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Why doesn't the coronavirus affect animals like dogs and cows? I know that the SARS-CoV-2 is a zoonotic virus i.e. it can affect both humans and other animals. I also know that the DNA composition and cell structure of almost every animal on earth is the same.
Even though the DNA sequence may be 90+% similar between two species, individual amino acids can make a huge difference in the interaction between two proteins. In this case, the most relevant proteins are the coronavirus spike protein and the ACE2 enzyme expressed on the surface of target cells. Even in the limited amount of time SARS-CoV-2 has existed and been studied, researchers have found single amino acid mutations in its spike protein that meaningfully affect how well it binds to ACE2. When constructing animal models for COVID-19, and for the original SARS, in some cases it has been necessary to introduce a human ACE2 gene to allow infection. It is worth noting, however, that this is not always the case--for instance ferrets and hamsters can be infected by SARS-CoV-2 without any genetic modification at all.
This paper gives a summary of the work so far: Muñoz-Fontela, C., Dowling, W.E., Funnell, S.G.P. et al. Animal models for COVID-19. Nature 586, 509-515 (2020).
Coronavirus pandemic linked to destruction of wildlife and world's ecosystems
COVID-19 is the latest example of how human impact on biodiverse areas and wildlife habitats is linked to the spread of infectious diseases.
After the novel coronavirus broke out in Wuhan, China in late December 2019, it didn't take long for conspiracy theorists to claim it was manufactured in a nearby lab.
Scientific consensus, on the other hand, is that the virus — SARS-CoV-2 — is a zoonotic disease that jumped from animal to human. It most likely originated in a bat, possibly before passing through another mammal.
While the virus was certainly not engineered in a laboratory, this doesn't mean we haven't played a role in the current pandemic. Human impingement on natural habitats, biodiversity loss and ecosystem degradation are making virus spillover events much more likely, a major new study from scientists in Australia and the US has found.
The number of emerging infectious disease outbreaks has more than tripled every decade since the 1980s. More than two thirds of these diseases originate in animals, and about 70% of those come from wild animals. Many of the infectious diseases we're familiar with — Ebola, HIV, swine and avian flu — are zoonotic.
Contrary to what conspiracy theorists say, the novel coronavirus was not created in a lab in Wuhan, but the pandemic is linked to human behavior
Aided by a hyper-connected global population, SARS-CoV-2 and the disease it causes, COVID-19, has also demonstrated how quickly modern outbreaks can become pandemics.
While the speed at which COVID-19 has spread across the world has shocked many, scientists have long been warning of such a pandemic.
By disrupting ecosystems, we have created the conditions that allow animal viruses to cross over into human populations, says Joachim Spangenberg, ecologist and vice-president of the Sustainable Europe Research Institute.
"We are creating this situation, not the animals," Spangenberg told DW.
Deforestation, habitat encroachment
As people move further into the territories of wild animals to clear forests, raise livestock, hunt and extract resources, we are increasingly exposed to the pathogens that normally never leave these places and the bodies they inhabit.
"We're getting closer and closer to wild animals," says Yan Xiang, professor of virology at the University of Texas Health Science Center, "and that brings us into contact with these viruses."
After the Amazon, the tar sands in Canada are responsible for the second fastest rate of deforestation on the planet
"As you increase human population density and increase encroachment onto natural habitats, not just by people but by our domesticated animals, you're increasing the rolls on the die," David Hayman, professor of infectious disease ecology at Massey University in New Zealand, told DW.
But, as well as increasing the likelihood of transfer, ecosystem disruption also has an impact on how many viruses exist in the wild and how they behave.
In the last century, tropical forests, home to around two thirds of the world's living organisms, have been halved. This profound loss of habitat has ripple effects throughout the entire ecosystem, including on the "parts we tend to forget — infections," says Hayman.
In some cases, scientists have observed that when animals at the top of the food chain disappear, the animals at the bottom of the food chain, like rats and mice that carry more pathogens, tend to fill that space.
"It's not just about how many species we have in an ecosystem," says Alice Latinne at the Wildlife Conservation Society, "it's about which species."
"Each species plays a different role in the ecosystem and sometimes, if you just replace one species with another, this can have a huge impact in terms of disease risk. And sometimes we can't predict it," she told DW.
Between August 2018 and July 2019, nearly 10,000 square kilometers of the Amazon were cut down
Habitat changes can also force animals — and their pathogens — to go elsewhere, including areas populated by people.
Latinne draws on the example of the emergence of Nipah virus in Malaysia in the late 1990s, where deforestation drove fruit bats from their forest habitat to mango trees on pig farms. Bats often carry pathogens that don't bother them, but in this case when the pigs came into contact with bat droppings and saliva, they became infected. The pigs then went on to infect farmers.
Evidence linking disruption of ecosystems to increased risk of novel infection transfer is why, Spangenberg says, experts talk about the importance of the "One Health" concept the idea that the health of animals, the ecosystem and humans are all interlinked, and when one is out of balance, others follow suit.
So-called "wet markets" selling produce, meat and live animals provide another incubator for the emergence of infectious disease. Scientists believe there's a strong possibility SARS-CoV-2 emerged at a wet market in Wuhan, China.
Cramming stressed, sick animals into cages together is, in many ways, the "perfect setting" to incubate new pathogens, Spangenberg says, and "an excellent way to transfer diseases from one species to another." For that reason, many scientists, including Spangenberg, say the world needs, at the very least, to introduce strict regulations for live animal markets.
Are animals vulnerable to COVID-19?
