Researchers Are Hatching a Low-Cost Coronavirus Vaccine


A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NDV-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make.

Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world.

If NDV-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NDV-HXP-S for themselves or acquire it at low cost from neighbors.

“That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center.

First, however, clinical trials must establish that NDV-HXP-S actually works in people. The first phase of clinical trials will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects.

“It’s a home run for protection,” said Dr. Bruce Innis of the PATH Center for Vaccine Innovation and Access, which has coordinated the development of NDV-HXP-S. “I think it’s a world-class vaccine.”

Vaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.

Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them.

In the case of the coronavirus, the best target for the immune system is the protein that covers its surface like a crown. The protein, known as spike, latches onto cells and then allows the virus to fuse to them.

But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies.

This insight emerged long before the Covid-19 pandemic. In 2015, another coronavirus appeared, causing a deadly form of pneumonia called MERS. Jason McLellan, a structural biologist then at the Geisel School of Medicine at Dartmouth, and his colleagues set out to make a vaccine against it.

They wanted to use the spike protein as a target. But they had to reckon with the fact that the spike protein is a shape-shifter. As the protein prepares to fuse to a cell, it contorts from a tulip-like shape into something more akin to a javelin.

Scientists call these two shapes the prefusion and postfusion forms of the spike. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don’t stop it.

Dr. McLellan and his colleagues used standard techniques to make a MERS vaccine but ended up with a lot of postfusion spikes, useless for their purposes. Then they discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline.

The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus.

The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans.

But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike.

Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike.

Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year.

Dr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.”The Coronavirus Outbreak ›

But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more.

“It made sense to try to have a better vaccine,” said Dr. McLellan, who is now an associate professor at the University of Texas at Austin.

In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations.

The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. Dr. McLellan called the new spike HexaPro, in honor of its total of six prolines.

The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine.

Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines.

“The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said.

To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties.

Meanwhile, Dr. Innis and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own.

The first wave of authorized Covid-19 vaccines require specialized, costly ingredients to make. Moderna’s RNA-based vaccine, for instance, needs genetic building blocks called nucleotides, as well as a custom-made fatty acid to build a bubble around them. Those ingredients must be assembled into vaccines in purpose-built factories.

The way influenza vaccines are made is a study in contrast. Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines.

The PATH team wondered if scientists could make a Covid-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make Covid-19 shots as well.

In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans.

For years, scientists had been experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes.

The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins.

At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S.

PATH arranged for thousands of doses of NDV-HXP-S to be produced in a Vietnamese factory that normally makes influenza vaccines in chicken eggs. In October, the factory sent the vaccines to New York to be tested. The Mount Sinai researchers found that NDV-HXP-S conferred powerful protection in mice and hamsters.

“I can honestly say I can protect every hamster, every mouse in the world against SARS-CoV-2,” Dr. Peter Palese, the leader of the research, said. “But the jury’s still out about what it does in humans.”

The potency of the vaccine brought an extra benefit: The researchers needed fewer viruses for an effective dose. A single egg may yield five to 10 doses of NDV-HXP-S, compared to one or two doses of influenza vaccines.

“We are very excited about this, because we think it’s a way of making a cheap vaccine,” Dr. Palese said.

PATH then connected the Mount Sinai team with influenza vaccine makers. On March 15, Vietnam’s Institute of Vaccines and Medical Biologicals announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S.

Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form.

To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok.

In Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.”

Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.”

Madhavi Sunder, an expert on intellectual property at Georgetown University Law Center, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said.

Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said.

In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro.

“There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’”

Testing and tracing could have worked better against covid-19


The first outbreak of a novel disease is the opening scene of a whodunnit. In 1976, when more than two dozen members of the American Legion died after a convention in Philadelphia, public-health officials spent months scouring the hotel they had met in before finally tracking down the culprit in the water tank on the roof: a new bacterium which, having caused the first known cases of Legionnaires’ disease, was named Legionella. In the 1980s it took years of hard work and acrimonious argument among epidemiologists and virologists to blame the terrible and varied symptoms of aids on hiv, a virus of a type never previously seen in humans.Listen to this story

For covid-19, the mystery was solved almost as soon as it had begun. The novel pneumonia that doctors in Wuhan noticed in December 2019 immediately brought to mind Severe Acute Respiratory Syndrome (sars), a disease caused by a coronavirus which broke out in 2002. As a result of sars and the subsequent outbreak in 2012 of Middle East Respiratory Syndrome (mers), also caused by a coronavirus, there were already established protocols for growing cells from the lining of the nose, throat and lungs in order to look for coronavirus infection. They were soon put to use.

To identify the possible coronavirus responsible meant producing a sequence of its genome. The first step in this process was to extract rna—the molecule on which coronavirus genomes are written—from the cell cultures. The genetic sequences in these rna molecules then had to be transcribed into complementary bits of dna, because that is what automated sequencing machines work with (see part A of diagram).

Computer programs assembled the sequences those machines produced into a recognisable, if gappy, coronavirus genome. Researchers used this to make dna “primers” with which to fish out the not-yet-sequenced bits of the genome. Finished sequences were published less than two weeks after the process had begun. On January 12th 2020 the world knew its enemy—soon thereafter named sars-cov-2—down to the last letter of its genome.

In terms of the science done, this was all routine; the appropriate use of standard laboratory techniques. In terms of its impact, it was enormous. Knowing the viral sequence was fundamental to vaccination efforts, made it possible to track the virus’s evolution and, most immediately, made it possible to test people with a cough and see if they were infected. The first aids tests were not available until four years after medical science became aware of the condition they tested for. For sars it took six months. Procedures for testing swabs from the nose and throat for rna from sars-cov-2 were published 11 days after the genome sequence, on January 23rd.

There was, however, a drawback to the tests. They required suitably equipped laboratories. Most countries did not have nearly enough of the relevant lab capacity; in others, much of it was being used for different things. “Prior to March 23rd my lab had never performed a viral diagnostic,” says Stacey Gabriel, who runs genetic-sequencing operations at the Broad Institute in Cambridge, Massachusetts. But with public institutions swamped she and her colleagues created one of the largest testing shops on America’s east coast from scratch, reconfiguring the specialised robots that populate one of the world’s most advanced cancer-genetics labs to do the grunt work.

Dr Gabriel learned two lessons in the process. The first is that uniformity matters a lot. The Broad started off testing samples from Massachusetts nursing homes which came in containers of varying size and with various amounts of liquid, some accompanied by handwritten forms, some by barcodes. Dealing with such messiness is no task for a robot, and so to begin with just a few thousand samples a day passed through machines capable of handling far more. The second is that you need software to track the whole process. Commercial software, dry swabs and barcoding soon had the lab firing on all cylinders. By March 2021 it could handle 200,000 tests a day and was serving customers as far afield as New York.

The data such labs produce are not just for patients and doctors. In most countries covid-19 is a notifiable disease; the authorities have a legal right to know who has been found to be infected. When a sample tests positive the lab has to pass the identity of the person it came from on to public-health officials. At that point a new sort of detective work begins: where did that person—the index case, in public-health speak—pick up the virus? To whom might they have given it?

Without a trace

Several East Asian countries demonstrated that, if started in the earliest days of an epidemic and pursued with vigour and persistence, such contact tracing can be a powerful tool. Some, such as Singapore and Taiwan, benefited in this from their experience with sars in the mid-2000s; tracing systems set in place back then were put to use with an urgency born of experience. A level of invasiveness from which most Western authorities shied away was often employed. In South Korea, for instance, contact tracers were able to download a list of all financial transactions made by those who tested positive; they could then obtain cctv footage from shops the index case had visited in search of other customers to check up on. “[Such snooping] has come up with discussions I’ve had with policymakers,” says Christophe Fraser, a digital epidemiologist at the University of Oxford. “We got very hung up on the idea of contact tracing disrupting people’s lives.”

Western governments acted in a slower, less thoroughgoing way. They failed to track the initial spread, in part because of insufficient testing capacity (and, in America, dud tests from the Centres for Disease Control and Prevention). They ended up with much less impressive systems. Tom Frieden, a former director of the cdc, says he thinks that, at its current level of effort, America could plausibly trace about 15,000 cases a day—a level that has been handsomely exceeded every day since April 2nd 2020. Britain has earmarked £37bn for testing and tracing over the 2020 and 2021 financial years, and though it may well spend less, the shoddiness that has dogged some elements of the campaign, such as a database cock-up which lost thousands of results in September 2020, will be remembered.

A basic problem is that contact tracing is a lot of work. Theoretical assessments based on analysing social networks and experience in Asia both suggest that some 30 contacts need to be identified for each index case. Digital tools can lessen the load. Resolve to Save Lives, a campaign run by Vital Strategies, an ngo, developed Locator, which taps into credit data to help tracers track down people who may have caught the virus from a specific index case. But the amount of work required remained enormous.

