholera. Salk tested his shots on thousands of children, and even his own family, showing in 1953 that they worked more than 60% of the time. His results sparked singing, dancing, and other celebrations throughout the US as a grateful nation embraced Salk as a hero, his image appearing on the front pages of newspapers, the covers of glossy magazines, and on television newscasts. Later, Salk’s bitter rival, Albert Sabin, introduced an oral polio vaccine based on a weakened, or attenuated, version of the virus, and it too proved effective. Together, the two vaccines effectively ended the scourge of polio for much of the world.
The human immune system features two lines of defence. A fast-acting, first-line “innate” immune system is composed of various white blood cells, such as macrophages, dendritic cells, and natural killer cells that stand guard at the body’s gateways—the skin, nose, throat, etc.—to detect and fend off viruses and other foreign invaders.
The innate immune system doesn’t need prior exposure to a pathogen to be activated against it, but it can have trouble handling especially powerful of clever pathogens. For these difficult battles, the body’s “adaptive” immune system joins the fight. Sensing danger, it sends other kinds of white blood cells, including T cells, which can recognise specific pathogens, and B lymphocytes, or B cells, which produce powerful antibodies to battle the pathogens.
T cells play important defensive roles, while B cells produce battalions of antibodies specifically trained to take on invaders. The problem is that the adaptive immune system is strong but a bit slow. It takes time deciding whether an invader is dangerous enough for it to send sufficient T cells and B cells to combat the intruder, giving a virus the opportunity to strengthen its hold and infect the body’s cells.
That’s where vaccines come in. Injected into the body’s bloodstream, traditional vaccines contain weakened or killed versions of what would otherwise be powerful pathogens. Once introduced into the body, the invading agents trigger the body’s adaptive immune system to pursue and disable them. The pathogen in the vaccine is harmless, but the body fights it off nonetheless, treating the weakling force as it it were a threatening army. The adaptive immune system, unable to shake memories of this simulated battle, continues to send antibodies to patrol for new signs of the pathogen, while training them to return to attack mode if there’s an invasion of a genuine foe bearing similarity to the one encountered as part of the vaccine.
HIV had an unusually high mutation rate and a devious ability to elude the immune system. Scientists concluded that it was just too dangerous to develop a vaccine using inactivated or watered-down versions of the lethal virus. They feared that if HIV was part of a vaccine, it might replicate uncontrollably or mutate into an even more virulent state. Concerns were heightened because so many of those suffering from the disease already had weakened immune systems.
Unlike most every other known virus, HIV exists as different genetic sequences in various people, and even within the same individual. The virus displays a devious ability to integrate into the host’s DNA, making it that much harder to eliminate. And HIV attacks the immune system itself, invading the very cells that normally fight dangerous pathogens. Once recognised, HIV changes its appearance, adopting a new coat almost hourly to continue its assault. When treated with drugs like AZT, the virus sometimes retreated, but it never fully cleared, remaining hidden in the body.
Still, a core group of scientists kept working on HIV, scoring under-the-radar advances they hoped might pay off, at least someday. Some of these accomplishments might sound obvious, even mundane, such as achieving a better understanding of the complex workings of the immune system and how it interacts with invading pathogens. In the past, though, this basic knowledge hadn’t always been necessary. For all their historic triumphs, vaccine pioneers often employed hit-or-miss approaches. Grab a piece of a pathogen, undertake repeated experiments to weaken or kill it, and try to find the right amount of the virus to use as the basis of a vaccine. Even Jonas Salk, Albert Sabin, and other vaccine heroes usually lacked a mastery of the diseases they were combating or even a full understanding of why their vaccines worked. They weren’t ashamed to acknowledge the huge role that serendipity or even dumb luck, played in their discoveries.
Merck scientists arrived at the idea of cloning genes for three key structural proteins found in HIV and inserting them into the genome of an adenovirus, which would ferry the vaccine into the body. Adenoviruses are common pathogens originally identified in 1953 in human tonsils, or adenoids, though they can be found in other tissues, too, including the guy, or even in animals. These viruses often result in bronchitis, conjunctivitis, or the common cold but generally don’t cause serious illness.
Using a virus to get a vaccine into the body was a clever move. Viruses are nature’s perfect delivery mechanism. Their whole reason for being is to enter the host’s body and replicate by putting their genes into its cells.
Adenoviruses seemed large enough for biologists to insert pieces of DNA into them, much like the insect baculoviruses Gale Smith liked to work with. With an adenovirus carrying a vaccine into the body’s cells and then making HIV proteins, the immune system would learn to identify these proteins and be ready to attack if HIV was ever encountered.
