The company plans to leverage its expansive retail footprint of 9,000 stores, as well as its pharmacy business and other care delivery assets, to connect patients with late-stage pharmaceutical trials either at retail clinics, at home, or virtually. To match patients with trials, Walgreens is partnering with health data company Pluto Health, which aggregates information across medical records, insurance claims, and other sources.
The Gist: The decentralized clinical trial business has been growing since the pandemic spurred a rapid switch to remote trial participation. This announcement comes roughly a year after competitor CVS announced its entry into the clinical trial space.
Most clinical research is centered in academic medical centers, which are disproportionally located in large urban areas, forcing many patients to travel long distances to participate. With large amounts of patient data and footprint spanning all fifty states, retail pharmacies are well-positioned to partner with investigators to reach patients who lack access to clinical trials today, given lack of financial resources or ability to travel.
CVS Health announced it has struck a deal with Medable, a decentralized clinical trial software company, incorporating its offerings into MinuteClinics to help reach more patients for late-stage clinical trials. With over 40 percent of Americans living near a CVS pharmacy, CVS says it can help gather data and manage patients at MinuteClinic locations, and through its home infusion service, Coram. CVS has already cut its teeth in the clinical research space by conducting COVID-19 vaccine and treatment trials and testing home dialysis machines, and said it plans to engage 10M patients and open up to 150 community research sites this year.
The Gist: With this deal, CVS Health joins companies like Verily, Alphabet’s life sciences subsidiary, in taking advantage of patient appetite for clinical trials without regularly traveling to a research center, which became difficult during the pandemic.
Clinical research is a $50B market that has largely revolved around academic medical centers in large urban areas, which could see their dominance of the research business challenged. CVS’s entry into this space could lower the barriers to entry for community health systems to expand into clinical research.
Ultimately, the decentralization of the clinical trials business is a win for patients, especially groups that have historically been under-represented in medical research, including rural and lower-income individuals. They may find participation through a local pharmacy—or even completely virtually from the comfort of their own home—much more accessible, affordable, and convenient.
Even as daily new COVID cases set all-time records and hospitals fill up, epidemiologists have arrived at a perhaps surprising consensus. Yes, the latest Omicron variant of the novel coronavirus is bad. But it could have been a lot worse.
Even as cases have surged, deaths haven’t—at least not to the same degree. Omicron is highly transmissible but generally not as severe as some older variants—“lineages” is the scientific term.
We got lucky. But that luck might not hold. Many of the same epidemiologists who have breathed a sigh of relief over Omicron’s relatively low death rate are anticipating that the next lineage might be much worse.
Fretting over a possible future lineage that combines Omicron’s extreme transmissibility with the severity of, say, the previous Delta lineage, experts are beginning to embrace a new public health strategy that’s getting an early test run in Israel: a four-shot regimen of messenger-RNA vaccine.
“I think this will be the strategy going forward,” Edwin Michael, an epidemiologist at the Center for Global Health Infectious Disease Research at the University of South Florida, told The Daily Beast.
Omicron raised alarms in health agencies all over the world in late November after officials in South Africa reported the first cases. Compared to older lineages, Omicron features around 50 key mutations, some 30 of which are on the spike protein that helps the virus to grab onto our cells.
Some of the mutations are associated with a virus’s ability to dodge antibodies and thus partially evade vaccines. Others are associated with higher transmissibility. The lineage’s genetic makeup pointed to a huge spike in infections in the unvaccinated as well as an increase in milder “breakthrough” infections in the vaccinated.
That’s exactly what happened. Health officials registered more than 10 million new COVID cases the first week of January. That’s nearly double the previous worst week for new infections, back in May. Around 3 million of those infections were in the United States, where Omicron coincided with the Thanksgiving, Christmas, and New Year holidays and associated traveling and family gatherings.
But mercifully, deaths haven’t increased as much as cases have. Worldwide, there were 43,000 COVID deaths the first week of January—fewer than 10,000 of them in the U.S. While deaths tend to lag infections by a couple weeks, Omicron has been dominant long enough that it’s increasingly evident there’s been what statisticians call a “decoupling” of cases and fatalities.
“We can say we dodged a bullet in that Omicron does not appear to cause as serious of a disease,” Stephanie James, the head of a COVID testing lab at Regis University in Colorado, told The Daily Beast. She stressed that data is still being gathered, so we can’t be certain yet that the apparent decoupling is real.