Credit: CC0 Public Domain
While there's no evidence so far that pets, livestock, or their owners can infect each other with COVID-19, there is also very little research about a potential crossover.
The novel coronavirus started with an animal, then mutated to transfer to people, but research hasn't yet shown if the virus has jumped back to animals, said Scott Kenney, a researcher at The Ohio State University College of Food, Agricultural, and Environmental Sciences (CFAES).
"Viruses are constantly sampling and evolving, trying to find other hosts," said Kenney, who studies coronaviruses, including those that cross over from one species to another.
Quickly spreading among people across the world, COVID-19 is believed to have originated in bats, but the bat virus changed, altering surface proteins to be able to efficiently transfer from person to person. These surface proteins are different in the mutated bat virus, so COVID-19 is now less likely to affect the original bats. Whether other animals are susceptible to COVID-19 has yet to be tested, he said.
When viruses infect an animal, they produce billions of copies of themselves. Some of the copies tend to be slightly changed from the original virus. According to Kenney, while most of these irregular copies die, occasionally one has a change that is beneficial for the virus, such as altering its ability to infect a different species.
"If the new species is exposed to this altered virus, it can now make many more copies of itself and potentially infect a whole new species," he said.
So far, the only research on COVID-19 and animals involves studies in China that showed two dogs tested positive for COVID-19. But neither of the infected dogs had symptoms of the virus, and researchers in those studies do not believe they transmitted the disease to any other animals or people.
Coronaviruses are a large family of viruses, with COVID-19 being the newest addition. Some coronaviruses cause illness in people, some cause illness in certain animals, and others sicken both people and animals. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) were both coronaviruses that started in animals and shifted to people, leading to outbreaks. Neither was as adept at transmitting to people as COVID-19.
"COVID-19 has managed to hit a virus evolution sweet spot," Kenney said. "Infected people can be either very sick or show few signs, leading to very rapid spread of the infection."
Coronaviruses are common among farm animals. If COVID-19 were to jump species again and be receptive to animals, a likely animal on the farm to catch it would be pigs, he said. That's because pigs have a similar protein to humans that the SARS virus, a coronavirus cousin to COVID-19, uses to infect humans. Studies show that it may work in pigs too.
Among farm animals, pigs seem to be the most susceptible to coronaviruses, able to contract up to six different pig-specific coronaviruses.
"I'm not sure anyone really knows why," he said. "Outside of bats, pigs and humans seem to be infected by the largest numbers of different coronaviruses."
More studies are needed to understand whether this is because of something in pigs' physiology or genetic makeup, or just that humans and pigs encounter coronaviruses more frequently than other animals. That results in more virus spillovers.
One of the more devastating coronaviruses among livestock in recent years affected only pigs: the porcine epidemic diarrhea virus. During a 2013 outbreak, the virus killed significant numbers of pigs in the United States and China, all of them young pigs.
"The virus continues to pop up and cause problems in many countries around the world," Kenney said.
Even if farmers have spent a lot of time around pigs or other livestock, including animals with coronaviruses, they do not have immunity to COVID-19, he said. That's why it is still important to be cautious.
"Any time you're around an animal, you should use good hygiene. There are many illnesses besides coronaviruses in animals that can be passed to humans, and vice versa.
Why does COVID-19 kill some, not others? Answer may lie in human immune system
1 of 3 Dr. Anthony Fauci at a White House news breifing on Tuesday, March 31, 2020. Fauci, the nation’s leading expert on infectious diseases, who has become a regular at President Donald Trump’s coronavirus briefings, will receive enhanced personal security after receiving threats following his repeated pleas for Americans to help slow the spread of the deadly pandemic, officials said on Wednesday, April 1, 2020. (Erin Schaff/The New York Times) Erin Schaff / New York Times Show More Show Less
2 of 3 Levi Garraway of Genentech Courtesy Genentech / Show More Show Less
3 of 3 Carolyn S. Calfee, MD MAS, Professor in Residence of Medicine and Anesthesia at UCSF, poses for a portrait on Thursday, March 26, 2020. San Francisco. Calif. Jana Asenbrennerova / Special to The Chronicle Show More Show Less
It is scary enough that a dangerous virus is multiplying throughout the world, but one of the most frightening aspects of COVID-19 is the mysterious way it affects its victims, killing some people and leaving others with mild or no symptoms.
It is a puzzle that has baffled medical professionals and prompted a batch of studies in the Bay Area and around the world to try to figure out what is going on. The early evidence is sobering.
Infectious disease specialists increasingly believe the perplexing randomness of who gets sickest may have less to do with SARS-CoV-2, the virus that causes the disease, than it does with some people&rsquos overly robust immune responses to the infection.
The quandary has taken on new urgency, given that many hard-hit victims are not old or harboring preexisting medical conditions, but young, healthy and active people. That troubling fact was highlighted this week by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and a member of President Trump&rsquos coronavirus task force.
&ldquoYou get so many people who do well and then some people who just, bingo, they&rsquore on a respirator, they&rsquore on ECMO (a life-support machine) and they&rsquore dead,&rdquo Fauci said during an interview with CNN medical correspondent Dr. Sanjay Gupta. &ldquoI mean, the dichotomy between that, there&rsquos something there, Sanjay, that we&rsquore missing from a pathogenesis standpoint. And I don&rsquot think it&rsquos only if you&rsquore elderly or if you have underlying conditions. There&rsquos something else going on there that hopefully we&rsquoll ultimately figure out.&rdquo
The death toll is, no doubt, highest among the elderly and those with underlying medical conditions, but the extreme respiratory distress that causes those deaths &mdash inflammation, the filling of the lungs with fluid, pneumonia &mdash seems to be less selective.