Apps and antibodies

A much discussed alternative to such programmes was to use the world’s most ubiquitous tracking devices: smartphones. Google and Apple worked together to develop a system which enabled phones to keep a list of occasions when they were near another phone for a significant period of time, and the identity of that second phone. When someone tests positive for sars-cov-2 they are asked to send a message from their phone which is used to notify all the other phones they had been near within a particular window of time. But everything is peer-to-peer; neither the big tech companies nor the public-health authorities get a list of contacts.

Unfortunately this built-in privacy makes it hard to assess the technology’s efficacy. British and Swiss studies suggest such apps do reduce spread, but not enough to make them more than an also-ran technology. None of the successful contact-tracing systems in East Asia relies on such things to any significant extent.

Even without good tracing, self isolation of those who tested positive helped slow the spread of the disease. But over time the shortcomings of the initial testing technology, reverse-transcriptase polymerase chain reaction (rt-pcr), became ever more apparent. It is conceptually elegant (see diagram) and easy for labs to use. But despite its familiarity, reliability and sensitivity, it has real disadvantages.

One is that it needs labs, and is carried out most efficiently in big ones. This means samples may have to travel a long way. It also means that they can get held in queues. The Broad runs its rt-pcr tests in just three and a half hours; but the average sample takes 15 hours to process. Results from rt-pcr tests normally come in days not minutes.

Another problem is that though the presence of viral rna clearly shows that a person has been infected, it says very little about where they stand in the course of the disease; rna is detectible from very soon after infection to long after the disease has run its course. In public-health terms what is needed is a test that spots people who are actually infectious—people with cells in their noses and throats actively churning out virus particles.

To look for the sars-cov-2 particles themselves means looking for their distinctive protein components, not for the rna that tells cells how to make them. The most detectible such component is the spike protein which studs the particles’ outer membranes. And one of the basic rules of modern biotechnology is that when you want to find a protein, use an antibody.

Antibodies are large molecules that come in millions of varieties, each of which sticks to one target—known as that antibody’s “antigen”—and one target only. A handy technology called lateral-flow testing makes use of that specificity. A sample is placed at one end of a porous membrane and, as it seeps along to the other, encounters a line of antibodies designed to recognise it. When the sample is urine and the antigen is a hormone found in expectant women, you have a pregnancy test. When the sample is mucus from a swab and the antigen is the spike protein, it is a covid-19 test—a cheap, convenient one which can provide results with in half an hour. Such tests may not pick up all the people in whom rt-pcr might detect a trace of the virus. But if their nose and throat cells are not producing enough antigen for the test to detect, they are probably not producing enough to be infectious, either.

At the beginning of the epidemic “the supply chain for the lateral-flow tests wasn’t there,” says Dr Gabriel. Chris Hand, the chairman of Abingdon Health, a British contract manufacturer of lateral-flow tests, says the main bottleneck was the speciality membranes that are part of every test kit. “They come on large reels of 100 metres plus, which go through automated equipment to add biochemicals by spraying them at low volumes,” he says. But once the biochemicals—the bespoke antibodies and some more generic bits and bobs—are ready, the production processes in place and the packaging sorted, the tests could be churned out by the million.

New technologies now reaching the market will further change the dynamics of test and trace. Quantumdx is one of a number of companies developing automated pcr-in-a-box systems that provide results within a couple of hours. Jonathan O’Halloran, the firm’s boss, says the British company has been relying on its own testing system for the past 22 weeks, testing its 90 staff members every morning (they are free to decline). About once a week lunchtime brings the news that someone has tested positive; they are immediately sent home to isolate. When things are done this fast, the fact that rna is detectable before people are infectious is a plus; isolating on the basis of an early pcr test means no one ever turns up to work infectious. The company claims not to have lost a single day to infection.

A combination of local, automated pcr and lateral-flow tests could be the basis of an ideal testing system—one which has a chance of keeping ahead of, and containing, a low level of disease rather than lagging behind one that is shooting up. Antigen tests would be used to scan the population for new infections. Those found would be referred to contact tracers; contacts who might have been infected could then be pcr-tested to find out which of them actually were.

Great for public health. No benefit, in itself, to the index cases who would wait, isolated, to see what fate the virus and their immune systems had in store for them—painfully aware that their next encounter with the wonders of modern medical technology could be in a hospital bed. 

The US Has a Covid ‘Scariants’ Problem. Here’s How to Fix It


LATE LAST YEAR, while the US was plunged into its worst days of the pandemic, new, more insidious versions of SARS-CoV-2—first identified in the United Kingdom and South Africa—silently arrived on its shores. For months now, Americans have been anxiously watching them spread. But recently, the specter of homegrown horrors have begun to steal the show.

Last week, The New York Times reported on two not-yet-peer-reviewed studies detailing a new variant that had been identified in Manhattan and was gaining ground in the city. Speaking to reporters on Tuesday about the variant, Dave Chokshi, New York City’s health commissioner, struck an ominous chord: “With the number of New Yorkers being vaccinated increasing every day, there is real reason for hope for better months ahead. But on the periphery of this growing light, there is also a shadow,” he said. This came a week after reports emerged of a deadlier and more contagious strain expanding through Southern California. Charles Chiu, the UC San Francisco infectious disease doctor who discovered it, told The Los Angeles Times “The devil is already here.” (A few outlets, including WIRED, were provided access to a manuscript describing studies conducted by Chiu and his collaborators, but it has not yet been posted publicly.)

If you were following all this news, you would not be blamed for believing that SARS-CoV-2 had mutated all the way into the antichrist. And some scientists are not happy about that—specifically, the part where impatient researchers and eager journalists pounce on any variant that seems even the slightest bit more dangerous, hyping them before careful and comprehensive studies show there’s real cause for alarm.

Eric Topol, founder and director of the Scripps Research Translational Institute, says this parade of “scariants” serves more to snag headlines and frighten the public than to further scientific understanding of the coronavirus. On Twitter this week, one of his colleagues, Scripps evolutionary biologist Kristian G. Andersen, called out news stories about the California and New York variants for “atrocious reporting and sloppy science.” Jim Musser, chair of the department of pathology and genomic medicine at Houston Methodist Hospital had his own term for this barrage of coverage: “mutant porn.”

And yes, the media bears some responsibility here. Everyone is scared of variants, so reporters are incentivized to track down the latest and scariest science, no matter how preliminary. But not every genetic change is a dangerous one. Most aren’t, in fact. And the question of how scary certain collections of mutations are can’t be answered by a single study. The proliferation of American variant news in recent weeks exposes this more fundamental problem with the US coronavirus response: a disconnect between the scientists who are out there hunting emerging variants and the ones who run the experiments necessary to know whether those never-before-seen strains actually pose a significant threat. But now, WIRED has learned, a national consortium is in the works with aims of closing that gap.

For the first nine months of the pandemic, the US had nothing resembling a national strategy for genomic surveillance. Any sequencing that did happen was patchy, under-funded, and inadequate to track where new variants were spreading. But starting in mid-December, the US Centers for Disease Control and Prevention started signing contracts and releasing funds for a rapid ramp-up in sequencing capacity. Since then, the US has gone from 3,000 viral genomes sequenced per week to more than 7,000. An infusion of $200 million from the Biden administration should soon push that number to 25,000, CDC director Rochelle Walensky told reporters last month.

This sequencing boost is helping scientists map in finer detail the mutational landscape of the coronaviruses circulating around the country. So it’s not surprising that they’re starting to turn up more surprises. But as the pace of generating genomic data has accelerated, there has not yet been a similar, concerted push forward in what’s called “variant characterization.”

Sequencing can help you identify mutations that might be problematic. But it can’t tell you if those mutations make that version of the virus behave differently than others. For that, you need to conduct studies with antibodies, living human cells, and animal models. Each type of experiment or analysis requires a unique set of skills, and there are many different methods for measuring the same things. You need immunologists, structural biologists, virologists, and a whole bunch of other -ologists, too. And, ideally, you’d want them to all adhere to the same scientific standards so you can compare one variant to the next and determine if a new strain is concerning from a public health standpoint or merely interesting

In the US, the CDC is the primary body with authority to designate any emerging strains as either of “variants of interest” or “variants of concern.” Crossing that threshold requires strong evidence that a particular constellation of mutations confers the ability to do any one of four things: spread faster and more easily, inflict more severe disease, weaken the effectiveness of Covid-19 treatments, or elude antibodies produced either from vaccination or during prior infection with an older version of the virus.

So far, the agency has only elevated three new versions of SARS-CoV-2 to the most concerning category: B.1.1.7, which was first detected in the UK, B.1.351 from South Africa, and P.1 from Brazil. (Though there’s an ongoing fight over which code-naming system to use, most scientists have agreed to steer clear of the “insert-place-name-here” nomenclature for its imprecision and stigmatizing effect. For simplicity’s sake, we’ll refer to B.1.1.7, B.1.351, and P.1 from here on out as the Big Three.)