Assuming the decoupling is happening, experts attribute it to two factors. First, Omicron tends to infect the throat without necessarily descending to the lungs, where the potential for lasting or fatal damage is much, much higher. Second, by now, countries have administered nearly 9.3 billion doses of vaccine—enough for a majority of the world’s population to have received at least one dose.
In the United States, 73 percent of people have gotten at least one dose. Sixty-two percent have gotten two doses of the best mRNA vaccines. A third have received a booster dose.
Yes, Omicron has some ability to evade antibodies, meaning the vaccines are somewhat less effective against this lineage than they are against Delta and other older lineages. But even when a vaccine doesn’t prevent an infection, it usually greatly reduces its severity.
For many vaccinated people who’ve caught Omicron, the resulting COVID infection is mild. “A common cold or some sniffles in a fully vaxxed and boosted healthy individual,” is how Eric Bortz, a University of Alaska-Anchorage virologist and public health expert, described it to The Daily Beast.
All that is to say, Omicron could have been a lot worse. Viruses evolve to survive. That can mean greater transmissibility, antibody-evasion or more serious infection. Omicron mutated for the former two. There’s a chance some future Sigma or Upsilon lineage could do all three.
When it comes to viral mutations, “extreme events can occur at a non-negligible rate, or probability, and can lead to large consequences,” Michael said. Imagine a lineage that’s as transmissible as Omicron but also attacks the lungs like Delta tends to do. Now imagine that this hypothetical lineage is even more adept than Omicron at evading the vaccines.
That would be the nightmare lineage. And it’s entirely conceivable it’s in our future. There are enough vaccine holdouts, such as the roughly 50 million Americans who say they’ll never get jabbed, that the SARS-CoV-2 pathogen should have ample opportunities for mutation.
“As long as we have unvaccinated people in this country—and across the globe—there is the potential for new and possibly more concerning viral variants to arise,” Aimee Bernard, a University of Colorado immunologist, told The Daily Beast.
Worse, this ongoing viral evolution is happening against a backdrop of waning immunity. Antibodies, whether vaccine-induced or naturally occurring from past infection, fade over time. It’s not for no reason that health agencies in many countries urge booster doses just three months after initial vaccination. The U.S. Centers for Disease Control and Prevention is an outlier, and recommends people get boosted after five months.
A lineage much worse than Omicron could evolve at the same time that antibodies wane in billions of people all over the world. That’s why many experts believe the COVID vaccines will end up being annual or even semi-annual jabs. You’ll need a fourth jab, a fifth jab, a sixth jab, et cetera, forever.
Israel, a world leader in global health, is already turning that expectation into policy. Citing multiple studies that showed a big boost in antibodies with an additional dose of mRNA and no safety concerns, the country’s health ministry this week began offering a fourth dose to anyone over the age of 60, who tend to be more vulnerable to COVID than younger people.
That should be the standard everywhere, Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, told The Daily Beast. “Scientifically, they’re right,” he said of the Israeli health officials.
If there’s a downside, it’s that there are still a few poorer countries—in Africa, mostly—where many people still struggle to get access to any vaccine, let alone boosters and fourth doses. If and when other richer countries follow Israel’s lead and begin offering additional jabs, there’s some risk of even greater inequity in global vaccine distribution.
“The downside is for the rest of the world,” Mokdad said. “I’m waiting to get my first dose and you guys are getting a fourth?”
The solution isn’t to deprive people of the doses they need to maintain their protection against future—and potentially more dangerous—lineages. The solution, for vaccine-producing countries, is to further boost production and double down on efforts to push vaccines out to the least privileged communities.
A sense of urgency is key. For all its rapid spread, Omicron has actually gone fairly easy on us. Sigma or Upsilon might not.
Scientists at UCL National Amyloidosis Centre at the Royal Free Hospital, London are hoping their gene editing therapy using CRISPR will be a breakthrough for patients suffering from hereditary transthyretin (ATTR) amyloidosis. In a phase 1 clinical trial, the first six patients have shown positive interim results for gene-editing treatment.
The CRISPR breakthrough comes in treating transthyretin amyloidosis, a mutation in the transthyretin (TTR) gene. Those with this mutation produce an abnormal protein, which gradually builds up in the heart and nerves. Symptoms can include numbness in the hands and feet, loss of control of the bowel and bladder, and loss of mobility.
