CRISPR diagnostics


Although clinical diagnostics take many forms, nucleic acid–based testing has become the gold standard for sensitive detection of many diseases, including pathogenic infections. Quantitative polymerase chain reaction (qPCR) has been widely adopted for its ability to detect only a few DNA or RNA molecules that can unambiguously specify a particular disease. However, the complexity of this technique restricts application to laboratory settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has underscored the need for the development and deployment of nucleic acid tests that are economical, easily scaled, and capable of being run in low-resource settings, without sacrifices in speed, sensitivity or specificity. CRISPR-based diagnostic (CRISPR-dx) tools offer a solution, and multiple CRISPR-dx products for detection of the SARS-CoV-2 RNA genome have been authorized by the US Food and Drug Administration (FDA). On page 941 of this issue, Jiao et al. (1) describe a new CRISPR-based tool to distinguish several SARS-CoV-2 variants in a single reaction.

There are multiple types of CRISPR systems comprising basic components of a single protein or protein complex, which cuts a specific DNA or RNA target programmed by a complementary guide sequence in a CRISPR-associated RNA (crRNA). The type V and VI systems and the CRISPR-associated endonucleases Cas12 (23) and Cas13 (45) bind and cut DNA or RNA, respectively. Furthermore, upon recognizing a target DNA or RNA sequence, Cas12 and Cas13 proteins exhibit “collateral activity” whereby any DNA or RNA, respectively, in the sample is cleaved regardless of its nucleic acid sequence (46). Thus, reporter DNAs or RNAs, which allow for visual or fluorescent detection upon cleavage, can be added to a sample to infer the presence or absence of specific DNA or RNA species (48).

Initial versions of CRISPR-dx utilizing Cas13 alone were sensitive to the low picomolar range, corresponding to a limit of detection of millions of molecules in a microliter sample. To improve sensitivity, preamplification methods, such as recombinase polymerase amplification (RPA), PCR, loop-mediated isothermal amplification (LAMP), or nucleic acid sequence–based amplification (NASBA), can be used with Cas12 or Cas13 to enable a limit of detection down to a single molecule (8). This preamplification approach, applicable to both Cas12 and Cas13 (67), enabled a suite of detection methods and multiplexing up to four orthogonal targets (7). Additional developments expanded CRISPR-dx readouts beyond fluorescence, including lateral flow (7), colorimetric (9), and electronic or material responsive readouts (10), allowing for instrument-free approaches. In addition, post–collateral-cleavage amplification methods, such as the use of the CRISPR-associated enzyme Csm6, have been combined with Cas13 to further increase the speed of CRISPR-dx tests (7). As an alternative to collateral-cleavage–based detection, type III CRISPR systems, which involve large multiprotein complexes capable of targeting both DNA and RNA, have been used for SARS-CoV-2 detection through production of colorimetric or fluorometric readouts (11).

FDA-authorized CRISPR-dx tests are currently only for use in centralized labs, because the most common CRISPR detection protocols require fluid handling steps and two different incubations, precluding their immediate use at the point of care. Single-step formulations have been developed to overcome this limitation, and these “one-pot” versions of CRISPR-dx are simple to run, operate at a single temperature, and run without complex equipment, producing either fluorescence or lateral flow readouts. The programmability of CRISPR makes new diagnostic tests easier to develop, and within months of the release of the SARS-CoV-2 genome, many COVID-19–specific CRISPR tests were reported and distributed around the world.

The broader capability for Cas enzyme–enhanced nucleic acid binding or cleavage has led to several other detection modalities. Cas9-based methods for cleaving nucleic acids in solution for diagnostic purposes have been combined with other detection platforms, such as destruction of undesired amplicons for preparation of next-generation sequencing libraries (12), or selective removal of alleles for nucleotide-specific detection (13). Alternatively, the programmable cleavage event from the Cas nuclease can be used to initiate an amplification reaction (14). Cas9-based DNA targeting has also been used for nucleotide detection in combination with solid-state electronics, promising an amplification-free platform for detection. In this platform, called CRISPR-Chip, the Cas9 protein binds nucleotide targets of interest (often in the context of the native genome) to graphene transistors, where the presence of these targets alters either current or voltage (15). By utilizing additional Cas9 orthologs and specific guide designs, CRISPR-Chip approaches have been tuned for single–base-pair sensitivity (15). Because they are integrated with electronic readers, CRISPR-Chip platforms may allow facile point-of-care detection with handheld devices.

