I was asked recently when life might return to normal. The question is simple but the answer is complex, with many knowns, lots of known unknowns, and some unknown unknowns. But I'll give it my best shot.
To get the fatality rate down to flu-like levels would require that we cut Covid-19 fatalities down by a factor of 5.
Since I'm human (and thus want my life back), I might be biased toward optimism.
Here's one way to think about it: Is there another infection that causes sickness and death at levels that we tolerate? The answer, of course, is 'yes': influenza.
According to the Centers for Disease Control, from 2010 to 2019, an average of 30 million Americans had the flu each year, leading to an annual average of 37,000 deaths. This works out to an infection-fatality rate, or IFR, of 0.12 percent. We've tolerated that level of illness death from influenza for a century.
Before going on, let's get one thing out of the way: Back in March, Covid-19 wasn't, as some maintained, "like the flu," and it still isn't. Since then, the U.S. has had 3.9 million confirmed Covid-19 cases and 140,000 deaths, for an IFR of 3.6 percent. Taking all the cases — including asymptomatic patients and those with minimal symptoms who were never tested for Covid-19 — into account, the real IFR is probably 0.6 percent, or roughly 5 times that of the flu.
Nonetheless, even a partly effective vaccine, combined with moderately effective medications, could bring Covid-19 numbers down to a tolerable, flu-like, threshold. It's a goal that seems within our reach.
Chronic mask-wearing and physical distancing are not my idea of normal, nor, I would venture to guess, would most other Americans consider these desirable states in which to live. We need both now to achieve some semblance of normalcy, but they're decidedly not normal life. My notion of normal: daily life with no or minimal mask wearing, open restaurants and bars, ballparks with fans, and theaters with audiences.
My projection for when we might get there: perhaps a year from now.
To get the fatality rate down to flu-like levels would require that we cut Covid-19 fatalities down by a factor of 5, via some combination of fewer symptomatic cases and a lower chance that a symptomatic patient will go on to die. How might that happen?
First, we have to make some impact on young people – getting them to follow the public health directives at higher rates than they are currently. The main reason we need to push younger people to stay safe is that they can spread Covid-19 to vulnerable people (those who are older, with underlying health problems). But, once the most vulnerable are protected (through the deployment of some combination of effective medications and a vaccine), the fact that some young people aren't acting safely – or maybe won't take a vaccine themselves – wouldn't cause so much concern. The key is whether the people at highest risk for bad outcomes are protected.
Then there's the vaccine. The first principle: We don't need a 100 percent-effective vaccine injected into 320 million deltoid muscles (in the U.S. alone). Thank God, since it's fanciful to believe that we can have a vaccine that's 100 percent effective, universally available by next summer, and that each and every American agrees to be vaccinated.
How are we doing in our vaccine journey? We've been having some banner days lately, with recent optimistic reports from several of the vaccine companies. In one report, the leading candidate vaccine, the one effort being led by Oxford University, led to both antibodies and a cellular immune response, a very helpful belt-and-suspenders approach that increases the probability of long-lasting immunity. This good news comes on the heels of the positive news regarding the American vaccine being made by Moderna earlier in July.
While every article about vaccines sounds the obligatory cautionary notes, to date we've checked every box on the path to a safe and effective vaccine. We might not get there, but most experts are now predicting an FDA-approvable vaccine (more than 50 percent effective with no show-stopping side effects) by early 2021.
It is true that we don't know how long immunity will last, but that can be a problem to solve later. In this area, time is our friend. If we can get to an effective vaccine that lasts for a year or two, over time we should be able to discover strategies (more vaccine boosters, new and better medications) to address the possibility of waning immunity.
All things considered, I'm going to put my nickel down on the following optimistic scenario: we'll have one, and likely several, vaccines that have been proven to be more than 50 percent effective and safe by January, 2021.
If only that were the finish line.
Once we vaccinate a large fraction of high-risk patients, having a moderate number of unvaccinated people running around won't pose as much threat.
The investments in manufacturing and distribution should pay off, but it's still inconceivable that we'll be able to get vaccines to 300 million people in three to six months. For the 2009 Swine Flu, we managed to vaccinate about 1 in 4 Americans over six months.
So we'll need to prioritize. First in line will likely be the 55 million Americans over 65, and the six to eight million patient-facing healthcare workers. (How to sort priorities among people under 65 with "chronic diseases" will be a toughie.) Vaccinating 80-100 million vulnerable people, plus clinicians, might be achievable by mid-21.
If we can protect vulnerable people with an effective vaccine (with the less vulnerable waiting their turn over a subsequent 6-12 month period), that may be enough to do the trick. (Of course, vulnerable people may also be least likely to develop immunity in response to a vaccine. That could be an Achilles' heel – time will tell.)
Why might that be enough? Once we vaccinate a large fraction of high-risk patients, having a moderate number of unvaccinated people running around won't pose as much threat. Since they're at lower risk, they have a lower chance of getting sick and dying than those who received the vaccine first.
We're likely to have better meds by then, too. Since March, we've discovered two moderately effective medications for Covid-19 — remdesivir and dexamethasone. It seems likely that we'll find others by next summer, perhaps even a treatment that prevents patients from getting ill in the first place. There are many such therapies, ranging from zinc to convalescent plasma, currently being studied.
Moreover, we know that hospitals that are not overrun with Covid-19 have lower mortality rates. If we've gotten a fairly effective vaccine into most high-risk people, the hospitals are unlikely to be overwhelmed – another factor that may help lower the mortality rate to flu-like levels.
All of these factors – vaccination of most vulnerable people, one or two additional effective medications, hospitals and ICU's that aren't overwhelmed – could easily combine to bring the toll of Covid-19 down to something that resembles that of the flu. Then, we should be able to return to normal life.
Whatever the reason, if enough people refuse the vaccine, all bets are off.
What do I worry about? There's the growing anti-vaxxer movement, for one. On top of that, it seems that many Americans worry that a vaccine discovered in record speed won't be safe, or that the FDA approval process will have been corrupted by political influences. Whatever the reason, if enough people refuse the vaccine, all bets are off.
Assuming only high-risk people do get vaccinated, there will still be cases of Covid-19, maybe even mini-outbreaks, well into 2021 and likely 2022. Obviously, that's not ideal, and we should hope for a vaccine that results in the complete eradication of Covid-19. But the point is that, even with flu-like levels of illness and death, we should still be able to achieve "normal."
Hope is not a strategy, as the saying goes. But it is hope, which is more than we've had for a while.
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce the two molecular components that make up CRISPR — a guide molecule and a cutting protein — to snip out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.