Hereditary transthyretin amyloidosis gets progressively worse and is fatal. Up until this point, most of the treatment options available to patients have included management of the symptoms and prevention of progression.
Those taking part in the trial have received a molecule knows as CRISPR/Cas9 via one-off infusion. The purpose of this is to deactivate the incorrect gene within the liver cell.
“With the gene no longer active in the liver, it is expected that the patient will only produce negligible levels of the harmful transthyretin protein,” UCL stated in a press release.
Scientists saw in the first six patients a reduced production of the harmful transthyretin protein by up to 96 percent, 28 days after the treatment. Additionally, there were no serious adverse effects witnessed. This data was published in the New England Journal of Medicine.
“As the trial progresses, patients will be given higher doses of the gene editing therapy with the hope that will drive the levels of toxic protein even lower,” UCL explained.
CRISPR/Cas9, a Nobel Prize-winning technology, has been used to edit cells outside the body in the past. However, UCL is presenting the first clinical data which CRISPR/Cas9 is being used as medicine itself for a potential therapy.
“This is wonderful news for patients with this condition. If this trial continues to be successful, the treatment may permit patients who are diagnosed early in the course of the disease to lead completely normal lives without the need for ongoing therapy,” Professor Julian Gillmore, the trial lead, of the UCL National Amyloidosis Centre, part of the UCL Centre for Amyloidosis and Acute Phase Proteins said in a press release.
“Until very recently, the majority of treatments we have been able to offer patients with this condition have had limited success. If this trial continues to go well, it will mean we can offer real hope and the prospect of meaningful clinical improvement to patients who suffer from this condition,” Gillmore continued.
The global trial includes patients from the Royal Free London and a hospital located in Auckland, New Zealand. The investigational therapy, designated NTLA-2001, is being developed by Intellia Therapeutics; a biotechnology company based in the United States.
This could be a big step forward in using CRISPR as gene therapy. Typically, the therapy is injected into the site of illness. However, this newest approach injects CRISPR directly into the bloodstream, which could revolutionize how clinicians treat certain illnesses.
There’s a lot of anxiety about the AstraZeneca vaccine thanks to recent reports of incomplete data, as well as reports on blood clot risks. Let’s take a look at both issues in context, understanding the efficacy data before and after numbers were updated, and understanding blood clot risk in relation to other common situations where blood clots are a potential concern.
In this last episode of our six-part series on vaccinations, supported by the National Institute for Health Care Management Foundation, we cover vaccine development – particularly in the context of the current global pandemic. We discuss the timeline of Covid-19 vaccine development and the mRNA vaccine approach.
A new piece in the Atlantic sparked debate this week about the risk of ongoing COVID exposure to children as the country navigates toward the end of the pandemic. Brown University economist Emily Oster equated a child’s risk of serious illness from the coronavirus to that of their vaccinated grandmother. If grandma receives the Pfizer vaccine, her risk of serious illness is decreased by 95 percent. According to Oster, the condition of “being a child” aged 0-17 is 98 percent protective against hospitalization—so go ahead, plan that family summer vacation!
Oster cites no clinical or scientific experts in her piece, but some doctors were quick to respond that the comparisons are not equivalent (and also provide ready-made scripting for the “anti-vaxx” movement, which could claim that kids are already “basically vaccinated”).
But the article does bring up a real question that millions of families will soon face: what can we do when grandma and grandpa (and hopefully mom and dad) are vaccinated, but the kids are not? Given the pace of clinical trials, teens could be eligible for vaccination as soon as late summer, but COVID vaccines might not be approved for younger children until months later—and this generational vaccine divide will likely linger into 2022.
Undoubtedly children are at lower risk from COVID than adults, and likely transmit the disease less frequently (although much of the data supporting the latter comes from studies in schools, where social distancing and masking are enforced). And we’re not out of the woods yet: as COVID cases surge again in Michigan, schools there have seen a spike in outbreaks as well.
As families look at conflicting data and messages in the media, they need clear, coordinated guidance from state and federal officials to help them gauge safety as they navigate their second “pandemic summer”.
The national COVID indicators all continued to move in the right direction this week, with new cases down 16 percent, hospitalizations down 26 percent, and deaths (while still alarmingly high at more than 3,000 per day) down 6 percent from the week prior.