Jiao et al. use a distinct characteristic of type II CRISPR systems, which involve Cas9, to develop a new type of noncollateral based CRISPR detection. Unlike Cas12s and Cas13, Cas9-crRNA complex formation requires an additional RNA known as the trans-activating CRISPR RNA (tracrRNA). By sequencing RNAs bound to Cas9 from Campylobacter jejuni in its natural host, the authors identified unexpected crRNAs, called noncanonical crRNA (ncrRNA), that corresponded to endogenous transcripts. Upon investigation of this surprising observation, it became clear that the tracrRNA was capable of hybridizing to semi-complementary sequences from a variety of RNA sources, leading to biogenesis of ncrRNAs of various sizes. Recognizing that they could program tracrRNAs to target a transcript of interest, the authors generated a reprogrammed tracrRNA (Rptr) that could bind and cleave a desired transcript, converting a piece of that transcript into a functional guide RNA. By then creating fluorescent DNA sensors that would be cleaved by the Rptr and ncrRNAs, the sensing of RNA by Cas9 could be linked to a detectable readout. This platform, called LEOPARD (leveraging engineered tracrRNAs and on-target DNAs for parallel RNA detection), can be combined with gel-based readouts and enables multiplexed detection of several different sequences in a single reaction (see the figure).

Jiao et al. also combined LEOPARD with PCR in a multistep workflow to detect SARS-CoV-2 genomes from patients with COVID-19. Although more work is needed to integrate this Cas9-based detection modality into a single step with RPA or LAMP to create a portable and sensitive isothermal test, an advantage of this approach is the higher-order multiplexing that can be achieved, allowing multiple pathogens, diseases, or variants to be detected simultaneously. More work is also needed to combine this technology with extraction-free methods for better ease of use; alternative readouts to gel-based readouts, such as lateral flow and colorimetric readouts, would be beneficial for point-of-care detection.

In just 5 years, the CRISPR-dx field has rapidly expanded, growing from a set of peculiar molecular biology discoveries to multiple FDA-authorized COVID-19 tests and spanning four of the six major subtypes of CRISPR systems. Despite the tremendous promise of CRISPR-dx, substantial challenges remain to adapting these technologies for point-of-care and at-home settings. Simplification of the chemistries to operate as a single reaction in a matter of minutes would be revolutionary, especially if the reaction could be run at room temperature without any complex or expensive equipment. These improvements to CRISPR-dx assays can be achieved by identification or engineering of additional Cas enzymes with lower-temperature requirements, higher sensitivity, or faster kinetics, enabling rapid and simple amplification-free detection with single-molecule sensitivity.

Often overlooked is the necessity for a sample DNA or RNA preparation step that is simple enough to be added directly to the CRISPR reaction to maintain a simple workflow for point-of-care testing. In addition, higher-order multiplexing developments would allow for expansive testing menus and approach the possibility of testing for all known diseases. As these advancements are realized, innovative uses of CRISPR-dx will continue in areas such as surveillance, integration with biomaterials, and environmental monitoring. In future years, CRISPR-dx assays may become universal in the clinic and at home, reshaping how diseases are diagnosed.

Send for the orphans: how the smallpox vaccine crossed the globe

The headlines are familiar. The availability of new vaccines to combat a deadly disease has prompted a global effort to jab as many people as possible, as quickly as possible. But it’s difficult to ensure adequate supplies, and logistical constraints hamper the delivery of delicate medicines across borders. Several national governments are engaging in “vaccine diplomacy”, supplying vaccines to other countries to win political favour. And though some of us can’t wait to be jabbed, others are sceptical. This much we all know, as countries grapple with the challenges of vaccinating their populations against covid-19. But it was also the situation two centuries ago, when the world’s first vaccine was introduced – for smallpox.

In 1798 Edward Jenner, an English doctor, published a book in which he described how to make people immune to smallpox: by deliberately infecting them with cowpox, a related disease. A friend of Jenner’s called this procedure “vaccination”, after vacca, the Latin word for cow. Because cowpox was a milder disease, Jenner suggested this was a safer way to protect people from smallpox than the existing technique, known as inoculation or variolation.

Variolation involved placing pus taken from a smallpox patient under the skin of a healthy person, in the hope of triggering a mild case of the disease, and subsequent immunity. This was risky because it caused full-blown smallpox in about 1% of recipients, and someone suffering even a mild case could infect others and spread the disease. Despite the risks, variolation was used widely in Europe during the 18th century.