By the late 1980s, scientists had been studying genes—the physical entities containing DNA for nearly a century. They knew DNA molecules helped determine inheritable traits in all living things, from eye and hair colour to height and weight. They also understood that DNA is a passive molecule that resides in the cell’s nucleus. That knowledge led to a scientific conundrum: How exactly does DNA, stuck in the nucleus, make the proteins that keep us functioning, which are all created in an entirely different compartment of the cell, its cytoplasm?
In 1961, researches at CalTech found the answer when they discovered that another molecule, a kind of RNA called messenger ribonucleic acid, or mRNA, carries a copy of the DNA’s genetic instructions to the cytoplasm. There, the instructions are translated into collagen, insulin, antibodies, and millions of other tiny yet crucial proteins.
By that time, the way proteins were created was familiar to most anyone with even a passing familiarity with biology, thanks to the earlier advances: Within our cells, DNA is copied, or transcribed, into mRNA, which is translated into protein. DNA makes mRNA makes protein makes life; it’s a central dogma of science.
Wolff realised that DNA, which contains the basic building blocks of life, is akin to a cell’s cookbook. It’s full of recipes for making proteins, but it’s so thick and bulky that it has to be kept in the library—the cell’s nucleus—because it’s too heavy to transport. Wolff knew that strings of nucleotides found in the DNA create specific genes, such as those he was struggling to correct. But for any of the protein recipes in the cookbook to get made, the DNA first needs to be transcribed in the cell’s nucleus into mRNA molecules, which can be seen as temporary copies of a few pages from that heavy cookbook. This mRNA is then easily transported to the cytoplasm, which is akin to the cell’s kitchen. There, proteins are made, as instructed, before the mRNA is discarded, its job done.
But if the recipes in someone’s DNA are faulty, she could end up missing proteins, which too much or too little of a protein, or with a faulty protein, leading to the types of disease Wolff was trying to treat.
Scientists were beginning to appreciate that if DNA or mRNA could be delivered into the body’s cells, they could theoretically read the instructions and make the corresponding protein, potentially curing genetic disease. It was all part of a new potential method of treatment being described as gene therapy.
But hardly anyone was considering injecting straight, or “naked”, DNA, an exercise that likely was useless, if not dangerous. There’s a reason it’s a two-step process—DNA to MRNA to proteins. Within a cell, DNA has to be transcribed into mRNA before it can create useful proteins. It’s not easy getting DNA into a cell to begin the protein-creation process. Since DNA is a huge, negatively charged molecule, most researchers expected the cell’s membrane to block it from entering the cell. Besides, messing around with DNA, which is the body’s permanent instructions, seemed risky.
After moving within the cell to the cytoplasm and providing necessary instructions to create proteins, mRNA is usually degraded, broken down, in a matter of hours. Just as a spare tire can hold up on a short drive but will break down on an arduous cross-country trip, researchers agreed it was folly to expect mRNA to survive a solo trip into the cell, in the hope that it could produce sufficient proteins. Everyone knew that the moment mRNA was injected, it would come into contact with bodily fluids chock-full of enzymes that would immediately chop it up.
Recent advances had shown that by mixing DNA or mRNA with certain liquids or fatty lipids prior to adding them to cells, it was possible to induce the cells to absorb the DNA or mRNA. The lipid packaging seemed to protect these two nucleic acids, helping to carry the molecules and their genetic messages through the cell’s membrane. But most of the research had been done only on cells growing in a Petri dish.
But when Wolff directly injected DNA and mRNA into the leg muscles of mice, he found that they were actually successful in creating the desired proteins in the mice cells.
Wolff had demonstrated that a functional protein could be created by injecting DNA or mRNA into cells, something that had never before been done. The cell’s enzymes were chopping up most of the injected molecule, as expected, but it turned out that enough was slipping by the body’s defences to create a bit of protein. The fact that he could generate protein with notoriously unstable mRNA was especially startling to Wolff and others.
The immune system does a better job identifying and eliminating tumour cells than is widely presumed. Autopsy studies have shown that as many as 30% of men aged 55 or older who die in car accidents show evidence of cancer, and there is similar evidence that a large percentage of women also have cancer cells without realising it.
“Most of us, probably all of us, have cancer but don’t know it and never will,” Gilboa says. “There is strong circumstantial evidence that in many instances, it is the immune system that keeps it in check.”
She (Karikó) and Barnathan soon made impressive progress. Inserting mRNA into cells in a cell-culture dish, they managed to instruct the cells to make a protein called the urokinase receptor. For Karikó, the feeling was empowering. “It was like playing God,” she says.