&ldquoSome of the symptoms are caused by the inflammatory response to the virus,&rdquo said Levi Garraway, chief medical officer at Genentech, which is conducting trials on a drug called Actemra, which was designed to control overactive immune responses. &ldquoThe response can be a good thing, but in some cases there may be an excessive response. That can lead to its own problems.&rdquo
Most autoimmune diseases, like rheumatoid arthritis, lupus and multiple sclerosis, are the result of a hyperactive immune response. Although the causes of most autoimmune diseases are unknown, it is believed that some kind of bacteria, virus or drug tricks the body and causes white blood cells to think healthy cells are invaders and attack them.
Experts theorize that it was the strong immune system responses of victims that caused so much death during the 1918 Spanish flu pandemic, which actually killed more young, healthy 20- to 40-year-olds than anyone else.
The coronavirus spreading across the globe appears to be triggering a similar autoimmune type reaction in certain people, experts say.
Dr. Carolyn Calfee, a professor of medicine and anesthesia at UCSF, is researching those reactions and trying to understand how this coronavirus differs from other infections.
One thing common in virtually every critical case, she said, is the onset of acute respiratory distress syndrome, or ARDS, which is characterized by fluid leaking into the lungs. That is why many victims need a ventilator to breathe.
Calfee, an expert on the condition, said ARDS is caused by inflammation in the lungs, similar to a burn or blister on the skin.
&ldquoImagine what happens when you burn your arm. Well, when you have acute injury to the air sacs in your lungs, a similar thing happens,&rdquo Calfee said. &ldquoThe nice clean barrier between the air sacs and the blood becomes leaky and inflames and fluids begin pouring into the lungs.&rdquo
What&rsquos strange, she said, is how suddenly ARDS materializes in COVID-19 patients and how difficult it is to eliminate.
She said patients may experience relatively mild, flu-like symptoms for as long as a week before symptoms of ARDS begin, and its onset is usually sudden, without warning. And then it often requires a week to several weeks on a ventilator &mdash an unusually long time for a patient with a respiratory illness &mdash for patients to recover, if they do.
Calfee and her colleagues are collecting blood and lung fluid samples trying to figure out what it is about some people&rsquos immune systems that causes them to have such severe reactions. These kinds of studies are the key for dozens of university laboratories and biological institutes around the world trying to develop medicines and a vaccine.
Dr. Melanie Ott, a senior investigator with the Gladstone Institute of Virology and Immunology in San Francisco&rsquos Mission Bay, said the extreme coronavirus cases are the result of a unique interaction between the virus and its human host.
Viruses such as SARS-CoV-2, she explained, are parasitical microbes that cannot reproduce or live very long outside of an animal.
&ldquoIt needs to go inside and hijack the machinery, which is what makes it so dangerous because it takes the host machinery away,&rdquo Ott said. &ldquoIt propagates its genome into a host cell.&rdquo
Many species are susceptible to infection because they contain a protein known as angiotensin-converting enzyme 2, or ACE2.
That's because the virus itself is covered in spiky projections that can latch onto ACE2 proteins on the surface of animal cells. The coronavirus "spikes" then lock into place and hijack the cell to replicate.
Using computer databases and modeling, researchers have examined the genes of species to find out if the ACE2 protein in their cells can be used by SARS-CoV-2. A recent study, published in the journal Microbes and Infection on March 19, showed SARS-CoV-2 could grab onto the ACE2 receptor of many different species -- including bats, civet cats and pigs -- and predicted it may also be able to do so in goats, sheep, horse, pangolins, lynx and pigeons.
The research undertaken by the Harbin Veterinary Research Institute in China suggests that the virus replicates poorly in chickens, ducks and pigs.
The first confirmed case of coronavirus in an animal in the US was documented on April 5, when 4-year-old Nadia, a Malayan tiger at the Bronx Zoo , was found to have contracted the virus, likely from an infected but asymptomatic zookeeper. It was later found that many of the big cats at the zoo had contracted the virus -- but most showed mild symptoms and were expected to recover.
Prior to 2003, the only known pathogenic coronaviruses were hCoV-229E and hCoV-OC43, both responsible for trivial respiratory diseases with symptoms similar to the common cold . The discovery of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus which caused the SARS (2003) and MERS (2012) outbreak, respectively, have raised enormous concerns about the dangerousness and high contagiousness of the new coronaviruses [2,3]. The rapid worldwide spread of the new coronavirus disease 2019 (COVID-19) has put global public health in serious difficulty since the beginning of 2020. COVID-19 is a respiratory disease, affecting mostly the lungs and causing symptoms of varying degrees of morbidity . To date, this infection caused by new coronavirus SARS-CoV-2 affected more than 120 million people all over the world—
30 million in the US and over 3 million in Italyusing a high number of deaths . Despite a global ongoing large-scale vaccination, the problems associated with this viral disease are far from being solved, in particular due to insurgence and diffusion of new strains and, in some cases, inadequacy of health services. Therefore, the need to find new therapeutic strategies for the prompt, effective, and affordable treatment of this dangerous infection is becoming crucial.
The causative agent of COVID-19 is SARS-CoV-2, a single stranded RNA virus (+ ssRNA) belonging to the Coronaviridae family capable of spreading among humans and animals . The genome of SARS-CoV-2 is represented by two open reading frames which encodes two large polyproteins, pp1a and pp1ab. Following proteolytic cleavage, these are translated into mature non-structural proteins (NSPs). The enzymes involved in this conversion are two cysteine proteases, namely the papain-like protease PL pro and the chymotrypsin-like protease 3CL pro , the latter more commonly known as M pro . They are indispensable for virus proliferation and infectivity, as they allow the maturation of viral polyproteins and, consequently, their assembly into new virions. It is commonly believed that finding specific new therapies aimed at inhibiting these proteolytic processes can be of great use in the fight against COVID-19, as well as in the prevention of subsequent viral epidemics.