It was already common knowledge among farming communities that cowpox could be used to protect people against smallpox. Jenner formalised that technique and, in a series of experiments, demonstrated that it was effective and safe. Initially, his ideas met with scepticism, but as others tried his approach, in a series of trials across Europe, they found that it worked well. Spreading the cowpox vaccine around the world was difficult, however, because cowpox occurred only sporadically in some European countries. So the vaccine’s proponents developed a number of techniques to produce, store and deliver it.

Even rival empires and countries at war exchanged information and vaccine supplies

This started with Jenner himself, who sent supplies of his vaccine through the post as far as North America. He did so in the form of threads which had absorbed fluid, or lymph, from a cowpox pustule and been left to dry. Such threads were moistened and then inserted into an incision in a patient’s arm.

To maintain the vaccine supply, doctors asked patients vaccinated in this way to return a few days later, so that new threads could be created from their cowpox pustules. Alternatively, lymph from the pustules of returning patients was used to vaccinate others directly, a technique known as “arm to arm” vaccination. In effect, the vaccine was kept alive in one patient before being passed to the next.

Spain used arm-to-arm vaccination to deliver the smallpox vaccine to its colonies in Latin America. In 1803 the Maria Pita, a 160-tonne ship, set sail for the Americas. On board were 22 orphan boys, aged between three and nine, two of whom had been vaccinated shortly before the voyage began. Every nine or ten days, two more boys were vaccinated using the arm-to-arm technique, to ensure the vaccine survived. When the ship arrived in Venezuela only one child still had cowpox pustules, but that was enough to allow the vaccination of local children to begin.

The leader of the expedition, Francisco Xavier de Balmis, established a vaccination centre in Caracas to train doctors in the technique and establish a sustainable supply of threads. Tens of thousands of people were vaccinated as the expedition proceeded to Bogota, Quito and Lima. Balmis then headed west to the Philippines, this time with 26 Mexican orphans to carry the vaccine, and established another vaccination centre in Manila, open to all citizens. From there, he went on to China, introducing the vaccine to Macau and helping the British establish a vaccination centre in what was then called Canton.

Britain wanted to introduce vaccination to India, parts of which were under its control. Smallpox was particularly deadly there. In 1799 Jenner sent vaccine lymph, dried onto threads and lancets, along with a group of volunteers trained to administer it, on a ship to Bombay, but the voyage foundered when rounding the Cape of Good Hope. Subsequent attempts to send the vaccine using orphan boys also failed. So people began to think about alternative routes via the Middle East.

In 1802 Lord Elgin, the British ambassador to the Ottoman Empire (who is today known less for his diplomacy than for his controversial removal of sculptures from the Parthenon), came up with a new plan. He suggested asking Jean de Carro, a Swiss doctor who had introduced vaccination into the Austro-Hungarian Empire, to send vaccine supplies from Vienna to Baghdad.

Carro used a combination of techniques: he sent vaccine-dipped lancets made of silver and ivory, and also threads impregnated with lymph, secured in glass slides, sealed inside wax balls and packed in a box filled with shreds of paper. When the package arrived at its destination, the lymph within the glass slides was still liquid. Vaccinations were carried out in Baghdad and the port of Basra. From there, the vaccine was sent on a three-week voyage to Bombay, and subsequently distributed throughout India.

“We have been able to disseminate vaccination in all of India, and the prestige that we have achieved by this one act has been the source of much good will from the people,” reported the governor of Bombay. From India, the vaccine was carried in 1803 to Ceylon (as Sri Lanka was then called), to the French colonies in the Indian Ocean, and from there to the Dutch East Indies. By 1804 the vaccine had reached Australia.

Despite this rapid spread, and a general enthusiasm for it among populations that had been ravaged by smallpox, vaccination was controversial. A British cartoon from 1802, entitled “The Wonderful Effects of the New Inoculation”, shows people turning into cows, or with small cows growing out of their arms.

Some people regarded the cowpox vaccine as unnatural and un-Christian because it came from an animal. Others questioned the ethics of deliberately infecting a healthy person. In India, some Hindus didn’t want the vaccine because it used material derived from cows, which they considered sacred.

Opposition to smallpox vaccination increased during the 19th century, particularly as governments in some countries tried to make it mandatory. After decades of rallies and demonstrations in Britain, the Vaccination Act of 1898 included a “conscientious objector” clause (the first use of the phrase), allowing people to refuse vaccination and removing the penalties for doing so.

The logistical challenges of production and distribution, vaccine hesitancy and vaccine diplomacy are, in short, as old as vaccines themselves. Of course, the situation today differs from the smallpox vaccination effort in many important respects. The smallpox vaccine could be multiplied and propagated using material from vaccinated individuals at almost no cost, which meant that providing vaccines to others didn’t diminish the donor’s own supply. Jenner’s vaccine didn’t require complex manufacturing techniques and was not protected by patents.