DNA has two strands of nucleotides that wind around each other like a twisted ladder, making it durable. By contrast, mRNA is single-stranded and notoriously labile, or unstable, the reason so many found it hard to work with in the lab. Inside the cell, mRNA usually sticks around only a short while before it is effectively chopped up and eliminated as part of the cell’s natural turnover. And since many viruses use RNA as their genetic material, the body has developed elaborate methods to ward off the molecule.
Anyone who dared work with mRNA in the lab knew it was an absolute nightmare. Researchers had to wear gloves just to touch equipment coming in contact with the molecule because enormous amounts of RNases exist on our skin. Just breathing on the instruments made them unusable for mRNA. Glassware used to study the molecule had to be baked in such high heat to destroy the RNases that accidents sometimes resulted. Once a Duke University assistant professor engulfed part of her department in fire—including her department chair’s office—while preparing pipettes in a 500 degree oven so they could be used with mRNA. For an academic hoping for tenure, it wasn’t the savviest career move.
To her (Karikó), mRNA was the perfect molecule—it only needed to get into the cell’s cytoplasm to create proteins, not all the way into the nucleus, like DNA. She agreed that mRNA was a short-lived molecule, but she thought that might be a good thing. Many illnesses and ailments didn’t seem to require the introduction of new genes, which can produce permanent changes in the body, as her colleagues were hoping to do with DNA. Sometimes, the body just needs a short-term boost or improvement, not a long-term alteration.
Back when Karikó and Weissman were putting mRNA in cells in tissue culture in the lab, they didn’t have to worry about the immune system fighting back. Now that they were injecting it in animals, though, they were setting off inflammatory cytokines, signs that they were inadvertently activating the first line of defence against invading pathogens. It was as if mice cells were so threatened by the injected molecule and its genetic instructions that they were damaging themselves to avoid having anything to do with it.
They noticed an intriguing pattern: The more that the nucleosides of the RNA were modified from their inherent structure, the less they activated the immune system of the cells; the less they were altered, the more they set off the immune system, a surprising, inverse correlation. It dawned on the researchers that when mRNA was modified, either naturally or in the lab, it was able to skirt the dreaded cell receptors, which act as the immune system’s sentries, thereby avoiding inflammation.
After doing some experimenting, they realized that whenever one of the building blocks for RNA, a ribonucleoside called uridine, was present in the mRNA, it triggered an immune reaction. But when nature for whatever reason adjusted the uridine, turning it into a slightly different form called pseudouridine, the cell’s immune system ignored the mRNA. They wondered: Could the secret to evading the immune system be as simple as swapping uridine for pseudouridine?
To test their theory, Karikó and Weissman created their own slightly modified version of mRNA, one that relied on pseudouridine, which scientists abbreviate with a code Ψ, instead of the usual uridine, or U. They also replaced another nucleoside, cytidine, with 5-methylcytidine. They injected their revamped molecule into mice and were shocked by what they saw: There was no sign of inflammation or other immune response, the exact result they were hoping for. The tweaked mRNA appeared innocuous to the mice’s defences, possibly because the mRNA of viruses and other invaders have few, if any, modifications, so the new, modified mRNA was perceived as self-created and therefore harmless.
Kyoto University, and one of his graduate students had astonished the scientific world by placing genes in retroviruses—viruses that invade host cells and integrate their genomes into the DNA of those cells—to reprogram adult cells. Yamanaka had used this technique to create “pluripotent” forms of the cells, which act much like embryonic stem cells. Yamanaka had, in effect, reverted the cells to their primitive state, turning the clock back on time.
The discovery changed the way scientists viewed cell identity and how fixed it truly was.
Embryonic stem cells are prized for their ability to turn into almost any kind of cell, making them valuable for various medical treatments. But because they’re usually harvested from embryos discarded during in vitro fertilization treatments, they have long been subject to intense criticism from those who believe embryos should be off-limits to medical experiments.
Yamanaka’s work, which earned him a Nobel Prize in 2012, raised the tantalizing prospect of sidestepping such controversy by allowing scientists to use these so-called induced pluripotent stem cells, or iPS cells, rather than embryonic cells. Yamanaka’s method also promised to produce cells and tissues that could be transplanted without the risk of rejection.
Using mRNA for drugs would also mean developing the same fast process each time, relying on a specific sequence of genetic code and cheap enzymes to produce each protein, thereby avoiding the enormous costs that come with building factories and dealing with cells for traditional medicines. DNA wouldn’t be directly involved so there wouldn’t be a risk of causing mutations that cause cancer, as with gene therapy. And the mRNA approach was so new and unique it likely wouldn’t infringe on existing patents, meaning almost every kind of medicine could be produced without legal troubles from drugmakers. Best of all: If patients can make proteins for themselves, it would be like having a medicine factory in their own bodies.