More good news: both nationally and globally, the number of people vaccinated against COVID now exceeds the total number of people infected with the virus, at least according to official statistics—the actual number of coronavirus infections is likely several times higher.
On the vaccine front, Johnson & Johnson filed with the Food and Drug Administration (FDA) for an Emergency Use Authorization for its single-dose COVID vaccine, which could become the third vaccine approved for use in the US following government review later this month. The J&J vaccine is reportedly 85 percent effective at preventing severe COVID disease, although it is less effective at preventing infection than the Pfizer and Moderna shots.
Elsewhere, TheLancet reported interim Phase III results for Russia’s Sputnik V vaccine trials, showing it to be 91 percent effective at preventing infection, and a new study found the Oxford-AstraZeneca vaccine to be 75 percent effective against the more-contagious UK virus variant.
Amid the positive vaccine news, the Biden administration moved to accelerate the vaccination campaign, invoking the Defense Production Act to boost production and initiating shipments directly to retail pharmacies. With the House and Senate starting the budget reconciliation process that could eventually lead to as much as $1.9T in stimulus funding, including billions more for vaccines and testing, it feels as though the tide may be finally turning in the battle against coronavirus.
While the key indicators are still worrisome—we’re only back to Thanksgiving-week levels of new cases—and emerging variants are cause for concern, it’s worth celebrating a week that brought more good news than bad.
Best to follow Dr. Fauci’s advice for this Super Bowl weekend, however: “Just lay low and cool it.”
Anti-inflammatory oral drug colchicine improved COVID-19 outcomes for patients with relatively mild cases, according to certain topline results from the COLCORONA trial announced in a brief press release.
Overall, the drug used for gout and rheumatic diseases reduced risk of death or hospitalizations by 21% versus placebo, which “approached statistical significance.”
However, there was a significant effect among the 4,159 of 4,488 patients who had their diagnosis of COVID-19 confirmed by a positive PCR test:
25% fewer hospitalizations
50% less need for mechanical ventilation
44% fewer deaths
If full data confirm the topline claims — the press release offered no other details, and did not mention plans for publication or conference presentation — colchicine would become the first oral drug proven to benefit non-hospitalized patients with COVID-19.
“Our research shows the efficacy of colchicine treatment in preventing the ‘cytokine storm’ phenomenon and reducing the complications associated with COVID-19,” principal investigator Jean-Claude Tardif, MD, of the Montreal Heart Institute, said in the press release. He predicted its use “could have a significant impact on public health and potentially prevent COVID-19 complications for millions of patients.”
Currently, the “tiny list of outpatient therapies that work” for COVID-19 includes convalescent plasma and monoclonal antibodies, which “are logistically challenging (require infusions, must be started very early after symptom onset),” tweeted Ilan Schwartz, MD, PhD, an infectious diseases researcher at the University of Alberta in Edmonton.
The COLCORONA findings were “very encouraging,” tweeted Martin Landray, MB ChB, PhD, of the Big Data Institute at the University of Oxford in England. His group’s RECOVERY trial has already randomized more than 6,500 hospitalized patients to colchicine versus usual care as one of the arms of the platform trial, though he did not offer any findings from that study.
“Different stage of disease so remains an important question,” he tweeted. “Maybe old drugs can learn new tricks!” Landray added, pointing to dexamethasone.
“I think this is an exciting time. Many groups have been pursuing lots of different questions related to COVID and its complications,” commented Richard Kovacs, MD, immediate past-president of the American College of Cardiology. “We’re now beginning to see the fruit of those studies.”
COLCORONA was conducted remotely, without in-person contact, with participants across Canada, the U.S., Europe, South America, and South Africa. It randomized participants double-blind to colchicine 0.5 mg or a matching placebo twice daily for the first 3 days and then once daily for the last 27 days.
Participants were ages 40 and older, not hospitalized at the time of enrollment, and had at least one risk factor for COVID-19 complications: age 70-plus, obesity, diabetes, uncontrolled hypertension, known asthma or chronic obstructive pulmonary disease, known heart failure, known coronary disease, fever of ≥38.4°C (101.12°F) within the last 48 hours, dyspnea at presentation, or certain blood cell abnormalities.