But perhaps the most striking difference between then and now was the lack of vaccine nationalism. Even rival empires and countries that were at war, like Britain and France, exchanged information and vaccine supplies. Jenner wrote of Balmis’s expedition: “I don’t imagine the annals of history furnish an example of philanthropy so noble, so extensive as this.”

In France, the revolutionary government brought in William Woodville, an English doctor, to provide training and a supply of lymph. He was hailed as “a learned man…meriting our gratitude and praise. Already he has vaccinated six thousand children with invariable success; for the prevention of smallpox this is a marvellous thing.”

The French government went on to vaccinate all its soldiers, at home and abroad, and Napoleon awarded Jenner a medal. When Jenner asked for two English prisoners-of-war to be released, Napoleon granted his request, remarking that he could not “refuse anything to one of the greatest benefactors of mankind”. It is all a far cry from today’s uk-eu squabbles over vaccine exports.

Today the covax initiative provides a way for rich countries to give coronavirus vaccines to poorer ones, as happened with the smallpox vaccine. But it is making slow progress, as donor countries focus on vaccinating their own populations first. Wealthy countries could do more to provide funding, transfer vaccine-making expertise and technology, and relax intellectual-property constraints, to boost the overall supply and give poorer countries the ability to produce their own vaccines. That is, after all, what they did with smallpox vaccines, 200 years ago.■

Covid-19 vaccines have alerted the world to the power of RNA therapies


Molecular biology is not a popularity contest. But if it were, it would be a partisan one. The evolutionary biologists would pledge their allegiance en masse to dna. The sequences contained in its regular coils knit together the stories of almost all life on the planet. Pharmacologists, being of a more practical bent, would instead vote for proteins. Proteins are not about sequence, but about shape; their complex, irregular outlines, and the ways that they can change, allow them to do almost all of the biological work that gets done in cells. And it is thanks to the way that particular drug molecules fit into those shapes that almost all drugs have their effects.Listen to this story

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There would be only a small following for ribonucleic acid (rna), widely seen as a helpmeet molecule. It could be argued that the production of rna is dna’s main purpose; it is certainly true that the production of proteins would be nowhere without it. But it is a backstage operator, not a star; hewing wood and drawing water, hard working but hardly glamorous, appreciated only by devotees.

Or at least that was the case until vaccines made of rna started giving protection against covid-19 to millions of people around the world every day. Now Cinderella has gone to the ball. Not only are rna vaccines being considered for all sorts of other diseases, some of which have yielded to no other approach; other pharmaceutical uses of rna look set to come into their own, as well. The way molecular biology is applied to medicine seems to be in the throes of revolution.

Incarnation incarnate

The great unifying truth of molecular biology, uncovered during the intellectual revolution which followed the discovery of dna’s double-helix structure, is the way in which the worlds of shape and sequence are linked. The shape of a protein depends on the intricate way in which the chain of amino acids of which it consists is folded up. That depends in turn on the order in which amino acids of different types are strung together on that chain. And the order of the amino acids is a crucial part of the genetic information stored in the dna sequences of the cell’s genome.

The transfer of information from the staid archival form it takes in the genome to its active physical instantiation in the machineries of the cell depends on rna, a molecule in which both sequence and shape play crucial roles. The gene sequence is first copied from dna to rna; that rna transcript is then edited to form a molecule called a messenger rna, or mrna (see diagram).

The end of the mrna molecule is formatted into a distinctive shape which is recognised by ribosomes, complex pieces of machinery composed of dozens of proteins draped around another set of rna molecules. With the help of yet more rna molecules—little ones called trnas which stick to the mrna sequence three letters at a time—the ribosome translates the genetic message into the protein it refers to by creating a chain of amino acids as it moves along the message.

This is the mechanism exploited by the rna vaccines developed by BioNTech, a German biotechnology company based in Mainz, and Moderna, an American one from Cambridge, Massachusetts, against sars-cov-2, the virus which causes covid-19. The companies mass produce the rna sequence describing the distinctive “spike” protein, which studs the outer membrane of the virus, formatted so as to look like a natural mrna. These rna molecules, wrapped in little fatty bubbles called liposomes are injected into patients, where the liposomes smuggle the mrna into cells. Ribosomes pick up on the mrna format and read the sequence, thus producing the spike protein. The immune system learns to recognise the spike which the vaccinated cells are producing and stores away the memory of how to do so. This allows it to mount a swift response if it later comes across the same protein on the surfaces of viral particles and infected cells.