Scientists had long struggled to find the perfect packaging for mRNA molecules. During the 1970s, Bob Langer, the Moderna cofounder, was among those who had helped pioneer early approaches to delivering large molecules, like DNA and RNA, overcoming deep skepticism from academics and others who were sure they were too big and fragile to make the journey from outside the body to the inside of a human cell. Langer and the others developed ways to wrap nucleic acids in tiny particles, including tiny polymer or lipid particles, which protected them from destruction by the body’s enzymes.
Their work helped lay the foundation for a company called Alnylam Pharmaceuticals, which in the 2000s managed to get RNA molecules into cells in LNPs. Alnylam succeeded in shutting off unhealthy gene expression, something called RNA interference, an important early sign of the benefits of LNPs. Later, a Canadian company invented a different kind of lipid encasement that did a good job shielding mRNA, a technology that Moderna had licensed.
But all LNP packaging, including the one from the Canadians, can generate problematic reactions as lipids accumulate in injection sites, something the Moderna team was now realising.
What Smith really wanted to do was create shots that could stop emerging diseases and pandemics. He was developing virus-like particles, or molecules intended to look like a virus and its key proteins, as a vaccine to teach the body’s immune system to recognize and later repel these signs of danger. In some ways, his strategy was similar to those of traditional vaccine makers, because he was injecting viral proteins into the body. But his were recombinant proteins, or those created in his lab to look like the real thing but not be infectious. Recombinant proteins were being used to produce all kinds of drugs, and Merck had already used this approach to develop a vaccine for HPV. Smith was convinced he could produce similar shots for viruses.
Bancel canceled plans to attend a board meeting in Germany and bought a one-way flight to Washington, D.C. At eight a.m. on Monday morning, January 27, Bancel walked into a conference room on the seventh floor of the National Institute of Allergy and Infectious Disease’s headquarters. He pulled up a leather chair at a long, faux-wooden table, across from Graham, Mascola, and Anthony Fauci, the NIAID’s director.
Within minutes, Fauci and his colleagues said they were just as intent on swiftly starting a phase 1 clinical trial for their vaccine. The whole reason the NIH had started working with Moderna was because mRNA shots can be designed and produced faster than those based on older technologies, which usually require growing a virus in eggs or a protein in enormous vats of cells, processes that can take months. In fact, Fauci needed to be convinced that Moderna wasn’t going to drag its feet.
“How quickly can you get into clinic?” Fauci asked, referring to a phase 1 trial, the first step to testing a vaccine.
“Sixty days,” Bancel replied confidently.
The meeting ended on an optimistic note. The NIH and Moderna would do everything they could to prevent impending horror. Bancel said he just needed to confirm the plans with his executive team.
In late February, Bancel convened a meeting with about thirty top Moderna executives in a ninth-floor conference room. By then, the company had shipped its first batch of Covid-19 vaccines, called mRNA-1273, to Corbett, the NIH scientist, to begin testing in mice. Within weeks, early results showed it elicited antibodies to the coronavirus, a promising, albeit early, sign.
If Pfizer was going to have an impact, the company would need to move quickly, Bourla told his team. He wanted a vaccine by October, a timetable that startled some of the scientists. Bourla had an idea to speed up their work: What if the various steps necessary to develop a vaccine could be done simultaneously, rather than sequentially? In other words, the research, trials, manufacturing, and distribution of a Covid-19 vaccine would be done in parallel, instead of waiting to see success after each phase. Perhaps that would allow Pfizer and BioNTech to produce a vaccine in months, rather than years? The cost would be high, but he said it was worth it.
“If we go in, we go all in,” Bourla told them.”
Vaccines, like drugs, need to be proven both safe and effective. After regulators sign off on a new-vaccine application, which can include preclinical animal studies, human trials begin—phase 1 trials to demonstrate safety, and phase 2 and phase 3 trials, involving a higher number of participants and randomised control groups, to prove effectiveness and that side effects are manageable.
Since the Oxford group was pretty certain its vaccine was safe, they proposed plans to combine phases 1 and 2 to speed things up, a schedule British regulators approved. The scientists also made plans to accelerate phase 3 human trials. Their trial design meant that they could quickly collect data on their Covid-19 vaccine’s safety, side effects, and the ideal dosage, and then see if their shots could trigger an immune-system response and were efficacious, all in a record-breaking length of time.
Novavax’s vaccine injected a synthesized, slightly modified version of the spike protein, using Jason McLellan’s two prolines to keep it stable. Novavax’s shots simply asked the body’s immune system to recognize the protein as a foreign invader and attack it if the protein were to be encountered down the line as part of an actual virus.