It had been planned as a 6,000-patient trial, but whether it was stopped for efficacy at a preplanned interim analysis or for some other reason was not spelled out in the press release. Whether the PCR-positive subgroup was preplanned also wasn’t clear. Key details such as confidence intervals, adverse effects, and subgroup results were omitted as well.
While a full manuscript is reportedly underway, “we don’t know enough to bring this into practice yet,” argued Kovacs.
Some physicians also warned about the potential for misuse of the findings and attendant risks.
Dhruv Nayyar, MD, of the University of Toronto, tweeted that he has already had “patients inquiring why we are not starting colchicine for them. Science by press release puts us in a difficult position while providing care. I just want to see the data.”
Angela Rasmussen, MD, a virologist with the Georgetown Center for Global Health Science and Security’s Viral Emergence Research Initiative in Washington, agreed, tweeting:“When HCQ [hydroxychloroquine] was promoted without solid data, there was at least one death from an overdose. We don’t need people self-medicating with colchicine.”
As was the case with hydroxychloroquine before the papers proved little efficacy in COVID-19, Kovacs told MedPage Today: “We always get concerned when these drugs are repurposed that we might see an unintended run on the drug and lessen the supply.”
Citing the well-known diarrheal side effect of colchicine, infectious diseases specialist Edsel Salvana, MD, of the University of Pittsburgh and University of the Philippines in Manila, tweeted a plea for use only in the trial-proven patient population with confirmed COVID-19 — not prophylaxis.
The dose used was on par with that used in cardiovascular prevention and other indications, so the diarrhea incidence would probably follow the roughly 10% rate seen in the COLCOT trial, Kovacs suggested.
In the clinic, too, there are some cautions. As Elin Roddy, MD, a respiratory physician at Shrewsbury and Telford Hospital NHS Trust in England, tweeted: “Lots of drug interactions with colchicine potentially — statins, macrolides, diltiazem — we have literally been running up to the ward to cross off clarithromycin if RECOVERY randomises to colchicine.”
I had been staring her in the eyes, as she had ordered, but when a doctor on my other side began jabbing me with a needle, I started to turn my head. “Don’t look at it,” the first doctor said. I obeyed.
This was in early August in New Orleans, where I had signed up to be a participant in the clinical trial for the Pfizer-BioNTech COVID-19 vaccine. It was a blind study, which meant I was not supposed to know whether I had gotten the placebo or the real vaccine. I asked the doctor if I would really been able to tell by looking at the syringe. “Probably not,” she answered, “but we want to be careful. This is very important to get right.”
I became a vaccine guinea pig because, in addition to wanting to be useful, I had a deep interest in the wondrous new roles now being played by RNA, the genetic material that is at the heart of new types of vaccines, cancer treatments and gene-editing tools. I was writing a book on the Berkeley biochemist Jennifer Doudna. She was a pioneer in determining the structure of RNA, which helped her and her doctoral adviser figure out how it could be the origin of all life on this planet. Then she and a colleague invented an RNA-guided gene-editing tool, which won them the 2020 Nobel Prize in Chemistry.
The tool is based on a system that bacteria use to fight viruses. Bacteria develop clustered repeated sequences in their DNA, known as CRISPRs, that can remember dangerous viruses and then deploy RNA-guided scissors to destroy them. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses—just what we humans need. Now, with the recently approved Pfizer-BioNTech vaccine and a similar one from Moderna being slowly rolled out across the U.S. and Europe, RNA has been deployed to make a whole new type of vaccine that will, when it reaches enough people, change the course of the pandemic.
Up until last year, vaccines had not changed very much, at least in concept, for more than two centuries. Most have been modeled on the discovery made in 1796 by the English doctor Edward Jenner, who noticed that many milkmaids were immune to smallpox. They had all been infected by a form of pox that afflicts cows but is relatively harmless to humans, and Jenner surmised that the cowpox had given them immunity to smallpox. So he took some pus from a cowpox blister, rubbed it into scratches he made in the arm of his gardener’s 8-year-old son and then (this was in the days before bioethics panels) exposed the kid to smallpox. He didn’t become ill.
Before then, inoculations were done by giving patients a small dose of the actual smallpox virus, hoping that they would get a mild case and then be immune. Jenner’s great advance was to use a related but relatively harmless virus. Ever since, vaccinations have been based on the idea of exposing a patient to a safe facsimile of a dangerous virus or other germ. This is intended to kick the person’s adaptive immune system into gear. When it works, the body produces antibodies that will, sometimes for many years, fend off any infection if the real germ attacks.