But the agency is currently tracking additional variants of interest—including B.1.256 out of New York and B.1427/429 in California—and keeping tabs on ongoing studies to assess these strains’ ability to evade immune responses and erode the protections afforded by existing vaccines. As new data becomes available, the agency may bump up any particularly worrying variants to this top tier. “The threshold for designating a variant of interest should be relatively low in order to monitor potentially important variants,” a CDC spokesperson told WIRED via email. “However, the threshold for designating a variant of concern should be high in order to focus resources on the variants with the highest public health implications.”

The spokesperson did not provide details on what the agency considers “strong evidence,” but said the CDC has been involved with international partners including the World Health Organization in discussing criteria for variant designation.

In other words, it’s not just a matter of finding new variants, it’s a matter of characterizing their biological behavior—what does it mean for someone to get infected with one versus another? “Getting sequences is just the beginning of the story,” says Topol. “There’s much more science that has to happen to know if a mutation is meaningful. And right now, lots of labs that are publishing on this are just looking at one part of the story, because that’s the quick thing to do. But what’s quick can also be misleading.”

For example, a number of studies in recent weeks have shown that antibodies trained to attack older versions of the virus have a much harder time recognizing the B.1.351 and P.1 variants. That’s raised alarms about vaccine effectiveness. But just because antibodies don’t fight these new mutants as well in a test tube doesn’t mean your immune system will have the same problems in a real-world Final Boss Fight. The immune system is more than antibodies, and far fewer labs have the expertise necessary to conduct tests with live T cells, the other major player in developing Covid-19 immunity. These cells, which clear the virus by culling herds of infected cells, are finicky to grow outside the human body. So it’s taken a little while longer to understand how they respond to the variants. But new data suggests they respond just fine.

In a preprint study posted online Monday, scientists at the La Jolla Institute for Immunology used the genomes of the Big Three variants of concern, plus the one spreading in California, to make lots of little protein fragments of each variant. This mimics a process that infected cells use to flag down help from the immune system, in which they grab pieces of their viral occupier and send them to the surface, where T cells can spot them. Then the researchers combined those variant fragments with blood isolated from people who’d recovered from an older version of Covid—Covid Classic, if you will—and blood from people who’d been vaccinated with either the Moderna or Pfizer shot. The T cells in those people’s blood had no problem spotting any of the four variants.

“It would have been horrifying to find out that—on top of a decrease in the neutralizing capacity of antibodies—that the T cell response was also wiped out,” says Alessandro Sette, an immunologist who led the research. “So the great news is that the T cells are in fact on the job. And that means that even if you do get infected, they should be able to decrease the severity of disease.”

Even though the experiments only examined the T cell response produced by the Moderna and Pfizer shots, Sette says the results help explain some of the interesting patterns observed in clinical trials of Johnson & Johnson’s vaccine. In the US, the company reported that its vaccine prevented 72 percent of moderate to severe cases of Covid-19. In South Africa, where B.1.351 was circulating during the trial, effectiveness dropped to 64 percent. But, across both trials, not a single person who received the shot in either country was hospitalized or died of Covid-19 during the study’s 28-day post-injection follow-up. “The J&J data totally fits with what we found,” says Sette.

With B.351’s genetic changes making it harder for antibodies to recognize it, the variant may have an easier time slipping into cells and establishing an infection. More people, then, might get sick. But once cells have been infected, the T cells seem to be able to still swing into attack, orchestrating an immune defense to fend off the worst symptoms. No hospitalizations, no deaths. “It doesn’t negate the fact that these variants are concerning,” says Sette. “It’s still best not to be infected. But the great thing is that the vaccine is still 100 percent effective against death.”

T cell studies are an important part of understanding the extent to which new variants will threaten vaccination efforts. But Musser says even those are not enough. “The real power in all this genomic info is to mate it up as much as we can with information from the patient side of the equation,” he says.

You can think of it this way: If a genomic sequence sketches the outline of a variant, lab studies then start to fill in the shapes and shadows, maybe a glimmer of a fang here or the flash of a talon there. But it takes real-life data from hospital records and contact tracing to get a clear picture. Only then can you know whether you’re looking at a gargoyle or a bunny rabbit.

Since the beginning of last March, Musser has led a uniquely ambitious effort at Houston Methodist Hospital to bank and sequence samples from all of its Covid-19 patients. So far, his team has sequenced more than 20,000. Along the way, they’ve matched up any variants they found with information about how the patients infected with it have fared. Instead of having to look at experiments in cells and animals for clues about the effects of variants on things like prevalence, mortality, resistance to drugs, and potential for reinfection, he can just see what happened in real people.

Those types of analyses are currently underway, says Musser. So far, he says, one preliminary finding is that B.1.1.7 has been no more deadly in the Houston Methodist patients infected with it than those infected with other strains, contrary to recent reports out of the United Kingdom that suggest B.1.1.7 is linked to higher rates of hospitalization and death.

It will be a little while before the full results are out—but they should be really interesting. According to a study his team posted online Tuesday that has not yet been peer-reviewed, Houston is the first US city where all the major variants, including the Big Three plus those recently found in California and New York, are currently circulating.

Until then, Musser is urging scientists and reporters to just “ratchet down” the variant-mania. “It’s fine and good for people to be ‘sequence-gazing’—that can yield some important initial insights,” he says. 

There are some good reasons why scientists might want to get the word out early about new discoveries. Such data could alert test manufacturers and vaccine makers that they may need to retool their products. Public health officials can use that information to more closely monitor strains with potential to do more damage in their communities. And it could even persuade the public that it’s still too soon to abandon masks and hit the bars. In an emergency situation, it might be better to be too cautious than to miss a dangerous escape variant while it’s still containable.

“Part of the motivation to post the preprint was so that other labs could follow up with more experiments,” says Anthony West, a computational and structural biologist at Caltech, who built a genome-scanning software tool that identified the new variant of interest in New York. Between Covid-19 capacity restrictions and other research commitments, the lab he works in wasn’t going to be able to make studying the new variant a priority. West also alerted New York City and state public health officials in early February, prior to posting a preprint describing what his team had found. Researchers at Columbia University also independently discovered the variant by sequencing samples from patients at their medical center. (The authors of that second study, as well as Chiu of UC San Francisco, did not respond to WIRED’s requests for interviews.)

Still, in the race to understand an evolving enemy, Musser worries scientists are flooding the field with incomplete intelligence and bogging down the whole endeavor. “Without having the entire context behind a viral genome, we’re not going to be able to adequately move the needle,” he says.

He’s not the only one who’s worried about that.

“Right now, while we’re in an emergency, it would be helpful to have a coordinating body that could make sure any variant that’s popping up is being characterized in a standardized and timely way,” says Lane Warmbrod, a senior analyst at the Johns Hopkins Center for Health Security and coauthor of a new report that reads like a policy roadmap for how to stay ahead of variants. In it, she and her colleagues argue that the US needs to establish a risk assessment framework for SARS-CoV-2, like the one the CDC began developing in 2010 to help scientists swiftly and systematically evaluate new influenza variants for pandemic potential.

For SARS-CoV-2, the first priority, says Warmbrod, should be to look for any enhancements in transmissibility. Does a new variant spread faster or more easily? Next would be trying to understand if it kills more frequently, eludes immune system responses, or resists antiviral treatments. A central coordinating agency could not only set standards for what kinds of experiments should be run to answer those kinds of questions, but it could also manage resources and delegate the study of each variant to different labs so that nothing slips through the cracks. “Nothing like that is happening now,” she says.

But it could be—very soon.

Topol and Andersen of Scripps have been working with the Rockefeller Foundation in New York to organize a national network of public, academic, and industry labs tasked with coordinating genomic surveillance and research into how new variants spread, evade drugs and immune cells, and make people sick. On February 16, the Rockefeller Foundation convened a virtual meeting of potential participants, including academic researchers and representatives from the Association of Public Health Laboratories, Illumina, LabCorp, the National Institutes of Health, and the CDC.

The idea, says Topol, is to link up a handful of regional sequencing centers that are already deeply involved in decoding coronavirus genomes with the research labs best-equipped to run those kinds of experiments. In essence, it will create what Topol calls an “immunologic phenotyping corps.” He says he expects plans for the consortium to go public in a matter of days.

A spokesperson for the Rockefeller Foundation declined to provide specifics, but did confirm that an announcement about the foundation’s work toward improving the US’s genomic surveillance systems will be made on Monday. In October, Rockefeller pledged a billion dollars over three years to address the Covid-19 crisis and its aftermath, including investing in pandemic preparedness.

Topol is hoping that at some point in the near future, the CDC and NIH will both get on board. With $200 million in dedicated genomic surveillance funds from the Biden administration, the CDC could be a powerful partner. (A spokesperson from the CDC declined to comment.) “I’m optimistic that with that funding we’re going to see better genomic surveillance. But we can’t just run with that. We have to get these immunotyping assays in high gear,” says Topol. “Otherwise we’re just going to have a lot of interesting sequences and not know what to do with them.”