The replication cycle of SARS-CoV-2 is depicted in Figure 1 . The entry of the virus into the lung cell is regulated by the interaction of the spike protein (S protein) with the angiotensin-converting enzyme 2 (ACE-2) receptor, located on the surface of the pneumocyte . The S protein is first processed by a proteolytic cleavage involving the S1/S2 (or S2 ‘) sites from a serine protease located on the surface of the human cell, called TMPRSS-2 . TMPRSS-2 belongs to a family of transmembrane serine proteases and it is essentially involved in the entrance of the virus into the host cell. The proteolytic cleavage carried out by TMPRSS-2 on the viral S protein allows the exposure of the binding site of the external surface of the virus to the ACE-2 receptor, enabling the entry. It is noteworthy that the affinity of the S protein of SARS-CoV-2 for the ACE-2 receptor is about 10 times greater than that of SARS-CoV . Thus, the virus penetrates the host cell by receptor-mediated endocytosis or fusion with the plasma membrane . Hoffmann M. et al. demonstrated how camostat, a TMPRSS2 inhibitor containing a terminal guanidine endowed with anti-inflammatory and antifibrotic properties, can block SARS-CoV-2 infection in lung cells , suggesting that targeting this protease may be one of the potential strategies to discover and develop novel anti-COVID-19 fusion inhibitors .
Sketched view of the SARS-CoV-2 replication cycle.
Various important proteolytic enzymes are involved in the replication and infectious capacity of SARS-CoV-2, including SARS-CoV-2 M pro , SARS-CoV-2 PL pro , and TMPRSS-2. However, only molecules capable of selectively inhibiting the SARS-CoV-2 M pro activity have been effectively developed. Despite their important role, the other two viral proteolytic enzymes are difficult to target due to their high degree of similarity with human proteases and the consequent drawbacks related to phenomena of non-specific inhibition. Therefore, this review is focused on the structure of the SARS-CoV-2 M pro and the discovery of its inhibitors (repurposed drugs or newly synthesized compounds) for the treatment of COVID-19. Furthermore, the main enzymatic assays and cell-based methods for their biological assessments will be briefly discussed.
Finding the best shot
Aiming to prevent a future pandemic like COVID-19, scientists are looking for ways to immunize people against many, if not all, coronaviruses. Several strategies for these pancoronavirus vaccines focus on spike, the surface protein common to all members of the viral family.
The crown’s jewel Spike initiates an infection when part of its head (S1) binds to a human cellular receptor and a human enzyme cleaves spike so its stem (S2) can fuse with the cell. Spike varies between coronaviruses and the most conserved regions of its head or stem may serve as a broadly protective vaccine.
Chimeric spike A messenger RNA (mRNA) vaccine that combines spike gene sequences from SARS-CoV, SARS-CoV-2, and other coronaviruses can produce a mix of protein domains that may confer broad immune protection.
RBD nanoparticles Because antibodies to spike’s receptor-binding domain (RBD) may be key to vaccine protection, scientists are assembling RBDs from multiple corona- viruses onto nanoparticles or into nanocages.
Serial vaccines One pancoronavirus vaccine approach would deliver a series of different spike proteins, each in its natural trimer configuration on a carrier particle.
Whole virus Vaccinemakers have long used inactivated or weakened viruses. Combining multiple coronaviruses from one or more genera could stimulate broader immune protection.
Family matters Coronaviruses are grouped into four genera. They infect many species, although most have been found in bats. Of the seven known to infect people, four cause mild colds and three can be lethal.
An ideal pancoronavirus vaccine would protect us from all four of its genera—alpha, beta, gamma, and delta—but most researchers have more modest goals. “The further you go, the harder it gets” for a vaccine, says immunologist Dennis Burton of Scripps Research, who often collaborates with Ward.
Gamma and delta coronaviruses, mainly found in birds and pigs, are not known to infect humans, so vaccine developers have paid them little attention. There’s more interest in alpha coronaviruses because two cause colds in humans. But it’s the betas that attract the most effort, and in particular the sarbecoviruses, a subset that includes SARS-CoV-2 and SARS-CoV but not the more genetically distinct MERS and its relatives. Sarbecoviruses are Ward’s targets, and Burton is optimistic. “We already know you can get pretty damn good antibodies that work against both SARS-CoV and -2,” he says.
Ralph Baric of the University of North Carolina, Chapel Hill, who has studied coronaviruses for 35 years, sees this subgroup as the paramount threat. “That SARS-CoV-2 is here doesn’t mean that that’s going to provide any kind of serious protection against another sarbecovirus from coming out of the zoonotic reservoirs,” he says. And if a “SARS-CoV-3” jumped into a person infected with the current pandemic virus and created something more lethal by swapping genetic regions—and coronaviruses frequently recombine—that’s the making of a Hollywood horror film.
Ward and others in this nascent field are following the lead of vaccine successes, for diseases from polio to human papillomavirus, that depend on combining components from multiple forms of a pathogen—up to 23 forms of a sugar molecule in a shot against pneumococcal disease, for example—to increase breadth of protection. Although Ward is still at the earliest stages of the design process, trying to identify the conserved viral targets he wants a vaccine to hit, structural biologist Pamela Bjorkman at the California Institute of Technology is a few steps further along. Her team has recently evaluated candidate pancoronavirus vaccines in mice.