This ability to get cells to churn out proteins for which their dna contains no genes is, in itself, enough to open up swathes of new therapeutic territory. But it is not the whole story. Cells make vast amounts of rna that does not describe proteins. Its ability to recognise specific genetic sequences makes it useful for all sorts of processes, including turning the translation of genes on and off. Its ability to fold itself into particular forms—hairpins, loops and the like—makes it good at interacting with proteins.

This alphabet soup of rnas (see table) seems to function a bit like a computer’s operating system, mediating the relationship between the cell’s hardware and its software. Many of the details of how this works remain obscure. But some are understood well enough for a lot of brainpower and money to have been poured into attempts to hack the operating system for therapeutic purposes.

These abilities should enable drugmakers to head upstream from the proteins whose shapes they have long studied into the realms of sequence. Where previously they targeted proteins which were already present, now they can in principle target the processes which control which proteins get made in the first place, adding helpful new ones to the roster and crossing harmful old ones off. There are rna-based drugs in clinical trials for the treatment of cancer, heart disease and numerous inherited disorders—as well as brain diseases such as Alzheimer’s and Parkinson’s.

Moreover, rna’s mixture of sequence and shape means that in many of these areas the once-haphazard process of drug discovery, long dependent on matching the shape of small synthetic molecules to the crannies and crevices of the proteins they targeted, can itself be systematised. A sequence which recognises, or forms a part of, one gene can be switched out for a sequence tailored to another. When what an rna drug does depends on its sequence, its target and action can be modified by the click of a mouse.

The medicine is the message

Both the firms with mrna vaccines on sale had other vaccines in the pipeline before covid-19 struck. It is part of the appeal of the technology that they were able to turn on a sixpence and refocus their efforts on sars-cov-2 as soon as the sequence for its spike gene was released last January. Now they are both getting on with what they had planned beforehand. Moderna is looking at vaccines to fend off infection by cytomegalovirus (a herpes virus which causes neurological problems in newborns), three lung viruses which cause respiratory disease in young children and Zika, a mosquito-borne virus found mainly in the tropics. BioNTech is focusing more on developing vaccines, and other treatments, with which to treat a wide range of cancers.

Cancer cells tend to have peculiar constellations of proteins on their surfaces, including both normal ones that are overexpressed and, more intriguingly, mutant forms peculiar to the development of that tumour. Comparing the genes expressed in a patient’s healthy cells with those used by their tumour cells reveals which mutant proteins the cancers are producing; mrnas for those proteins can then be incorporated into a vaccine.

Produced as a result of vaccination, the proteins can engender a vigorous immune response the cancer itself does not—part of being a successful tumour is deploying mechanisms that stop the immune system from coming to grips with you. According to Ozlem Tureci, BioNTech’s co-founder, the firm has 500 patients enrolled in clinical trials for cancer. Moderna is pursuing similar ideas.

BioNTech is also testing mrna vaccines aimed at overexpressed but unmutated proteins. Moderna, meanwhile, is looking into vaccines that train the immune system to recognise proteins created by common mutations in kras, a gene implicated in about 20% of human cancers. CureVac, based in Tübingen, an mrna firm which also has a sars-cov-2 vaccine in trials, is conducting trials of a vaccine for non-small-cell lung cancer.

Vaccination is not the only way that mrna injection might fight viruses and tumours. The technique could also be used to get cells to produce therapeutic proteins that are currently administered through injection or infusion: interleukins and antibodies. Designer antibodies are a massive faff to make in industrial quantities; getting patients’ cells to take on the manufacturing duties instead would be a great step forward if it proved practical.

There are many other sorts of proteins which can be stimulated to therapeutic effect. A project on which Moderna is collaborating with AstraZeneca, a pharmaceutical giant, delivers the mrna for a protein which encourages the regrowth of blood vessels. The idea is that the therapy, now in phase 2 clinical trials, could stimulate the growth of new cardiac blood vessels after heart attacks.

Getting the body to produce a protein it needs just for a short while—an antibody, say, or a growth factor—is one thing. But what about a protein that it needs on an everyday basis, but lacks the gene for? Such genetic diseases have always been the most obvious targets for gene therapy—treatments which add a missing gene to a patient’s cells, or repair a broken one, thus allowing them to make a protein they have hitherto lacked. But at least some such conditions might instead be treated with mrna. Inserting a gene might be more elegant—but getting it in the right place and regulated in the right way is challenging. If mrna treatments get the job done, they might offer a nice alternative.