One approach is to inject a safely weakened version of the virus. These can be good teachers, because they look very much like the real thing. The body responds by making antibodies for fighting them, and the immunity can last a lifetime. Albert Sabin used this approach for the oral polio vaccine in the 1950s, and that’s the way we now fend off measles, mumps, rubella and chicken pox.
At the same time Sabin was trying to develop a vaccine based on a weakened polio virus, Jonas Salk succeeded with a safer approach: using a killed or inactivated virus. This type of vaccine can still teach a person’s immune system how to fight off the live virus but is less likely to cause serious side effects. Two Chinese companies, Sinopharm and Sinovac, have used this approach to develop vaccines for COVID-19 that are now in limited use in China, the UAE and Indonesia.
Another traditional approach is to inject a subunit of the virus, such as one of the proteins that are on the virus’s coat. The immune system will then remember these, allowing the body to mount a quick and robust response when it encounters the actual virus. The vaccine against the hepatitis B virus, for example, works this way. Using only a fragment of the virus means that they are safer to inject into a patient and easier to produce, but they are often not as good at producing long-term immunity. The Maryland-based biotech Novavax is in late-stage clinical trials for a COVID-19 vaccine using this approach, and it is the basis for one of the two vaccines already being rolled out in Russia.
The plague year of 2020 will be remembered as the time when these traditional vaccines were supplanted by something fundamentally new:genetic vaccines, which deliver a gene or piece of genetic code into human cells. The genetic instructions then cause the cells to produce, on their own, safe components of the target virus in order to stimulate the patient’s immune system.
For SARS-CoV-2—the virus that causes COVID-19—the target component is its spike protein, which studs the outer envelope of the virus and enables it to infiltrate human cells. One method for doing this is by inserting the desired gene, using a technique known as recombinant DNA, into a harmless virus that can deliver the gene into human cells. To make a COVID vaccine, a gene that contains instructions for building part of a coronavirus spike protein is edited into the DNA of a weakened virus like an adenovirus, which can cause the common cold. The idea is that the re-engineered adenovirus will worm its way into human cells, where the new gene will cause the cells to make lots of these spike proteins. As a result, the person’s immune system will be primed to respond rapidly if the real coronavirus strikes.
This approach led to one of the earliest COVID vaccine candidates, developed at the aptly named Jenner Institute of the University of Oxford. Scientists there engineered the spike-protein gene into an adenovirus that causes the common cold in chimpanzees, but is relatively harmless in humans.
The lead researcher at Oxford is Sarah Gilbert. She worked on developing a vaccine for Middle East respiratory syndrome (MERS) using the same chimp adenovirus. That epidemic waned before her vaccine could be deployed, but it gave her a head start when COVID-19 struck. She already knew that the chimp adenovirus had successfully delivered into humans the gene for the spike protein of MERS. As soon as the Chinese published the genetic sequence of the new coronavirus in January 2020, she began engineering its spike-protein gene into the chimp virus, waking each day at 4 a.m.
Her 21-year-old triplets, all of whom were studying biochemistry, volunteered to be early testers, getting the vaccine and seeing if they developed the desired antibodies. (They did.) Trials in monkeys conducted at a Montana primate center in March also produced promising results.
Bill Gates, whose foundation provided much of the funding, pushed Oxford to team up with a major company that could test, manufacture and distribute the vaccine. So Oxford forged a partnership with AstraZeneca, the British-Swedish pharmaceutical company. Unfortunately, the clinical trials turned out to be sloppy, with the wrong doses given to some participants, which led to delays. Britain authorized it for emergency use at the end of December, and the U.S. is likely to do so in the next two months.
Johnson & Johnson is testing a similar vaccine that uses a human adenovirus, rather than a chimpanzee one, as the delivery mechanism to carry a gene that codes for making part of the spike protein. It’s a method that has shown promise in the past, but it could have the disadvantage that humans who have already been exposed to that adenovirus may have some immunity to it. Results from its clinical trial are expected later this month.
In addition, two other vaccines based on genetically engineered adenoviruses are now in limited distribution: one made by CanSino Biologics and being used on the military in China and another named Sputnik V from the Russian ministry of health.