Bjorkman and co-workers chose a portion of spike from a range of beta coronaviruses: SARS-CoV and SARS-CoV-2, a virus isolated from a pangolin, and five bat viruses. They used each virus’ receptor-binding domain (RBD), the spike region that initiates an infection by docking onto angiotensin-converting enzyme 2 (ACE2), a protein on human cells. The RBD is the apparent target for most antibodies that thwart SARS-CoV-2.
Comparisons of the RNA genes encoding the spikes showed the top section of the RBD varied a great deal, but the lower part was conserved across the different viruses. So the investigators fashioned eight multimers—small proteins—from the conserved RNA sequences. Then, they fastened combinations of them onto the surface of a nanoparticle built from a bacterial protein to create various “mosaic” vaccines. In theory, a mosaic would produce antibodies that protected against the known viruses—and because the sequences are conserved, the vaccine might protect against distant relatives of those viruses as well.
Last year, Bjorkman and colleagues injected mice with some of their mosaic vaccines. They report in the 12 February issue of Science that in lab dishes, antibodies harvested from the mice powerfully neutralized the infectivity of a wide array of sarbecoviruses, including ones not used to make the vaccine.
Graham, who worked on pancoronavirus vaccines even before the pandemic, reasons that the whole trimer of spike might stimulate better or broader immune protection than just the RBDs. His team has taken spike trimers from SARS-CoV-2 and two beta coronaviruses that cause human colds and placed them in malleable nanocages, made from two different proteins developed by computational biologist Neil King of the University of Washington (UW), Seattle. The NIAID group is also using a second scaffolding: nanoparticles created from ferritin, a blood protein that normally sequesters and releases iron.
In a third strategy, Graham envisions giving people a series of vaccines, each one containing trimers from a different member of the beta genus, to create a broad defense against the viruses. “It’s what we do right now for influenza, basically, only it is occurring over a lifetime instead of more deliberately in a shorter period of time,” he says. (The flu shot contains surface proteins from three or four strains of that virus, and as it mutates, vaccinemakers change the ingredients annually.)
By arraying spike proteins on nanoparticles, vaccine developers aim to follow the style of upscale restaurants, where presentation matters nearly as much as the food on the plate. The goal is to cater to the tastes of B cells, the immune cells that pump out antibodies. The cells identify foreigners using Y-shaped proteins called immunoglobulins on their surfaces. (When secreted, the same proteins are antibodies.) B cells respond most strongly when each arm attaches to a different epitope. King says nanocages are ideal for presenting epitopes this way. “We can control spacing and geometry [of the viral pieces] in a much more precise way than anybody could before,” he says.
The resulting B cell cross-linking primes legions of the cells to spit out what researchers have dubbed “superantibodies” for their remarkably high potency. These superantibodies add to a vaccine’s breadth of protection because even when they aren’t a perfect match to a strain, they still retain some neutralizing activity.
Structural biologist Andrew Ward studies the nooks and crannies of a coronavirus spike protein for features common to spikes in other members of the virus family.
Baric’s group is exploring a different way to present diverse antigens. Rather than arranging them on scaffolds, the team uses mRNA coding for a chimeric protein that mixes and matches different parts of spike from distant human and bat sarbecovirus cousins. “Spike is really plastic, so it’s kind of a modular design,” Baric says. “You can move component parts around without any problem.” Four of these mRNA spike chimeras solidly protected mice from a variety of challenges with human and bat sarbecoviruses, Baric and colleagues reported in a bioRxiv preprint posted on 12 March.
Along with calculated strategies, luck can also aid the quest for a pancoronavirus vaccine. Barton Haynes and his team at Duke University, working with Baric’s group, recently designed a vaccine that contains a SARS-CoV-2 RBD in a ferritin nanoparticle. Intended as a booster dose for mRNA COVID-19 vaccines, it turned out to be far more versatile. In monkeys, it worked as intended against SARS-CoV-2. But much to the researchers’ surprise, antibodies taken from the vaccinated monkeys also neutralized SARS-CoV and two related bat coronaviruses in lab studies.
A clue to this surprisingly broad protection came when the team isolated an antibody from a person who had recovered from SARS many years ago. It, too, could neutralize a wide range of sarbecoviruses—and it turned out to bind tightly to the same RBD used in their COVID-19 vaccine booster. A structural analysis of the antibody bound to the RBD shows it latches onto the domain’s side, not the top region favored by most vaccine-induced neutralizing antibodies.
Because this antibody doesn’t interfere with ones that attach to the top, Haynes thinks a vaccine designed to trigger it and more common neutralizing antibodies could provide a one-two punch to multiple viruses. He expects clinical trials of this idea could begin within 6 months.
Some groups have turned their sights far from the RBD, in molecular terms. Spike has both a head, which includes the RBD, and a stem—known as S2—that varies little between coronaviruses. “The S2 subunit is by far the most conserved portion of coronavirus spike,” says Jason McLellan, a structural biologist at the University of Texas, Austin, who co-authored the failed grant proposal with Ward.
After spike lands on a human cellular receptor, a human enzyme slices off the head, or S1, to expose the stem. That then, yes, spikes the cell and initiates the fusion that allows the virus to unload its genetic cargo. Immune responses against S2 can derail that key process, even though the stem isn’t always visible enough normally to initiate them.