We Still Don’t Know How Well Covid Vaccines Stop Transmission

THIS WEEK, THE US passed a grim milestone in the ongoing coronavirus crisis: 500,000 deaths, more than the number of Americans killed in World War II, the Korean War, and the Vietnam War combined. And yet there is a growing sense of hope that the worst might now be behind us. With new cases declining and immunizations accelerating—45.2 million people have so far received at least one dose of a Covid-19 vaccine, including 20.6 million who have been fully vaccinated—many Americans are beginning to allow themselves to imagine what post-pandemic life might be like.

Achieving that is likely to take a few more months—provided vaccine makers don’t hit any production snags and worrisome variants don’t derail current progress. In the interim, an increasing number of people will find themselves in a liminal state, navigating what it means to be a vaccinated person moving through an unvaccinated world. What are its rules, and what will it take to be a good citizen of it? Answering those questions means confronting an even more fundamental unknown. A vaccinated person may be well-protected from the worst ravages of Covid-19. But it’s not clear if they can still carry the coronavirus and transmit it to susceptible people around them.

This week, two new studies—neither of which have yet gone through peer review—made splashy headlines about the extent to which vaccines slash viral spread. The first, a leaked manuscript first reported by Israeli news site Ynet before being covered by MIT Technology Review, BloombergThe Financial Times, and Vox, found that two doses of Pfizer-BioNTech’s shot drove an 89.4 percent drop in infections—both symptomatic and asymptomatic—among vaccinated people in Israel. Though they did not directly measure transmission, the study’s authors—researchers from the Israel Ministry of Health, Hebrew University, and Pfizer—stated in the abstract that the Pfizer vaccine “was highly effective in preventing SARS-CoV-2 infections.” Subsequent news coverage hailed it as the first evidence from the real world that the vaccine could strongly suppress spread of the virus. But scientists not associated with the study say that was an overstatement. (Indeed, Bloomberg later updated its story to include such criticisms, though not the headline.)

In the report, which WIRED has obtained, the research team analyzed aggregated data from Israel’s national testing and disease surveillance system, comparing infection rates in vaccinated versus unvaccinated groups of people between January 17 and February 6. However, as the study authors noted, the ministry’s testing recommendations exempt vaccinated people from requirements like getting tested after travel or being exposed to a known Covid case. Under these protocols, unvaccinated people aren’t just required to get tested more often, they might also choose to, because they’re more worried about contracting Covid-19 than people who’ve gotten the jab. And because infections—especially asymptomatic ones—are more likely to be detected in the group that’s testing more frequently, the estimated 89.4 percent transmission-blocking effect of the vaccine is almost certainly too optimistic (a caveat the authors acknowledged, saying more research is needed to confirm their findings).

“The testing rates were such a hodgepodge, I don’t know you can make any conclusions about how much the vaccine cut transmission in Israel, let alone assigning a number as concrete as 89.4 percent,” says Eric Topol, a professor of molecular medicine at the Scripps Research Institute. The only way to do a careful study of asymptomatic spread and how well the shots curtail it, he says, is to swab both groups—vaccinated and unvaccinated people—every day, ideally for months. Though perhaps prohibitively expensive, the most rigorous version of that experiment would be to also follow each positive test up with contact tracing and genomic sequencing to confirm the route of transmission. The way the Israeli team did it is not the way to get the answer, he says: “It’s a way to get a lot of interest, because everybody wants to hear this.”

Indeed, right on cue, a few hours after the Israeli study began making the rounds in American media, one of my family members sent it to me. Just a few days prior, this person—who is vaccinated with the Pfizer shot—had asked me how safe it would be to fly and immediately join a pod of unvaccinated relatives. They did not like my answer (probably still risky, but we really don’t know just how risky just yet). They liked the Israeli study’s answer much better.

Scott Halpern, an epidemiologist and critical care physician at the University of Pennsylvania, says this is a pretty classic case of optimism bias—the general proclivity of the human species to believe that our desired outcome is likely to be the correct one. (Halpern has written about how other cognitive biases have hampered a smart and effective public health response here in the US.) It’s the same neural tick that drives people who’ve been told their loved one hooked up to a ventilator in the Covid-19 ward has a 5 percent chance of surviving. Most people believe their loved one will be in that 5 percent. Halpern knows this one from first-hand experience; he’s still seeing Covid-19 patients in the ICU most weeks.

Mix that optimism bias with pandemic fatigue, and you have a recipe for some under-baked science getting slung around as rationale for people doing the things they really want to do. “Once you’ve been bombarded with bad news long enough, any glimmer of good news is something we just emotionally latch onto,” says Halpern. “That’s just human nature.”

The Israeli team did not respond to WIRED’s emailed questions. A Pfizer spokesperson declined to comment on the 22-page report, which was first described last week by Israeli journalist Nadav Eyal, who published screenshots of the text on Twitter.

The second report, a preprint posted on The Lancet Monday, blew that glimmer of good news into a bigger flame. It described a Public Health England study of health care workers in the United Kingdom who’d received the Pfizer-BioNTech vaccine, and who were tested every 14 days for Covid-19. The study found that in addition to making people less likely to get sick from the coronavirus—no surprise there—the vaccine sliced the risk of the recipient getting infected, period. By how much? Vaccinated health care workers were 72 percent less likely at 21 days after the first dose, and 86 percent 7 days after the second dose. The logical jump here is that a vaccinated person has far fewer chances to spread the virus, since the shot reduces the odds they’ll ever be carrying it around. “We provide strong evidence that vaccinating working age adults will substantially reduce asymptomatic and symptomatic SARS-CoV-2 infection and therefore reduce transmission of infection in the population,” the study authors concluded.

While this study was better controlled, Topol says testing every two weeks still isn’t frequent enough to catch new infections. “It’s really got to be daily,” he says. Those kinds of experiments are much harder and costlier to do. But both Pfizer and Moderna are reportedly working on them right now, with data rumored to drop sometime in the next few weeks. (A Pfizer spokesperson declined to confirm that timeline or provide any details until data from a study has been published. Moderna did not respond to an emailed request for more information.)

WIRED’s questions did not immediately receive a response from the research team or Public Health England.

For now, that leaves the public without a lot of firm answers. “We’re going to be sitting with incomplete knowledge on this topic for some time still,” says Topol—even though he and other scientists say they’re confident vaccination against Covid-19 will eventually be shown to reduce the chance of transmitting the virus. The question is: By how much?

“I think it is highly likely that there is some transmission-blocking effect to these vaccines,” says Kawsar Talaat, an infectious disease physician and vaccine safety researcher at the Johns Hopkins Bloomberg School of Public Health. She also led the Johns Hopkins Center for Immunization Research’s clinical trial of the Pfizer vaccine. But, she says, putting a number on the size of that effect is really tricky.

For one thing, scientists have yet to determine how many copies of the virus need to be in an infected person’s nose to make them contagious to others. “There’s not a clear threshold yet for the amount of viral load at which transmission happens,” says Talaat. Which means you can’t look at someone’s PCR result and know with certainty that the amount of virus the test is detecting is enough to make other people sick.

In general, researchers have found that less virus means milder symptoms and a lower risk of passing it on. But not always. People’s bodies and immune systems behave differently. We all breathe at different rates, exhaling particle plumes of varying size and density. Researchers also haven’t pinpointed exactly how much SARS-CoV-2 has to get into your nose to cause an infection. And that number is also subject to similar biological variables, as well as environmental ones, like which strains are circulating in your area. More transmissible variants, like B.1.1.7, which is currently spreading across much of the US, might need to take fewer cracks at the ACE2 receptor. So being able to say that X amount of virus in the nose equals Y risk of spreading to other people is just beyond the scope of the current science.

Even so, several research groups in Israel are measuring viral load in vaccinated people who later test positive for SARS-CoV-2. One team from the Israel Institute of Technology and Tel-Aviv University recently observed that people who caught the virus two to four weeks after receiving their first dose of the Pfizer vaccine had up to 4 times smaller viral loads than people who got infected in the first two weeks after getting the shot. The results suggest the vaccine reduces the risks of transmission, while not erasing them entirely.

That’s an expected result, says Talaat. No vaccine out there right now, no matter how good (and the Pfizer and Moderna shots are very good), will stop the coronavirus from causing infections in at least some people who’ve gotten the shots. Here’s why.

The two FDA-authorized vaccines in the US are first-in-their-generation genetic vaccines. What comes out the tip of that needle and into the muscles of your arm are microscopic, fat-encapsulated strands of mRNA. These strings of genetic letters carry the instructions for making bits of the coronavirus spike protein, which the live virus uses to infect human cells. Capillaries that run through the muscle whisk the mRNA molecules into the bloodstream and carry them to the nearest lymph node. Once there, the vaccine components encounter dendritic cells and macrophages—two types of immune cells that can sense when something foreign is sneaking around in the body. They grab the mRNA and use it to produce pieces of the spike protein, which they then display on their surfaces to flag down other immune cells. These begin churning out antibodies and activating T-cells to fight off what the body perceives as an infection.

