by Megan Molteni: If approved by the FDA, Pfizer and BioNTech’s mRNA vaccine would be the first of its kind, setting a record for speed—but raising questions about distribution…


ON MONDAY MORNING, when representatives from the drug company Pfizer said that its Covid-19 vaccine appears to be more than 90 percent effective, stocks soared, White House officials rushed to (falselyclaim credit, and sighs of relief went up all around the internet. “Dear World. We have a vaccine! Best news since January 10,” tweeted Florian Krammer, a virologist and vaccinologist at the Mount Sinai School of Medicine (who also happens to be a participant in the Pfizer Covid-19 vaccine trial).

But having a press release from a pharmaceutical company saying a vaccine works is very different from actually having a vaccine that works. Pfizer, and its German partner on the vaccine, BioNTech, have yet to release any data from their Phase III trial. The findings this week are based on the trial’s first interim analysis, conducted by an outside panel of experts after 94 of the 43,538 participants contracted the coronavirus. That analysis suggests that most of the people who became ill had received a placebo, instead of the vaccine. But it doesn’t say much beyond that. (More on why that matters, later.)

And logistically, there’s still a lot that has to happen before people who aren’t study subjects can start rolling up their sleeves. Pfizer researchers are now collecting at least two months’ worth of safety follow-up data. If those findings raise no red flags, the company could then apply for an emergency use authorization from the US Food and Drug Administration. Only then could execs start doling out the 50 million or so doses they expect to make by the end of the year, a process complicated by the fact that until it’s ready to be shot into someone’s arm, Pfizer’s vaccine needs to be kept at temperatures downwards of -80 degrees Fahrenheit, which is way colder than the usual vaccine cold chain. Completing the immunization also requires two doses given three weeks apart. Oh yeah, and states that at this moment are trying to do all the other things you have to do to prepare for such a complicated immunization push—hiring vaccinators, setting up digital registries, deciding who will get vaccine priority—are doing so without any extra money dedicated to the effort.

Those are a lot of caveats. But still, there’s reason to be hopeful. If the results hold up, a Covid-19 vaccine that’s 90 percent effective will have vastly exceeded the efficacy bar set by the FDA. That level of protection would put it up there with the measles shot, one of the most potent vaccines developed to date.

The arrival of an effective vaccine to fight SARS-CoV-2 less than a year after the novel coronavirus emerged would smash every record ever set by vaccine makers. “Historic isn’t even the right word,” says Larry Corey of the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Center. A renowned virologist, Corey has spent the last three decades leading the search for a vaccine against the virus that causes AIDS. He’s never seen an inoculation developed for a new bug in under five years, let alone one. “It’s never happened before, never, not even close,” he says. “It’s just an amazing accomplishment of science.”

And perhaps even more monumental is the kind of vaccine that Pfizer and BioNTech are bringing across the finish line. The active ingredient inside their shot is mRNA—mobile strings of genetic code that contain the blueprints for proteins. Cells use mRNA to get those specs out of hard DNA storage and into their protein-making factories. The mRNA inside Pfizer and BioNTech’s vaccine directs any cells it reaches to run a coronavirus spike-building program. The viral proteins these cells produce can’t infect any other cells, but they are foreign enough to trip the body’s defense systems. They also look enough like the real virus to train the immune system to recognize SARS-CoV-2, should its owner encounter the infectious virus in the future. Up until now, this technology has never been approved for use in people. A successful mRNA vaccine won’t just be a triumph over the new coronavirus, it’ll be a huge leap forward for the science of vaccine making.

Edward Jenner and Jonas Salk weren’t just pioneers, they were cowboys. They used coarse methods (like sticking children with pus scraped from a milkmaid’s cowpox blister) that only let them see the results at the end of their research, not the mechanism by which the inoculation worked. Over the centuries, the methods got slightly more refined, but vaccinology largely maintained this culture of empirical gunslinging.

Effective immunizations are all about exposing the immune system to a harmless version of a pathogen so it can respond faster in the event of a future invasion. Vaccines have to look enough like the real thing to produce a robust immune response. But too close a resemblance and the vaccine might wind up making people sick. To strike the balance, scientists have tried inactivating and crippling viruses with heat and chemicals. They’ve engineered yeast to produce bits and pieces of viral proteins. And they’ve Frankensteined those bits and pieces into more innocuous viral relatives, like sheep in wolves’ clothing. These substitutes for a working virus weren’t exact—scientists couldn’t precisely predict how the immune system would respond—but they were close enough that they sometimes worked.

But in the last decade, the field has started to move away from this see-what-sticks approach toward something pharma folks call “rational drug design.” It involves understanding the structure and function of the target—like say, the spiky protein SARS-CoV-2 uses to get into human cells—and building molecules that can either bind to that target directly, or produce other molecules that can. Genetic vaccines represent an important step in this scientific evolution. Engineers can now design strands of mRNA on computers, guided by algorithms that predict which combination of genetic letters will yield a viral protein with just the right shape to prod the human body into producing protective antibodies. In the last few years, it’s gotten much easier and cheaper to make mRNA and DNA at scale, which means that as soon as scientists have access to a new pathogen’s genome, they can start whipping up hundreds or thousands of mRNA snippets to test—each one a potential vaccine. The Chinese government released the genetic sequence of SARS-CoV-2 in mid-January. By the end of February, BioNTech had identified 20 vaccine candidates, of which four were then selected for human trials in Germany.