There is another way to get genetic material into a human cell and cause it to produce the components of a dangerous virus, such as the spike proteins, that can stimulate the immune system. Instead of engineering the gene for the component into an adenovirus, you can simply inject the genetic code for the component into humans as DNA or RNA.
Let’s start with DNA vaccines. Researchers at Inovio Pharmaceuticals and a handful of other companies in 2020 created a little circle of DNA that coded for parts of the coronavirus spike protein. The idea was that if it could get inside the nucleus of a cell, the DNA could very efficiently churn out instructions for the production of the spike-protein parts, which serve to train the immune system to react to the real thing.
The big challenge facing a DNA vaccine is delivery.How can you get the little ring of DNA not only into a human cell but into the nucleus of the cell? Injecting a lot of the DNA vaccine into a patient’s arm will cause some of the DNA to get into cells, but it’s not very efficient.
Some of the developers of DNA vaccines, including Inovio, tried to facilitate the delivery into human cells through a method called electroporation, which delivers electrical shock pulses to the patient at the site of the injection. That opens pores in the cell membranes and allows the DNA to get in. The electric pulse guns have lots of tiny needles and are unnerving to behold. It’s not hard to see why this technique is unpopular, especially with those on the receiving end. So far, no easy and reliable delivery mechanism has been developed for getting DNA vaccines into the nucleus of human cells.
That leads us to the molecule that has proven victorious in the COVID vaccine race and deserves the title of TIME magazine’s Molecule of the Year: RNA. Its sibling DNA is more famous. But like many famous siblings, DNA doesn’t do much work. It mainly stays bunkered down in the nucleus of our cells, protecting the information it encodes. RNA, on the other hand, actually goes out and gets things done. The genes encoded by our DNA are transcribed into snippets of RNA that venture out from the nucleus of our cells into the protein-manufacturing region. There, this messenger RNA (mRNA) oversees the assembly of the specified protein. In other words, instead of just sitting at home curating information, it makes real products.
Scientists including Sydney Brenner at Cambridge and James Watson at Harvard first identified and isolated mRNA molecules in 1961. But it was hard to harness them to do our bidding, because the body’s immune system often destroyed the mRNA that researchers engineered and attempted to introduce into the body. Then in 2005, a pair of researchers at the University of Pennsylvania, Katalin Kariko and Drew Weissman, showed how to tweak a synthetic mRNA molecule so it could get into human cells without being attacked by the body’s immune system.
When the COVID-19 pandemic hit a year ago, two innovative young pharmaceutical companies decided to try to harness this role played by messenger RNA: the German company BioNTech, which formed a partnership with the U.S. company Pfizer; and Moderna, based in Cambridge, Mass. Their mission was to engineer messenger RNA carrying the code letters to make part of the coronavirus spike protein—a string that begins CCUCGGCGGGCA … —and to deploy it in human cells.
BioNTech was founded in 2008 by the husband-and-wife team of Ugur Sahin and Ozlem Tureci, who met when they were training to be doctors in Germany in the early 1990s. Both were from Turkish immigrant families, and they shared a passion for medical research, so much so that they spent part of their wedding day working in the lab. They founded BioNTech with the goal of creating therapies that stimulate the immune system to fight cancerous cells. It also soon became a leader in devising medicines that use mRNA in vaccines against viruses.
In January 2020, Sahin read an article in the medical journal Lancet about a new coronavirus in China. After discussing it with his wife over breakfast, he sent an email to the other members of the BioNTech board saying that it was wrong to believe that this virus would come and go as easily as MERS and SARS. “This time it is different,” he told them.
BioNTech launched a crash project to devise a vaccine based on RNA sequences, which Sahin was able to write within days, that would cause human cells to make versions of the coronavirus’s spike protein. Once it looked promising, Sahin called Kathrin Jansen, the head of vaccine research and development at Pfizer. The two companies had been working together since 2018 to develop flu vaccines using mRNA technology, and he asked her whether Pfizer would want to enter a similar partnership for a COVID vaccine. “I was just about to call you and propose the same thing,” Jansen replied. The deal was signed in March.
By then, a similar mRNA vaccine was being developed by Moderna, a much smaller company with only 800 employees. Its chair and co-founder, Noubar Afeyan, a Beirut-born Armenian who immigrated to the U.S., had become fascinated by mRNA in 2010, when he heard a pitch from a group of Harvard and MIT researchers. Together they formed Moderna, which initially focused on using mRNA to try to develop personalized cancer treatments, but soon began experimenting with using the technique to make vaccines against viruses.