There isn’t one, of course. But this fire drill prepares the immune system to quickly kick into action should the vaccinated person encounter the real coronavirus in the future. The Pfizer-BioNTech and Moderna vaccines are especially good at it. But to an antibody or a T-cell, the body is a big place, and the nose is a battlefront far-removed from the initial action in the arm. “If you give a shot in the arm, you’re likely to get immunity in the body,” says Talaat. “But it’s hard to create immunity in the mucosal surfaces where the virus colonizes.”

SARS-CoV-2 might cause its deadliest damage in the lungs, heart, and blood vessels. But its first stop in the human body is usually the nose, because that’s where inhaled viral particles first encounter cells they can invade and hijack in order to make copies of themselves. From there, the swarm of new viruses can expand into other organs—if the immune system doesn’t shut them down. And it’s from the nose that infected people can send out new clouds of contagion.

So in order for a vaccine to block transmission completely, it would have to recruit a cast of SARS-CoV-2-targeted antibodies and immune cells specifically to patrol the nasal passages, where they could glom onto any coronaviruses just after they get inhaled, and before they start their self-replication spree. This is how the nasal spray versions of flu vaccines work. But that’s just not what Pfizer or Moderna’s shots were designed to do. They were designed to create a sparser crew of wider-roaming immune defenders that can jump-start a bigger response wherever they encounter the virus, giving an infected person a better chance of beating back full-blown symptoms. “The goal of these vaccines has always been to prevent people getting hospitalized and dying, because that has the biggest public health impact,” says Talaat.

The good news about the Israeli and UK studies, even with their methodological flaws regarding transmission, Talaat says, is that they show that out in the real world, away from the controlled parameters of a clinical trial, the vaccines are working fabulously at preventing people from getting seriously ill. In the leaked Israeli report, the vaccines led to a 95 percent drop in hospitalizations and 92 percent dip in deaths. And newer, better-vetted data is already starting to back that up.

A study published Wednesday in the New England Journal of Medicine that analyzed 600,000 pairs of vaccinated and unvaccinated Israeli individuals found that two doses of the Pfizer’s shot was 92 percent protective against severe disease and 87 percent effective at preventing hospitalization. Though the study did not have data on deaths following the second dose, just a single shot lowered death rates by 72 percent. So from a public health standpoint, that makes the question of whether or not the Pfizer vaccine, or any other, stops viral spread really a secondary concern, says Talaat. “If you vaccinate enough people, then you don’t need a vaccine that stops carriage in the nose and potential transmission,” she says.

But that number does matter for answering questions like these: Is it safe to eat inside a restaurant? Or get on an airplane? Or hug your grandkids?

Say the vaccine you get is 80 percent effective at blocking viral spread. That means that should you contract the virus, you may not get seriously ill or even have a single symptom—but there’s still a 20 percent chance you’ll pass it on to someone else. And what if the vaccine you get is only 50 percent effective at blocking spread? Now it’s a coin flip.

“This is exactly the type of gray area where reasonable people might reasonably arrive at different answers,” says Halpern. “It all comes down to the fact that we don’t all have the same risk tolerance.”

Talaat’s version of this calculus involves navigating family get-togethers with her parents (vaccinated) and her siblings (unvaccinated). Since she herself is vaccinated, Talaat still wears a mask when she’s visiting her siblings. And she’ll continue to do so until they get their shots. But she feels more relaxed around her parents. “If you are in a household or pod with someone who’s not vaccinated, you should still be as careful as you can to prevent potential transmission, especially if that person is high-risk,” she says.

That doesn’t mean your post-shot life has to look exactly the same as pre-jab. But it does mean continuing to wear masks and socially distancing. Both of those further reduce the risk of spread—how much exactly, no one can say, so public health experts say better to do them all. At least for now.

That’s because whatever the “real” transmission rate for vaccinated people may turn out to be, that number doesn’t exist in a vacuum. A 50 percent reduction in risk of transmission isn’t (or shouldn’t be) particularly liberating if the virus is still running rampant in your area. But it might be if local case prevalence shrinks to the point where your odds of exposure to the coronavirus are virtually zero. The calculation can’t just be about the level of protection of the vaccine against viral spread, but also about the risks in your particular community, says Halpern.

“So where we are today is that you have to keep your mask on after getting vaccinated—not because the vaccine doesn’t work, but because there’s still too much virus in pretty much every neighborhood in America,” he says. “If everyone keeps doing it, we’re going to get to a point where the masks can come off. But we’re not there yet.”

Drugmakers Look for New Ways to Test Covid-19 Vaccines


As more Covid-19 vaccines become available in the U.S., it is getting tougher to run large clinical trials to test a new vaccine’s ability to prevent disease because people are less willing to take a placebo—forcing drugmakers and researchers to look for workarounds as they vet the next generation of shots and test new uses for authorized ones.

One potential workaround would be to determine what level of immune response a vaccine has to trigger to protect people from the coronavirus, as measured in blood samples, and to use that information to create smaller, faster and less-expensive clinical trials.

Instead of requiring tens of thousands of volunteers and costing several hundred-million dollars, such trials could involve only hundreds of people at a fraction of the cost. They could be used to speed the availability of new vaccines targeting emerging variants.

Moderna Inc., MRNA +1.71% Pfizer PFE -0.98% and its partner BioNTech SEBNTX -1.21% and a federally funded network of researchers are conducting analyses to learn what immune response is necessary for protection with current vaccines, known as an immune correlate of protection. They say it could come in handy for new studies of already-authorized vaccines—such as testing the shots in children or whether reduced doses are effective—as well as for trials of the next generation of shots, including those targeting new coronavirus strains. Over time, such knowledge could also help determine how long protection from the vaccines lasts.

Another workaround is to run future large efficacy trials outside the U.S., in places where viral transmission is high and vaccine availability is more limited. Arcturus Therapeutics Holdings Inc., whose Covid-19 vaccine is in mid-stage testing, may run a large Phase 3 trial of its experimental shot outside the U.S. because of the diminishing feasibility of running it in the U.S., Chief Executive Joseph Payne said in an interview. The company hasn’t disclosed which country or countries.

Large studies involving tens of thousands of people have been launched in the U.S. for five Covid-19 vaccines, including the two authorized for use from Moderna and Pfizer and a vaccine from Johnson & JohnsonJNJ -0.41% which plans to seek U.S. authorization soon. In these studies, researchers randomly assign the volunteers to receive either the vaccine or a placebo and then compare how many get sick with Covid-19 in each group.

Vaccine vs. Placebo

But it is becoming more difficult to run these placebo-controlled efficacy trials because prospective recruits increasingly want one of the highly effective authorized shots rather than an experimental shot or a placebo, researchers say. The challenge is heightened among groups that now have access to the vaccines, like health-care workers and the elderly.

In a large study of Novavax Inc.’s NVAX +1.15% vaccine, about 1.5% of the volunteers who were assigned to receive a placebo subsequently decided to get one of the authorized vaccines, Gregory Glenn, the company’s head of research, said in an online scientific forum this week. More than half of those making that choice were over the age of 65.

“People in the U.S. don’t want a placebo anymore if they’re in a group that can get the authorized vaccines,” said Dr. Kathleen Neuzil, a vaccine researcher at the University of Maryland who helps lead the federally funded Covid-19 Prevention Network, made up of research sites running large clinical trials of Covid-19 shots.

Covid-19 vaccines are designed to work by inducing a person’s immune system to produce antibody proteins that can neutralize the coronavirus. The immune correlate of protection is the concentration of those antibodies at a level that prevents Covid-19 disease; antibodies below that level aren’t protective, while at or above that level are protective.

The immune correlate of protection wouldn’t be definitive proof that a vaccine is effective at protecting people from disease, but it could be sufficient to guide regulatory authorization of new vaccines or new uses for existing vaccines, said Peter Gilbert, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle and part of the Covid-19 Prevention Network. Regulators would still require reports of any side effects to determine safety and might require further studies to confirm efficacy.

A Predictive Blueprint

Such correlates of protection have been used for past vaccine development. The Food and Drug Administration has approved certain meningitis vaccines based on their ability to induce an immune response that correlates with protection, rather than requiring large placebo-controlled efficacy trials.

“It saves time, it saves money and it may be the only thing that’s logistically feasible going forward,” Dr. Neuzil said.

Covid-19 vaccines researchers expect to determine the immune correlate of protection by comparing antibody levels in blood samples taken from vaccinated people who stayed healthy with antibody levels in the relatively small number of vaccinated people in the studies who still got sick from Covid-19.

Researchers from the Covid-19 Prevention Network are running analyses to try to determine the immune correlate of protection for Moderna’s vaccine within the next couple of months. They are examining some of the blood samples taken from all subjects about one month after the second dose in the large clinical study of the Moderna vaccine.

They plan to conduct similar analyses for other Covid-19 vaccines from J&J, AstraZeneca PLC and Novavax, which are being tested in trials run by the researchers’ network.