A few years ago, McLellan developed a vaccine from the S2 of the MERS virus that protects mice from the virus as effectively as vaccines that feature the full spike. The antibodies produced by the vaccine also bind to, but do not neutralize, SARS-CoV, SARS-CoV-2, and a human cold beta coronavirus. McLellan’s lab is now conducting cryo-EM of antibody-stem conjugates, using S2 from SARS-CoV-2, to develop a vaccine for beta coronaviruses. “Our initial immunogens target all of S2, but we might want to refine that and target smaller portions,” McLellan says.
Like most developers of a pancoronavirus vaccine, McClellan is trying to rally antibody-producing B cells. A few groups, however, hope to also rouse the immune system’s other great army: T cells, which protect the body by destroying infected cells. On 18 May 2020 in Nature, Vir Biotechnology working with UW structural biologist David Veesler described an antibody, isolated from someone who had SARS in 2003, that neutralized infectivity of both SARS-CoV and SARS-CoV-2—but with help from T cells.
Chances are, in the next 10 to 50 years, we may have another outbreak like SARS-CoV-2.Andrew Ward, Scripps Research
Although the antibody binds to the RBDs of spike of each virus, it does not block them from attaching to ACE2, cryo-EM showed. The groups instead found it may bind to the surface of immune warriors that educate T cells to destroy already infected cells. This “vaccinal effect” was first described more than 15 years ago in cancer research when scientists found that certain monoclonal antibodies can trigger killer T cells to eliminate tumors.
T cells are also central to the vaccine quest of Bette Korber, a computational biologist at Los Alamos National Laboratory. She designs algorithms to scour the genome sequences of beta coronaviruses, looking for regions of viral proteins that can trigger T cell responses, and that vary little among the different coronaviruses. Those conserved T cell epitopes, Korber says, might make a good vaccine.
She hopes to initially combine this T cell approach with a B cell strategy that would protect against all SARS-CoV-2 variants. It draws on an analysis of close to 1 million sequences of the virus now in databases to understand the “evolutionary space” of the pathogen—what changes could help it evade antibody responses and what mutations it cannot afford.
“You need to show the immune system what it needs to recognize to have breadth,” says Korber, who has applied similar techniques to designing vaccines for HIV, flu, and Ebola. Her collaborators plan to convert the sequences she selects into mRNA vaccines.
Finally, there’s an old-school approach to a pancoronavirus vaccine, one that should call into battle both B and T cells. NIAID’s veteran flu researchers Matthew Memoli and Jeffery Taubenberger want to combine inactivated versions of representative coronaviruses from the four known lineages in the beta genus. Vaccines based on the entire virus help the immune system take “multiple shots at the target,” Memoli explains, rather than focusing all the responses on spike or bits of it.
“Some antigens give you antibodies, some antigens may give you more T cell responses, some antigens may do both. Some antigens may be better at inducing mucosal immunity than systemic immunity,” he says. “The reality is that the best vaccine is going to deliver antigens that induce all of these responses.”
How can developers of pancoronavirus vaccines prove their shots protect against a hypothetical SARS-CoV-3? Baric highlights one hurdle: “You have to have a good panel of challenge viruses to actually begin to test these vaccines” in the lab. The U.S. government considers SARS-CoV, MERS, and many coronaviruses to be “select agents,” subjecting labs that handle them to greater restrictions. Baric notes that his lab is one of the few that has the biosecurity needed to grow and experiment with those coronaviruses.
Another regulation could ease the path. Created by the U.S. Food and Drug Administration in the wake of 9/11, when there was increased worry about engineered viruses or other biothreats, the “animal rule” says a therapy or vaccine can receive approval without an efficacy trial if the study cannot ethically or practically be done in humans. A pancoronavirus vaccine might establish its bona fides under that rule if it works in mice or monkey challenge studies against a variety of known coronaviruses, appears safe in humans, and is capable of triggering broadly neutralizing antibodies or other relevant immune responses in people.
If a pancoronavirus vaccine gets authorized, would countries create stockpiles to quickly extinguish an outbreak of a new virus? Or would they instead plan to rapidly start to produce the vaccine from its blueprint once that fresh threat is seen? Those are issues CEPI’s initiative will explore, but there’s a third, simpler option many in the field propose: using it in the current pandemic, as the ultimate booster shot to prevent potentially waning immunity and protect against the menacing new variants of SARS-CoV-2 that keep emerging.
Efforts have already begun to develop second generation COVID-19 vaccines that could protect against those variants. But Haynes says this is a game of “whack-a-mole” that has no end in sight. “You’re just waiting on the next variant to come up.” He and others instead propose that a pancoronavirus vaccine could do double duty. If it can handle other members of the coronavirus family tree, it should have no problem dealing with variations of SARS-CoV-2, which are minor in comparison.
“Over time, it may be that the boosting will be with a vaccine that is more broadly protective,” says Luciana Borio, who led a White House unit on medical and biodefense preparedness and now works for a venture capital firm, In-Q-Tel, whose portfolio includes biotech companies.
That might help end the current pandemic and forestall the next one. “A broadly protective vaccine has the goal of preventing a pandemic from happening,” Memoli says. “The issue we have is right now is if a completely new virus appears, we have nothing.”
Anderson Explains Role of Nanoparticles in Vaccines
If and when effective vaccines for Covid-19 are developed, some will surely rely on a nanoparticle delivery system whose origins lie in decades of painstaking groundwork.
Offering a tour of that effort on July 15 was Dr. Dan Anderson of MIT, who gave the ninth lecture in NIH’s Covid-19 scientific interest group lecture series.
The poster child for the talk was the mRNA vaccine that had just been reported on in the New England Journal of Medicine the Moderna candidate, whose promising early results were described, relies on nanoparticle delivery.