There are thus mrna treatments being studied for phenylketonuria, a metabolic disorder which requires sufferers to restrict their diets for their entire lives; glycogen-storage disease, which enlarges the liver and kidneys and stunts children’s growth; and propionic and methylmalonic acidemias, two illnesses in which the body cannot properly break down proteins and fats. All are conditions that gene therapists are looking at, too.

That BioNTech, Curevac, Moderna and some others now have all these projects on the go is largely down to the fact that they have spent many years developing the basics of their platforms. Many hurdles had to be crossed before they could get cells to accept and act on messages from beyond; the rna had to be subtly toughened up so that it would not itself fall prey to the immune system or get dismantled inside cells; the right lipids had to be found for delivery, sometimes tailored to particular tissues like those of the liver or lymph nodes. The potential inherent in the idea meant that their work was not completely ignored; in 2018 Moderna’s ipo valued the company at $7.5bn, a record for the biotech sector. But biotechnology has a long history of proving biology to be messier and more contrary than those seeking to exploit its loopholes expect.

Stop making sense

Scepticism was also warranted, it seemed, by the fact that messing around with rna had been through bursts of popularity before. One of the very oldest companies in the field, Ionis Pharmaceutials (known as Isis until that name was appropriated by a would-be caliphate) was founded in 1989. Its intention, then and now, was not to make use of mrna, but to hobble it.

The sequence of an mrna molecule carries the same information as can be found in the gene which served as its template; but thanks to the way rna is made it carries it in a complementary way. Where the dna has a letter called C for cytosine, the rna will have G for guanine; where the rna has a C the dna will have a G, and so on. Complementary strands stick together; that is what keeps dna molecules paired up in double helices. If you introduce an mrna to a molecule with a complementary sequence the two will stick together, too, rendering the mrna useless (see bottom deck of diagram above).

Again, getting the neat idea to work in ways that helped proved hard. It took Ionis a quarter century to start getting its “antisense” drugs to market on a regular basis. It now has three: nusinersen, approved in America in 2016 and Europe in 2017 for use against childhood spinal muscular atrophy, a muscle-wasting illness; inotersen, approved in 2018 for hereditary transthyretin-mediated amyloidosis (hattr), which damages the peripheral nervous system; and volanesorsen, approved in Europe in 2019, which lowers levels of triglyceride fats in the blood of people with a metabolic error that makes them far too high.

Ionis currently has a further 37 antisense molecules in clinical trials for conditions including Huntington’s disease (a study being carried out in collaboration with Roche, a large Swiss pharma company); amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease (in collaborations with Biogen, a specialist in treatments for neurological disease); beta thalassaemia, a blood disorder similar to sickle-cell anaemia; and cystic fibrosis.

The firm is also developing, in collaboration with Novartis, another Swiss company, a way of reducing levels of lipoprotein(a), a particularly damaging form of low-density-lipoprotein (ldl) cholesterol. Lipoprotein(a) levels are untreatable with existing medicines; Pelacarsen, as the drug is known, is in phase 3 clinical trials to see if it can change that.

Unlike molecules of mrna, which can tolerate only a small amount of chemical tinkering before becoming ribosome-unfriendly, antisense molecules can be tweaked quite a bit, and thus made long-lasting. Ionis’s researchers have worked out how to stabilise them so that they will hang around inside cells for months. This is important because most of Ionis’s targets are chronic diseases that require continuous treatment. The fewer injections per year the better.

While biotech companies were beavering away at antisense molecules in the 1990s, researchers elsewhere discovered that nature had a similar technology of its own: gene silencing, a process guided by small interfering rnas (sirnas). The early 2000s saw a gene-silencing biotech boom led by Alnylam, founded in Cambridge, Massachusetts in 2002, and Sirna Therapeutics, which got going in San Francisco the following year.

Established pharma companies, including Abbott, Merck, Novartis, Pfizer, Roche and Takeda, waded in, too, with Merck buying Sirna for more than $1bn in 2006. For almost a decade, attention and money were showered on the field. But though there were many promising leads, they failed to turn into drugs. By the early 2010s it seemed that the party was over.

Nonlinear, nonvisual and inclusive

Alnylam, though, kept dancing. In 2014 it bought what was left of Sirna from Merck for a knock-down price. It launched its first product, patisiran, a treatment for hattr, in 2018. It now has two others, givosiran and lumasiran, which also address rare genetic disorders.