Pfizer and BioNTech are conducting their own analysis to determine the correlate of protection for their Covid-19 vaccine. A Pfizer spokeswoman said the company would explore the use of immune responses in additional studies of its vaccine, such as in pregnant women, children and people with compromised immune systems.

Leaders of the Covid-19 Prevention Network expect that future vaccines could be approved based on trials of only several hundred people, if results show that they had an immune response believed to be protective.

Moderna is exploring the use of an immune correlate of protection to test whether a half-dose of its vaccine could offer sufficient protection against Covid-19 disease, Chief Medical Officer Tal Zaks said at a recent investor conference.

An FDA spokeswoman said that when immune correlates of protection are established for these vaccines, they will be useful for a variety of studies including the evaluation of vaccines in children and assessing the response to new variants.

There are challenges for determining protective immune responses. There were relatively few cases of symptomatic Covid-19 in people who received the Moderna and Pfizer vaccines in the large studies at the time they were authorized, making statistically significant comparisons difficult. But researchers continue to follow study subjects and expect to see higher numbers.

As Virus Grows Stealthier, Vaccine Makers Reconsider Battle Plans


As the coronavirus assumes contagious new forms around the world, two drug makers reported on Monday that their vaccines, while still effective, offer less protection against one variant and began revising plans to turn back an evolving pathogen that has killed more than two million people.

The news from Moderna and Pfizer-BioNTech underscored a realization by scientists that the virus is changing more quickly than once thought, and may well continue to develop in ways that help it elude the vaccines being deployed worldwide.

The announcements arrived even as President Biden banned travel to the United States from South Africa beginning on Saturday, in hopes of stanching the spread of one variant. And Merck, a leading drug company, on Monday abandoned two experimental coronavirus vaccines altogether, saying they did not produce a strong enough immune response against the original version of the virus.

Moderna and Pfizer-BioNTech both said their vaccines were effective against new variants of the coronavirus discovered in Britain and South Africa. But they are slightly less protective against the variant in South Africa, which may be more adept at dodging antibodies in the bloodstream.

The vaccines are the only ones authorized for emergency use in the United States.

As a precaution, Moderna has begun developing a new form of its vaccine that could be used as a booster shot against the variant in South Africa. “We’re doing it today to be ahead of the curve, should we need to,” Dr. Tal Zaks, Moderna’s chief medical officer, said in an interview. “I think of it as an insurance policy.”

“I don’t know if we need it, and I hope we don’t,” he added.

Moderna said it also planned to begin testing whether giving patients a third shot of its original vaccine as a booster could help fend off newly emerging forms of the virus.

Dr. Ugur Sahin, the chief executive of BioNTech, said in an interview on Monday that his company was talking to regulators around the world about what types of clinical trials and safety reviews would be required to authorize a new version of the Pfizer-BioNTech vaccine that would be better able to head off the variant in South Africa.

Studies showing decreased levels of antibodies against a new variant do not mean a vaccine is proportionately less effective, Dr. Sahin said.

BioNTech could develop a newly adjusted vaccine against the variants in about six weeks, he said. The Food and Drug Administration has not commented on what its policy will be for authorizing vaccines that have been updated to work better against new variants.

But some scientists said that the adjusted vaccines should not have to go through the same level of scrutiny, including extensive clinical trials, that the original versions did. The influenza vaccine is updated each year to account for new strains without an extensive approval process.

“The whole point of this is a rapid response to an emerging situation,” said John Moore, a virologist at Weill Cornell Medicine in New York.

Dr. Sahin said a similar booster shot eventually might be necessary to stop Covid-19. The vaccine’s reduced efficacy may also mean that more people would need to get the shots before the population achieves herd immunity.

Scientists had predicted that the coronavirus would evolve and might acquire new mutations that would thwart vaccines, but few researchers expected it to happen so soon. Part of the problem is the sheer ubiquity of the pathogen.CORONAVIRUS BRIEFING: An informed guide to the global outbreak, with the latest developments and expert advice.Sign Up

There have been nearly 100 million cases worldwide since the pandemic began, and each new infection gives the coronavirus more chances to mutate. Its uncontrolled spread has fueled the development of new forms that challenge human hosts in various ways.

“The more people infected, the more likely that we will see new variants,” said Dr. Michel Nussenzweig, an immunologist at Rockefeller University in New York. “If we give the virus a chance to do its worst, it will.”

Several variants have emerged with mutations that worry scientists. A form first detected in Britain is up to 50 percent more contagious than the virus identified in China a year ago, and researchers have begun to think that it may also be slightly more deadly.

Researchers in South Africa identified another variant after doctors there discovered a jump in Covid-19 cases in October. They alerted the World Health Organization in early December that the variant seemed to have mutations that might make the virus less susceptible to vaccines.Covid-19 Vaccines ›

While the exact order of vaccine recipients may vary by state, most will likely put medical workers and residents of long-term care facilities first. If you want to understand how this decision is getting made, this article will help.When can I return to normal life after being vaccinated?If I’ve been vaccinated, do I still need to wear a mask?Will it hurt? What are the side effects?Will mRNA vaccines change my genes?

A variant found in Brazil has many of the mutations seen in the South African form, but genetic evidence suggests that the two variants evolved independently. Preliminary studies in the laboratory had hinted that those viruses may have some degree of resistance to the immunity that people develop after recovering from the infection or being inoculated with the Moderna or Pfizer-BioNTech vaccines.

The variant identified in Britain has been found in at least 20 states in the United States. The version found in South Africa has not been reported in this country, but on Monday health officials in Minnesota announced that they had documented the first case of infection with the Brazilian variant.

It is far from certain that these are the only worrying variants out there. Few countries, including the United States, have invested in the kind of genetic surveillance needed to detect emerging variants. Britain leads the world in these efforts, sequencing of about 10 percent of its virus samples.

The United States has analyzed less than 1 percent of its samples; officials at the Centers for Disease Control and Prevention said this month that they expect to swiftly ramp up those efforts.

Researchers at Moderna examined blood samples from eight people who had received two doses of the vaccine, and two monkeys that had been immunized. Neutralizing antibodies — the type that can disable the virus — were just as effective against the variant identified in Britain as they were against the original form of the virus.

But with the variant circulating in South Africa, there was a sixfold reduction in the antibodies’ effectiveness. Even so, the company said, those antibodies “remain above levels that are expected to be protective.”

The results have not been published or peer-reviewed, but were posted online at BioRxiv. Moderna collaborated on the study with the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

Dr. Zaks said that the new version of the Moderna vaccine, aimed at the South African variant, could be used if needed as a booster one year after people received the original vaccine.

The need for such a booster may be determined by blood tests to measure antibody levels or by watching the population of vaccinated people to see if they begin falling ill from the new variant.

“We don’t yet have data on the Brazilian variant,” Dr. Zaks said. “Our expectation is that if anything it should be close to the South African one. That’s the one with the most overlap.” New forms of the virus will continue to emerge, he said, “and we’ll continue to evaluate them.”

Noting that Moderna took 42 days to produce the original vaccine, he said the company could make a new one “hopefully a little faster this time, but not much.”

One reason the current vaccine remains effective is a “cushion effect,” meaning it provokes such a powerful immune response that it will remain highly protective even with some drop in antibody strength, Dr. Anthony S. Fauci, the government’s leading expert on infectious diseases, and President Biden’s adviser on the coronavirus, said at a news briefing on Friday.

Experts also cautioned against assuming that a decrease in neutralizing ability meant the vaccines were powerless against the new variants. Neutralizing antibodies are just one component of the body’s immune defense, noted Akiko Iwasaki, an immunologist at Yale University.

“In real life, there’s also T cells and memory B cells and non-neutralizing antibodies and all these other effectors that are going to be induced by the vaccine,” Dr. Iwasaki said. Neutralizing power is “very important, but it’s not the only thing that’s going to protect someone.”

So long as the authorized vaccines continue to work against the variants, the challenge will be to inoculate as many people as possible and to prevent the coronavirus from evolving into more impervious forms. “That for me is still the highest priority,” said Dr. Sahin, of BioNTech.

Then, he said, perhaps six to nine months later, people could be given a boost that was customized for the variant.

The pace of the vaccine rollout in the United States, at least, may be picking up. Dr. Fauci predicted on Sunday that two million inoculations daily might soon be possible.

But there are many countries where no one has been immunized. With richer countries buying up doses early, some populations may have to wait till 2022 at the earliest to gain access to any vaccines.

In theory, new variants emerging in other parts of the world could render the virus resistant to the vaccines, Dr. Nussenzweig said, and they would inevitably spread. It is therefore in everyone’s interest to immunize the world as quickly as possible, he added: “We can’t hermetically seal ourselves from the rest of the world.”

Hoping to contain the new variants, the administration has upheld bans on travel by noncitizens into the United States from Europe and Brazil. President Biden will ban travel by noncitizens from South Africa starting Saturday. But that variant may already be in the United States, researchers said.How Moderna’s Vaccine WorksTwo shots can prime the immune system to fight the coronavirus.