“One of the heroes of this story is the nanoparticle,” said Anderson, professor of chemical engineering and of health sciences and technology at the MIT Koch Institute for Integrative Cancer Research.
“Encapsulating RNA in a package that can travel through the bloodstream and reach target cells is quite a challenge,” he explained. “Endocytosis is how it gets into the cell. Then it has to escape the endosome and release its payload. Decades of work have gone into this. It isn’t easy.”
Years of experiments on animal models have shown that injected nanoparticles usually end up in the organs that filter blood—liver, spleen, bone marrow and kidney.
But, as Anderson pointed out, “RNA or DNA is simply not a great drug. It does not cross cellular membranes. We need expression of these constructs to get function.”
An important precursor to nanoparticle vaccinology is basic research on small interfering RNA (siRNA), a breakthrough that won the 2006 Nobel prize. siRNAs can seek and destroy complementary strands of RNA. “In essence, we can turn off any gene we want,” Anderson said.
He described three key steps to turn nucleic acids into drugs: sequence selection, chemical modification and encapsulation.
“The first question with nanoparticles is, what do you build it out of?” Early biomaterials, such as the artificial heart, were made of material found in ladies’ girdles—polyether urethane. The tubing used for dialysis originated in sausage casing (cellulose acetate). The first vascular grafts came from the world of clothing—the synthetic fabric Dacron.
“Can we permanently turn genes off in vivo?” asked Anderson.
Since nothing off the shelf suggests a nanoparticle, scientists have engaged in what Anderson called the rational design of biomaterials. Biodegradable sutures, developed in the 1970s, are an example of this approach.
“How do we build the perfect material if we don’t know the design criteria?” he asked.
Anderson and his colleagues believe the best approach is to test lots of options, using four basic building blocks: a helper phospholipid, cholesterol, polyethylene glycol lipids and immune lipids.
“Every nano vaccine manufacturer is focused on figuring out the structure of ionizable lipids,” he said.
Anderson has 15 years of experience with DNA delivery systems that harken back to such early compounds as DOTMA, DOTAP, DOPE and DOGS.
“The key question is, how do we increase the diversity of these compounds?” he said. “It’s a chemistry problem. The goal is a cationic lipid.”
One early success in developing RNA therapeutics was use of siRNA to silence the TTR gene, which, when misfolded, causes transthyretin-mediated amyloidosis, a serious liver disease.
The treatment was effective in primates, which Anderson said “surprised us. It was not as hard as we thought to make lipids that could do this.”
The first siRNA lipid nanoparticle was approved for human use in August 2018, in a drug called patisiran.
“This was proof to the field that these particles…actually can be translated and approved as medicine,” Anderson noted. “This inspired us…These types of particles could have broader use.”
They decided to take advantage of endogenous lipid-trafficking pathways in the body. These pathways feature chylomicrons, which is where the fats in the last Snickers bar you ate ended up.
While liver is a relatively easy target for nanoparticles, other targets include endothelium and perhaps even immune cells, including peripheral blood leukocytes. That would enable nanotherapy for some infectious diseases, Anderson said.
Moderating the Q&A session was Dr. Kaitlyn Sadtler, chief of the section on immunoengineering at NIBIB. Prior to her arrival at NIH, she was a postdoctoral fellow at MIT with Anderson.
His team has been able to silence 5 genes in the lung in vivo using nanoparticles, and he cited a report of 20 genes being knocked down by a single particle.
At the moment, all cells within the liver in animal models can be targeted, as can the endothelium of many organs, including kidney, liver, spleen, heart, skeletal muscle and lung. Also amenable to nanotherapy are leukocyte populations including monocytes, macrophages and dendritic cells, along with a variety of tumors, and even some T and B cells in primates.
Anderson said his MIT colleague, Nobel laureate Dr. Phillip Sharp, has labeled the new technology “modular pharmacology.”
The Moderna vaccine described in the recent NEJM article uses mRNA to activate, not silence, a gene, as with siRNA. “It’s even more challenging than siRNA,” said Anderson. “It’s much bigger.”
It is not enough, he warned, to create an mRNA that encodes an antigen to SARS-CoV-2. “You also need to activate the immune system and have the antigen present for the correct amount of time in order to get the appropriate response.”
In a mouse study, mRNA led to large amounts of circulating protein produced in the liver, as modeled with the kidney hormone EPO. DARPA scientists have been investigating mRNA therapies that can produce antibodies against infectious agents used on the battlefield.
mRNA delivery is not limited to the liver, Anderson said. “Nanoformulations can be generated to express mRNA in different tissues.”
Nanoparticle mists could be inhaled, as with a nebulizer. “We can get very high expression in lung epithelium in animals,” he reported. One company is exploring this approach for patients with cystic fibrosis.
Anderson concluded with a discussion of genome editing using the CRISPR-Cas9 system, which permanently modifies DNA for some beneficial purpose.
“Can we permanently turn genes off in vivo?” he asked. Using chemically modified guide RNA to direct such editing, Anderson thinks better versions of the system can be developed, leveraging knowledge gained in studies of antisense molecules.
Scientists are currently trying to craft a nanoparticle that can permanently lower cholesterol one candidate resulted in a 35 percent reduction in mice.
“I invite the creative scientists at NIH to propose gene targets, to either partially or fully knock them out, in infectious diseases,” Anderson said.
Already, a single-particle Ebola vaccine has been made whose payload targets three strains of Ebola, Anderson noted. “It offered complete protection in mice from a lethal dose of the virus.”