A fourth substance developed using its technology has broader appeal. This is inclisiran, developed to treat an inherited disorder that pushes the concentration of ldl cholesterol in the blood to dangerous levels; around 30m people worldwide suffer from it. A firm called the Medicines Company licensed Inclisiran from Alnylam to bring it to market. With approval looking likely (it was given in Europe late last year) Novartis bought the Medicines Company for $9.7bn in January 2020.

According to Akshay Vaishnaw, Alnylam’s head of r&d, the firm has another 14 sirna drugs in clinical trials. These including potential treatments for haemophilia, hepatitis B and recurrent kidney stones. Arrowhead Pharmaceuticals, of Pasadena, California, has eight potential sirna drugs in trials, including one directed at cystic fibrosis. Dicerna Pharmaceuticals, of Lexington, Massachusetts, has three.

These sirnas work by straddling the worlds of shape and sequence. Their shape fits them into a group of proteins called an rna-induced silencing complex (risc). But a bit of the sirna is left sticking out of this complex; this tail contains a sequence complementary to that of the rna to be silenced. When sirna and mrna meet, the proteins in the risc chop the messenger to pieces. (A conceptually similar mechanism for the rna-guided protein-executed chopping up of genes found in bacteria is the basis of the crispr tools now revolutionising gene editing.)

In plants and invertebrates the natural function of the sirna mechanism is clear: cutting up mrnas associated with viruses. They do not seem to serve that function in vertebrates, and no one is quite sure what they do instead. But that does not stop them from looking like promising drugs.

So do another set of rnas associated with riscs: micro-rnas, which use their complementary sequences not to destroy mrnas but to regulate them. The human genome seems to contain about 2,600 of these mirnas, and they are thought to be involved in regulating the rate at which about 60% of the genes describing proteins get transcribed. Several look like promising therapeutic targets.

Since the active bit of an mirna is a single-stranded sequence-specific tail, the obvious way to target them is with antisense. Regulus Pharmaceuticals, a firm that started life as a collaboration between Ionis and Alnylam, is trying to develop antisense molecules aimed at mirna-21 to treat two kidney-related genetic conditions in which that mirna plays a role. When you start targeting mirnas, though, things get positively baroque. Santaris Pharma, a Danish firm, has developed Miravirsen, an antisense suppressor for mirna-122 which the hepatitis C virus uses for its own unhelpful ends. The drug has now been taken on by Roche.

The innovation continues. Mina Therapeutics, a startup in London, is working on the potential of sarnas, which activate genes which otherwise stay silent. Others are investigating systems for “self-amplifying” mrna drugs. These mrnas would inveigle a cell’s ribosomes into producing not just the protein that was meant to be delivered, but also a second protein, called rna-replicase, which would make more of the mrna, thus leading to even more protein being expressed. There is surely further cleverness to come.

Could be so exciting

Even if only a fraction of these possibilities pan out it looks certain that, in popularity contests to come as in stockmarkets today (see chart), more people will be plumping for rna. Their support will be welcomed by the small band of biologists with an interest in the very earliest history of life that has long formed the discerning core of the molecule’s following. Life needs both a way of doing things in the now—catalysing the reactions on which its metabolism depends—and of passing information into the future. Of the molecules known today only rna, in its shape-and-sequence versatility, can do both those things, dealing with the needs of the everyday at the same time as encoding instructions for its own reproduction in the form of a legible sequence. This suggests to many that early life spent some time in an “rna world” before the division of labour allocated doing things to the proteins and storing data to dna, reducing rna to a supporting role in the world it had created.

The application of rna has met many obstacles over past decades, and the fact that it has proved itself in vaccines does not mean it will not meet more in the future. But it does seem that medicine now has a way to target drugs not just at proteins, but at the processes that make them, and that opens up new realms of possibility. The next rna world awaits.

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.”

Scientists Are Trying to Spot New Viruses Before They Cause Pandemics

Back in the summer, Dr. Michael Mina made a deal with a cold storage company. With many of its restaurant clients closed down, the firm had freezers to spare. And Dr. Mina, an epidemiologist at the Harvard T.H. Chan School of Public Health, had a half-million vials of plasma from human blood coming to his lab from across the country, samples dating back to the carefree days of January 2020.

The vials, now in three hulking freezers outside Dr. Mina’s lab, are at the center of a pilot project for what he and his collaborators call the Global Immunological Observatory. They envision an immense surveillance system that can check blood from all over the world for the presence of antibodies to hundreds of viruses at once. That way, when the next pandemic washes over us, scientists will have detailed, real-time information on how many people have been infected by the virus and how their bodies responded.