The mRNA technology used in both the Pfizer-BioNTech and Moderna vaccines allows them to be created and reformulated much faster than vaccines made with more traditional methods.

“This is the beauty of the mRNA vaccines — they’re very versatile,” Dr. Iwasaki said. But a new formulation may not even be necessary, she added. A third dose of the current vaccine may be enough to boost levels of antibodies.

Dr. Zaks said that discussions with regulators about what would be required to bring a new version of the vaccine to the public were just starting.

“It’s early days,” he said.

Could a Smell Test Screen People for Covid?


In a perfect world, the entrance to every office, restaurant and school would offer a coronavirus test — one with absolute accuracy, and able to instantly determine who was virus-free and safe to admit and who, positively infected, should be turned away.

That reality does not exist. But as the nation struggles to regain a semblance of normal life amid the uncontrolled spread of the virus, some scientists think that a quick test consisting of little more than a stinky strip of paper might at least get us close.

The test does not look for the virus itself, nor can it diagnose disease. Rather, it screens for one of Covid-19’s trademark signs: the loss of the sense of smell. Since last spring, many researchers have come to recognize the symptom, which is also known as anosmia, as one of the best indicators of an ongoing coronavirus infection, capable of identifying even people who don’t otherwise feel sick.

A smell test cannot flag people who contract the coronavirus and never develop any symptoms at all. But in a study that has not yet been published in a scientific journal, a mathematical model showed that sniff-based tests, if administered sufficiently widely and frequently, might detect enough cases to substantially drive transmission down.

Daniel Larremore, an epidemiologist at the University of Colorado, Boulder, and the study’s lead author, stressed that his team’s work was still purely theoretical. Although some smell tests are already in use in clinical and research settings, the products tend to be expensive and laborious to use and are not widely available. And in the context of the pandemic, there is not yet real-world data to support the effectiveness of smell tests as a frequent screen for the coronavirus. Given the many testing woes that have stymied pandemic control efforts so far, some experts have been doubtful that smell tests could be distributed widely enough, or made sufficiently cheat-proof, to reduce the spread of infection.

“I have been intimately involved in pushing to get loss of smell recognized as a symptom of Covid from the beginning,” said Dr. Claire Hopkins, an ear, nose and throat surgeon at Guy’s and St. Thomas’ Hospitals in the United Kingdom and an author of a recent commentary on the subject in The Lancet. “But I just don’t see any value as a screening test.”

A reliable smell test offers many potential benefits. It could catch far more cases than fever checks, which have largely flopped as screening tools for Covid-19. Studies have found that about 50 to 90 percent of people who test positive for the coronavirus experience some degree of measurable smell loss, a result of the virus wreaking havoc when it invades cells in the airway.

“It’s really like a function of the virus being in the nose at this exact moment,” said Danielle Reed, the associate director of the Monell Chemical Senses Center in Philadelphia. “It complements so much of the information you get from other tests.” Last month, Dr. Reed and her colleagues at Monell posted a study, which has not yet been published in a scientific journal, describing a rapid smell test that might be able to screen for Covid-19.

In contrast, only a minority of people with Covid-19 end up spiking a temperature. Fevers also tend to be fleeting, while anosmia can linger for many days.

A smell test could also come with an appealingly low price tag, perhaps as low as 50 cents per card, said Derek Toomre, a cell biologist at Yale University and an author on Dr. Larremore’s paper. Dr. Toomre hopes that his version will fit the bill. The test, the U-Smell-It test, is a small smorgasbord of scratch-and-sniff scents arrayed on paper cards. People taking the test pick away at wells of smells, inhale and punch their guess into a smartphone app, shooting to correctly guess at least three of the five odors. Different cards contain different combinations of scents, so there is no answer key to memorize.The Coronavirus Outbreak ›

He estimated that the test could be taken in less than a minute. It is also a manufacturer’s dream, he said: A single printer “could produce 50 million of these tests per day.” Numbers like that, he argued, could make an enormous dent in a country hampered by widespread lack of access to tests that look directly for pieces of the coronavirus.

In their study, Dr. Larremore, Dr. Toomre and their collaborator Roy Parker, a biochemist at the University of Colorado, Boulder, modeled such a scenario using computational tools. Administered daily or almost daily, a smell screen that caught at least 50 percent of new infections was able to quash outbreaks nearly as well as a more accurate, slower laboratory test given just once a week.

Such tests, Dr. Larremore said, could work as a point-of-entry screen on college campuses or in offices, perhaps in combination with a rapid virus test. There might even be a place for them in the home, if researchers can find a way to minimize misuse.

“I think this is spot on,” said Dr. Carol Yan, an ear, nose and throat specialist at the University of California, San Diego. “Testing people repeatedly is going to be a valuable portion of this.”The Coronavirus Outbreak ›

Dr. Toomre is now seeking an emergency use authorization for the U-Smell-It from the Food and Drug Administration, and has partnered with a number of groups in Europe and elsewhere to trial the test under real-world conditions.

Translating theory into practice, however, will come with many challenges. Smell tests that can reliably identify people who have the coronavirus, while excluding people who are sick with something else, are not yet widely available. (Dr. Hopkins pointed to a couple of smell tests, developed before the pandemic, that cost about $30 each and remain in limited supply.) Should they ever be rolled out in bulk, they would inevitably miss some infected people and, unlike tests that look for the actual virus, could never diagnose disease on their own.

And smell loss, like fever, is not exclusive to Covid-19. Other infections can blunt a person’s sense of smell. So can allergies, nasal congestion from the common cold, or simply the process of aging. About 80 percent of people over the age of 75 have some degree of smell loss. Some people are born anosmic.

Moreover, in many cases of Covid-19, smell loss can linger long after the virus is gone and people are no longer contagious — a complication that could land some people in a post-Covid purgatory if they are forced to rely on smell screens to resume activity, Dr. Yan said.

There are also many ways to design a smell-based screen. Odors linked to foods that are popular in some countries but not others, such as bubble gum or licorice, might skew test results for some individuals. People who have grown up in highly urban areas might not readily recognize scents from nature, like pine or fresh-cut grass.

Smell also is not a binary sense, strictly on or off. Dr. Reed advocated a step in which test takers rate the intensity of a test’s odors — an acknowledgment that the coronavirus can drastically reduce the sense of smell but not eliminate it.

But the more complicated the test, the more difficult it would be to manufacture and deploy speedily. And no test, even a perfectly designed one, would function with 100 percent accuracy.

Dr. Ameet Kini, a pathologist at Loyola University Medical Center, pointed out that smell tests would also not be free of the problems associated with other types of tests, such as poor compliance or a refusal to isolate.

Smell screens are “probably better than nothing,” Dr. Kini said. “But no test is going to stop the pandemic in its tracks unless it’s combined with other measures.”

SARS-CoV-2 is following the evolutionary rule book


Natural selection is a powerful force. In circumstances that are still disputed, it took a bat coronavirus and adapted it to people instead. The result has spread around the globe. Now, in two independent but coincidental events, it has modified that virus still further, creating new variants which are displacing the original versions. It looks possible that one or other of these novel viruses will itself soon become a dominant form of sars-cov-2.

Knowledge of both became widespread in mid-December. In Britain, a set of researchers called the Covid-19 Genomics uk Consortium (cog-uk) published the genetic sequence of variant b.1.1.7, and nervtag, a group that studies emerging viral threats, advised the government that this version of the virus was 67-75% more transmissible than those already circulating in the country. In South Africa, meanwhile, Salim Abdool Kalim, a leading epidemiologist, briefed the country on all three television channels about a variant called 501.v2 which, by then, was accounting for almost 90% of new covid-19 infections in the province of Western Cape.

Britain responded on December 19th, by tightening restrictions already in place. South Africa’s response came on December 28th, in the wake of its millionth recorded case of the illness, with measures that extended a night-time curfew by two hours and reimposed a ban on the sale of alcohol. Other countries have reacted by discouraging even more forcefully than before any travel between themselves and Britain and South Africa. At least in the case of b.1.1.7, though, this has merely shut the stable door after the horse has bolted. That variant has now been detected in a score of countries besides Britain—and from these new sites, or from Britain, it will spread still further. Isolated cases of 501.v2 outside South Africa have been reported, too, from Australia, Britain, Japan and Switzerland.

So far, the evidence suggests that despite their extra transmissibility, neither new variant is more dangerous on a case-by-case basis than existing versions of the virus. In this, both are travelling the path predicted by evolutionary biologists to lead to long-term success for a new pathogen—which is to become more contagious (which increases the chance of onward transmission) rather than more deadly (which reduces it). And the speed with which they have spread is impressive.

The first sample of b.1.1.7 was collected on September 20th, to the south-east of London. The second was found the following day in London itself. A few weeks later, at the beginning of November, b.1.1.7 accounted for 28% of new infections in London. By the first week of December that had risen to 62%. It is probably now above 90%.