In January 2020, Afeyan took one of his daughters to a restaurant near his office in Cambridge to celebrate her birthday. In the middle of the meal, he got an urgent text message from the CEO of his company, Stéphane Bancel, in Switzerland. So he rushed outside in the freezing temperature, forgetting to grab his coat, to call him back.
Bancel said that he wanted to launch a project to use mRNA to attempt a vaccine against the new coronavirus. At that point, Moderna had more than 20 drugs in development but none had even reached the final stage of clinical trials. Nevertheless, Afeyan instantly authorized him to start work. “Don’t worry about the board,” he said. “Just get moving.” Lacking Pfizer’s resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, was supportive. “Go for it,” he declared. “Whatever it costs, don’t worry about it.”
It took Bancel and his Moderna team only two days to create the RNA sequences that would produce the spike protein, and 41 days later, it shipped the first box of vials to the National Institutes of Health to begin early trials. Afeyan keeps a picture of that box on his cell phone.
An mRNA vaccine has certain advantages over a DNA vaccine, which has to use a re-engineered virus or other delivery mechanism to make it through the membrane that protects the nucleus of a cell. The RNA does not need to get into the nucleus. It simply needs to be delivered into the more-accessible outer region of cells, the cytoplasm, which is where proteins are constructed.
The Pfizer-BioNTech and Moderna vaccines do so by encapsulating the mRNA in tiny oily capsules, known as lipid nanoparticles.Moderna had been working for 10 years to improve its nanoparticles.This gave it one advantage over Pfizer-BioNTech: its particles were more stable and did not have to be stored at extremely low temperatures.
By November, the results of the Pfizer-BioNTech and Moderna late-stage trials came back with resounding findings: both vaccines were more than 90% effective. A few weeks later, with COVID-19 once again surging throughout much of the world, they received emergency authorization from the U.S. Food and Drug Administration and became the vanguard of the biotech effort to beat back the pandemic.
The ability to code messenger RNA to do our bidding will transform medicine. As with the COVID vaccines, we can instruct mRNA to cause our cells to make antigens—molecules that stimulate our immune system—that could protect us against many viruses, bacteria, or other pathogens that cause infectious disease. In addition, mRNA could in the future be used, as BioNTech and Moderna are pioneering, to fight cancer. Harnessing a process called immunotherapy, the mRNA can be coded to produce molecules that will cause the body’s immune system to identify and kill cancer cells.
RNA can also be engineered, as Jennifer Doudna and others discovered, to target genes for editing. Using the CRISPR system adapted from bacteria, RNA can guide scissors-like enzymes to specific sequences of DNA in order to eliminate or edit a gene. This technique has already been used in trials to cure sickle cell anemia. Now it is also being used in the war against COVID. Doudna and others have created RNA-guided enzymes that can directly detect SARS-CoV-2 and eventually could be used to destroy it.
More controversially, CRISPR could be used to create “designer babies” with inheritable genetic changes. In 2018, a young Chinese doctor used CRISPR to engineer twin girls so they did not have the receptor for the virus that causes AIDS. There was an immediate outburst of awe and then shock. The doctor was denounced, and there were calls for an international moratorium on inheritable gene edits. But in the wake of the pandemic, RNA-guided genetic editing to make our species less receptive to viruses may someday begin to seem more acceptable.
Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. One of the earliest known was the Babylon flu epidemic around 1200 B.C. The plague of Athens in 429 B.C. killed close to 100,000 people, the Antonine plague in the 2nd century killed 5 million, the plague of Justinian in the 6th century killed 50 million, and the Black Death of the 14th century took almost 200 million lives, close to half of Europe’s population.
The COVID-19 pandemic that killed more than 1.8 million people in 2020 will not be the final plague. However, thanks to the new RNA technology, our defenses against most future plagues are likely to be immensely faster and more effective. As new viruses come along, or as the current coronavirus mutates, researchers can quickly recode a vaccine’s mRNA to target the new threats. “It was a bad day for viruses,” Moderna’s chair Afeyan says about the Sunday when he got the first word of his company’s clinical trial results. “There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.”
The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes are transcribed into RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to destroy viruses. Great inventions come from understanding basic science. Nature is beautiful that way.