It might even offer some early notice, like a tornado warning. Although this monitoring system will not be able to detect new viruses or variants directly, it could show when large numbers of people start acquiring immunity to a particular kind of virus.

The human immune system keeps a record of pathogens it has met before, in the form of antibodies that fight against them and then stick around for life. By testing for these antibodies, scientists can get a snapshot of which flu viruses you have had, what that rhinovirus was that breezed through you last fall, even whether you had a respiratory syncytial virus as a child. Even if an infection never made you sick, it would still be picked up by this diagnostic method, called serological testing.

“We’re all like little recorders,” keeping track of viruses without realizing it, Dr. Mina said.

This type of readout from the immune system is different from a test that looks for an active viral infection. The immune system starts to produce antibodies one to two weeks after an infection begins, so serology is retrospective, looking back at what you have caught. Also, closely related viruses may produce similar responses, provoking antibodies that bind to the same kinds of viral proteins. That means carefully designed assays are needed to distinguish between different coronaviruses, for example.

But serology uncovers things that virus testing does not, said Derek Cummings, an epidemiologist at the University of Florida. With a large database of samples and clinical details, scientists can begin to see patterns emerge in how the immune system responds in someone with no symptoms compared to someone struggling to clear the virus. Serology can also reveal before an outbreak starts whether a population has robust immunity to a given virus, or if it is dangerously low.

“You want to understand what has happened in a population, and how prepared that population is for future attacks of a particular pathogen,” Dr. Cummings said.

The approach could also detect events in the viral ecosystem that otherwise go unnoticed, Dr. Cummings said. For example, the 2015 Zika outbreak was detected by doctors in Brazil who noticed a cluster of babies with abnormally small heads, born seven to nine months after their mothers were infected. “A serological observatory could conceivably have picked this up before then,” he said.

Serological surveys are often small and difficult to set up, since they require drawing blood from volunteers. But for several years Dr. Mina and his colleagues have been discussing the idea of a large and automated surveillance system using leftover samples from routine lab tests.

“Had we had it set up in 2019, then when this virus hit the U.S., we would have had ready access to data that would have allowed us to see it circulating in New York City, for example, without doing anything different,” Dr. Mina said.The Coronavirus Outbreak ›

Although the observatory would not have been able to identify the new coronavirus, it would have revealed an unusually high number of infections from the coronavirus family, which includes those that cause common colds. It might also have shown that the new coronavirus was interacting with patients’ immune systems in unexpected ways, resulting in telltale markers in the blood. That would have been a signal to start genetic sequencing of patient samples, to identify the culprit, and might have provided grounds to shut down the city earlier, Dr. Mina said. (Similarly, serology would not be able to spot the emergency of a new virus variant, like the contagious coronavirus variants that were discovered in South Africa and England before spreading elsewhere. For that, researchers must rely on standard genomic sequencing of virus test samples.)

The observatory would require agreements with hospitals, blood banks and other sources of blood, as well as a system for acquiring consent from patients and donors. It also faces the problem of financing, noted Alex Greninger, a virologist at the University of Washington. Health insurance companies would be unlikely to foot the bill, since serology tests are usually not used by doctors to treat people.The Coronavirus Outbreak ›

Dr. Mina estimated that the observatory would cost about $100 million to get off the ground. He pointed out that, according to his calculations, the federal government has allocated more than twice that much to diagnostics company Ellume to produce enough rapid Covid tests to cover the American demand for only a handful of days. A pathogen observatory, he said, is like a weather forecasting system that draws on vast numbers of buoys and sensors around the globe, passively reporting on events where and when they arise. These systems have been funded by government grants and are widely valued.

The predictive power of serology is worth the investment, said Jessica Metcalf, an epidemiologist at Princeton and one of the observatory team members. A few years ago, she and her collaborators found in a smaller survey that immunity to measles was ominously low in Madagascar. Indeed, in 2018 an outbreak took hold, killing more than 10,000 children.

Now, the half-million plasma samples in Dr. Mina’s freezers, collected by the plasma donation company Octopharma from sites across the country last year, are starting to undergo serological tests focused on the new coronavirus, funded by a $2 million grant from Open Philanthropy. Testing had to wait for the researchers to set up a new robotic testing facility and process the samples, but now they are working through their first batches.

The team hopes to use this data to show how the virus flowed into the United States, week by week, and how immunity to Covid has grown and changed. They also hope it will spark interest in using serology to illuminate the movement of many more viruses.

“The big idea is to show the world that you don’t have to spend huge dollars to do this kind of work,” Dr. Mina said. “We should have this happening all the time.”

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.”

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.