Variant 501.v2 has a similar history. It began in the Eastern Cape, the first samples dating from mid-October, and has since spread to other coastal provinces.

The rapid rise of b.1.1.7 and 501.v2 raises several questions. One is why these particular variants have been so successful. A second is what circumstances they arose in. A third is whether they will resist any of the new vaccines in which such store is now being placed.

The answers to the first of these questions lie in the variants’ genomes. cog-uk’s investigation of b.1.1.7 shows that it differs meaningfully from the original version of sars-cov-2 in 17 places. That is a lot. Moreover, several of these differences are in the gene for spike, the protein by which coronaviruses attach themselves to their cellular prey. Three of the spike mutations particularly caught the researchers’ eyes.

One, n501y, affects the 501st link in spike’s amino-acid chain. This link is part of a structure called the receptor-binding domain, which stretches from links 319 to 541. It is one of six key contact points that help lock spike onto its target, a protein called ace2 which occurs on the surface membranes of certain cells lining the airways of the lungs. The letters in the mutation’s name refer to the replacement of an amino acid called asparagine (“n”, in biological shorthand) by one called tyrosine (“y”). That matters because previous laboratory work has shown that the change in chemical properties which this substitution causes binds the two proteins together more tightly than normal. Perhaps tellingly, this particular mutation (though no other) is shared with 501.v2.

Golden spike

b.1.1.7’s other two intriguing spike mutations are 69-70del, which knocks two amino acids out of the chain altogether, and p681h, which substitutes yet another amino acid, histidine, for one called proline at chain-link 681. The double-deletion attracted the researchers’ attention for several reasons, not the least being that it was also found in a viral variant which afflicted some farmed mink in Denmark in November, causing worries about an animal reservoir of the disease developing. The substitution is reckoned significant because it is at one end of a part of the protein called the s1/s2 furin-cleavage site (links 681-688), which helps activate spike in preparation for its encounter with the target cell. This site is absent from the spike proteins of related coronaviruses, such as the original sars, and may be one reason why sars-cov-2 is so infective.

The South African variant, 501.v2, has only three meaningful mutations, and all are in spike’s receptor-binding domain. Besides n501y, they are k417n and e484k (k and e are amino acids called lysine and glutamic acid). These two other links are now the subject of intense scrutiny.

Even three meaningful mutations is quite a lot for a variant to have. Just one would be more usual. The 17 found in b.1.1.7 therefore constitute a huge anomaly. How this plethora of changes came together in a single virus is thus the second question which needs an answer.

The authors of the cog-uk paper have a suggestion. This is that, rather than being a chance accumulation of changes, b.1.1.7 might itself be the consequence of an evolutionary process—but one that happened in a single human being rather than a population. They observe that some people develop chronic covid-19 infections because their immune systems do not work properly and so cannot clear the infection. These unfortunates, they hypothesise, may act as incubators for novel viral variants.

The theory goes like this. At first, such a patient’s lack of natural immunity relaxes pressure on the virus, permitting the multiplication of mutations which would otherwise be culled by the immune system. However, treatment for chronic covid-19 often involves what is known as convalescent plasma. This is serum gathered from recovered covid patients, which is therefore rich in antibodies against sars-cov-2. As a therapy, that approach frequently works. But administering such a cocktail of antibodies applies a strong selection pressure to what is now a diverse viral population in the patient’s body. This, the cog-uk researchers reckon, may result in the success of mutational combinations which would not otherwise have seen the light of day. It is possible that b.1.1.7 is one of these.

The answer to the third question—whether either new variant will resist the vaccines now being rolled out—is “probably not”. It would be a long-odds coincidence if mutations which spread in the absence of a vaccine nevertheless protected the virus carrying them from the immune response raised by that vaccine.

This is no guarantee for the future, though. The swift emergence of these two variants shows evolution’s power. If there is a combination of mutations that can get around the immune response which a vaccine induces, then there is a fair chance that nature will find it.

A New Study Questions Whether Masks Protect Wearers. You Need to Wear Them Anyway.


Researchers in Denmark reported on Wednesday that surgical masks did not protect the wearers against infection with the coronavirus in a large randomized clinical trial. But the findings conflict with those from a number of other studies, experts said, and is not likely to alter public health recommendations in the United States.

The study, published in the Annals of Internal Medicine, did not contradict growing evidence that masks can prevent transmission of the virus from wearer to others. But the conclusion is at odds with the view that masks also protect the wearers — a position endorsed just last week by the Centers for Disease Control and Prevention.

Critics were quick to note the study’s limitations, among them that the design depended heavily on participants reporting their own test results and behavior, at a time when both mask-wearing and infection were rare in Denmark.

Coronavirus infections are soaring throughout the United States, and even officials who had resisted mask mandates are reversing course. Roughly 40 states have implemented mask requirements of some sort, according to a database maintained by The New York Times.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, advocates a national mask mandate, as does President-elect Joseph R. Biden Jr.

“I won’t be president until January 20th, but my message today to everyone is this: wear a mask,” Mr. Biden recently wrote on Twitter.Masks Work. Really. We’ll Show You HowA visual journey through the microscopic world of the coronavirus shows how masks provide an important defense against transmission.

From early April to early June, researchers at the University of Copenhagen recruited 6,024 participants who had been tested beforehand to be sure they were not infected with the coronavirus.

Half were given surgical masks and told to wear them when leaving their homes; the others were told not to wear masks in public.

At that time, 2 percent of the Danish population was infected — a rate lower than that in many places in the United States and Europe today. Social distancing and frequent hand-washing were common, but masks were not.

About 4,860 participants completed the study. The researchers had hoped that masks would cut the infection rate by half among wearers. Instead, 42 people in the mask group, or 1.8 percent, got infected, compared with 53 in the unmasked group, or 2.1 percent. The difference was not statistically significant.CORONAVIRUS BRIEFING: An informed guide to the global outbreak, with the latest developments and expert advice.Sign Up

“Our study gives an indication of how much you gain from wearing a mask,” said Dr. Henning Bundgaard, lead author of the study and a cardiologist at the University of Copenhagen. “Not a lot.”

Dr. Mette Kalager, a professor of medical decision making at the University of Oslo, found the research compelling. The study showed that “although there might be a symbolic effect,” she wrote in an email, “the effect of wearing a mask does not substantially reduce risk” for wearers.

Other experts were unconvinced. The incidence of infections in Denmark was lower than it is today in many places, meaning the effectiveness of masks for wearers may have been harder to detect, they noted.

Participants reported their own test results; mask use was not independently verified, and users may not have worn them correctly.States That Imposed Few Restrictions Now Have the Worst Outbreaks

“There is absolutely no doubt that masks work as source control,” preventing people from infecting others, said Dr. Thomas Frieden, chief executive of Resolve to Save Lives, an advocacy group, and former director of the C.D.C., who wrote an editorial outlining weaknesses of the research.

“The question this study was designed to answer is: Do they work as personal protection?” The answer depends on what mask is used and what sort of exposure to the virus each person has, Dr. Frieden said, and the study was not designed to tease out those details.

“An N95 mask is better than a surgical mask,” Dr. Frieden said. “A surgical mask is better than most cloth masks. A cloth mask is better than nothing.”

The study’s conclusion flies in the face of other research suggesting that masks do protect the wearer. In its recent bulletin, the C.D.C. cited a dozen studies finding that even cloth masks may help protect the wearer. Most of them were laboratory examinations of the particles blocked by materials of various types.

Susan Ellenberg, a biostatistician at the University of Pennsylvania Perelman School of Medicine, noted that protection conferred by masks on the wearer trended “in the direction of benefit” in the trial, even if the results were not statistically significant.

“Nothing in this study suggests to me that it is useless to wear a mask,” she said.Confused About Masks? Here’s What Scientists KnowThe accumulating research may be imperfect, and it’s still evolving, but the takeaway is simple. Right now, masks are necessary to slow the pandemic.

Dr. Elizabeth Halloran, a statistician at Fred Hutchinson Cancer Research Center in Seattle, said the usefulness of masks also depends on how much virus a person is exposed to.

“If you show this article to a health care provider who works in a Covid ward in a hospital, I doubt she or he would say that this article convinces them not to wear a mask,” she said.

But Dr. Christine Laine, editor in chief of the Annals of Internal Medicine, described the previous evidence that masks protect wearers as weak. “These studies cannot differentiate between source control and personal protection of the mask wearer,” she said.

Dr. Laine said the new study underscored the need for adherence to other precautions, like social distancing. Masks “are not a magic bullet,” she said. “There are people who say, ‘I’m fine, I’m wearing a mask.’ They need to realize they are not invulnerable to infection.”

Why It’s a Big Deal If the First Covid Vaccine Is ‘Genetic’


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).

Here’s all the WIRED coverage in one place, from how to keep your children entertained to how this outbreak is affecting the economy. 

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.News of the future, now.Get WIRED for as low as $5.Subscribe Now

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.Get WIRED AccessSUBSCRIBEMost Popular

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.”Most Popular

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.