Since small companies like BioNTech, Moderna, and Inovio began developing genetic vaccines about 10 years ago, that speed has always been the brightest of its promises. The faster you can make and test vaccines, the faster you can respond to outbreaks of new diseases. But with any novel approach comes risk—risks that the vaccine won’t work well or, worse, that it harms someone, and millions of dollars will be wasted on a technology that turns out to be a flop. Until this year, major vaccine developers had shied away from genetic vaccines. Before 2020, only 12 mRNA vaccines ever made it to human trials. None were approved. Then came the coronavirus.

“Before the pandemic, there weren’t the financial incentives or the opportunities for the big pharmaceutical companies to get involved,” says Peter Hotez, a vaccine researcher and dean of the National School of Tropical Medicine at Baylor College of Medicine. But with governments rushing to fund not just clinical trials but boosts in manufacturing, as in the US’ Operation Warp Speed, it got a lot less risky to try something new. The spoils of that investment, and the potential success of a Pfizer/BioNTech vaccine, will long outlive this pandemic, says Hotez. “It provides a glidepath for using mRNA technology for other vaccines, including cancer, autoimmune disorders, and other infectious diseases, as well as vehicles for genetic therapies. It really does help accelerate the whole biomedical field.”

In addition to Pfizer/BioNTech, Moderna also has an mRNA-based Covid-19 vaccine in Phase III trials and is expecting to receive its first interim findings later this month. Inovio’s DNA-based vaccine has stalled over concerns about the device used to inject the vaccine; company officials announced this week they expect the FDA to make a decision about whether or not the Phase II/III trial can continue later this month. So for now, all eyes remain on Pfizer and BioNTech. And everyone is eager to see more.

“Until the full data set is available, it is hard to interpret the true potential,” says Carlos Guzman, head of the Department of Vaccinology and Applied Microbiology at the Helmholtz Centre for Infection Research in Germany. Important to note, he says, is that Pfizer’s effectiveness claim is based on a relatively small number of trial participants who tested positive for Covid-19, and that so far nobody knows anything about them. How old are the people who are getting sick? How old are the ones who don’t? That’s important information for understanding how well the vaccine will work across different age groups, which could inform who gets it first.

Another question mark is what’s happening with people’s symptoms and viral loads. According to Pfizer’s trial protocol, one would conclude that the vaccine is preventing people from getting severe cases of Covid-19—but does that mean they’re not getting infected at all? The answer could be the difference between a vaccine that builds up a protective wall of immunity in communities and one that just keeps people out of the hospital (and the morgue). Still another unanswered question is how long any such immunity might last. For that, expect to keep waiting a little while longer, says Guzman: “Data in the coming months will provide a better picture of longer-term vaccine efficacy and whether this vaccine can also protect against severe forms of disease and death.”

The dissemination of such information will be vital for any vaccine to win public trust—a crucial step in any immunization campaign, but especially one that would roll out amidst rising vaccine skepticism and misinformation. “The scientific community needs to be able to evaluate the study’s results through peer review and transparent data sharing,” says Ariadne Nichol, a medical ethics researcher at Stanford University. So far, Pfizer and BioNTech have published safety data from earlier-stage trials of the vaccine. No serious safety concerns have been observed.

If the Pfizer formula is approved by the FDA, the US will be at the front of the line to receive the first batches of the vaccine. In July, the Trump administration agreed to pay almost $2 billion for 100 million doses of Pfizer and BioNTech’s shot, or enough to immunize about 50 million people. According to The Wall Street Journal, Pfizer will handle the distribution of its products, rather than relying on the federal government. But that also raises questions about how long it could take the vaccine to reach less wealthy nations, especially where the extreme cold chain necessary to keep the formula stable isn’t compatible with local infrastructure. “This is a sprint where Pfizer may end up finishing first,” says Nichol. “But we still have a marathon ahead to tackle issues of production and equitable distribution within our global population.”

Genetic vaccines might be proving they can work—but it’s still not definitive, and they may not yet work for everyone. That’s why experts say it’s so crucial to continue supporting ongoing trials for the more than 60 other vaccine candidates still in various stages of human testing. What older technologies lack in terms of speed, they make up for in durability. Vaccines like the ones against measles, yellow fever, and rabies can be freeze-dried so they’re shelf-stable and can go anywhere. That also makes them less expensive. “We cannot rapidly immunize the world with just mRNA alone,” says Corey. Ending the pandemic, and breaking the stranglehold the virus has on the global economy, will take more than one vaccine, and probably more than two or three. “The need to keep the pedal to the metal hasn’t gone away one bit,” he says.

Source: Wired