He imagines second-generation vaccines delivered by nanoparticle that will target cancer and Covid-19, as more is learned about lipid formulations and the best pathways to target.
If Covid-19 was like the flu, you’d expect the outbreaks in different places to be mostly the same size. But Dr. Kucharski and his colleagues found a wide variation. The best way to explain this pattern, they found, was that 10 percent of infected people were responsible for 80 percent of new infections. Which meant that most people passed on the virus to few, if any, others.
Dr. Kucharski and his colleagues published their study in April as a preprint, a report that has not been reviewed by other scientists and published in a scientific journal. Other epidemiologists have calculated the dispersion parameter with other methods, ending up with similar estimates.
In Georgia, for example, Dr. Nelson and her colleagues analyzed over 9,500 Covid-19 cases from March to May. They created a model for the spread of the virus through five counties and estimated how many people each person infected.
In a preprint published last week, the researchers found many superspreading events. Just 2 percent of people were responsible for 20 percent of transmissions.
Now researchers are trying to figure out why so few people spread the virus to so many. They’re trying to answer three questions: Who are the superspreaders? When does superspreading take place? And where?
As for the first question, doctors have observed that viruses can multiply to bigger numbers inside some people than others. It’s possible that some people become virus chimneys, blasting out clouds of pathogens with each breath.
Some people also have more opportunity to get sick, and to then make other people sick. A bus driver or a nursing home worker may sit at a hub in the social network, while most people are less likely to come into contact with others — especially in a lockdown.
Dr. Nelson suspects the biological differences between people are less significant. “I think the circumstances are a lot more important,” she said. Dr. Lloyd-Smith agreed. “I think it’s more centered on the events.”
A lot of transmission seems to happen in a narrow window of time starting a couple days after infection, even before symptoms emerge. If people aren’t around a lot of people during that window, they can’t pass it along.
And certain places seem to lend themselves to superspreading. A busy bar, for example, is full of people talking loudly. Any one of them could spew out viruses without ever coughing. And without good ventilation, the viruses can linger in the air for hours.
A study from Japan this month found clusters of coronavirus cases in health care facilities, nursing homes, day care centers, restaurants, bars, workplaces, and musical events such as live concerts and karaoke parties.
This pattern of superspreading could explain the puzzling lag in Italy between the arrival of the virus and the rise of the epidemic. And geneticists have found a similar lag in other countries: The first viruses to crop up in a given region don’t give rise to the epidemics that come weeks later.
Many countries and states have fought outbreaks with lockdowns, which have managed to draw down Covid-19’s reproductive number. But as governments move toward reopening, they shouldn’t get complacent and forget the virus’s potential for superspreading.
“You can really go from thinking you’ve got things under control to having an out-of-control outbreak in a matter of a week,” Dr. Lloyd-Smith said.
Singapore’s health authorities earned praise early on for holding down the epidemic by carefully tracing cases of Covid-19. But they didn’t appreciate that huge dormitories where migrant workers lived were prime spots for superspreading events. Now they are wrestling with a resurgence of the virus.
On the other hand, knowing that Covid-19 is a superspreading pandemic could be a good thing. “It bodes well for control,” Dr. Nelson said.
Since most transmission happens only in a small number of similar situations, it may be possible to come up with smart strategies to stop them from happening. It may be possible to avoid crippling, across-the-board lockdowns by targeting the superspreading events.
“By curbing the activities in quite a small proportion of our life, we could actually reduce most of the risk,” said Dr. Kucharski.
How the novel coronavirus is mutating, and if you should be concerned
Representational Image | Commons
Bengaluru/New Delhi: As the coronavirus outbreak continues to spread across the world, the cyberspace has been abuzz with claims that the Covid-19 strain in India is a less virulent mutation than the one travelling abroad. BJP leader and Rajya Sabha MP Subramanian Swamy and gastroenterologist D. Nageshwar Reddy are among those who have made such claims.
While Swamy quoted an “American friend” in a tweet last week to say the Covid-19 “strain in India” can be “defeated more effectively by our body’s natural defense mechanism than the strains abroad”, Reddy in an interview floated similar claims without quoting any research.
My US based friend,a scientist Ramesh Swamy informs me that a US researcher has found: “the #COVID19 strain in India is a less virulent mutation. Uniquely it is able to be targetted and defeated more effectively by our body’s natural defensive mechanism than the strains abroad.”
&mdash Subramanian Swamy (@Swamy39) March 24, 2020
Some users responded to Swamy’s tweet posting a link to a study that they claimed supported his notion. But this study, which is yet to be peer reviewed, has faults of its own, including use of limited data.
A number of experts in the field have termed such assertions baseless. Dr Gagandeep Kang, executive director at the Translational Health Science & Technology Institute in Faridabad, called Reddy’s comments “appalling & misleading”.
This is appalling & misleading (unless I missed something). The 2 *shared* Indian sequences are from 2 Wuhan returnees end-Jan. They are near identical to sequenced strains from Wuhan. Nothing special here, move on. Trust the right scientists. @PriyankaPulla @ShekharGupta https://t.co/M4cFaz8g9n
&mdash G Kang (@GKangInd) March 30, 2020
As such claims circulate online, ThePrint highlights the science of virus mutation and whether you should be worried.
Is there an Indian strain?
The overarching problem is the use of the term ‘Indian SARS-CoV-2 strain’ that is in itself misleading.
A ’strain’ is a sub-type of a virus, characterised by different cell surface proteins, eliciting a different immune response from other strains. A mutation, however, is very minor genetic errors in genome sequences made during replication that doesn’t fundamentally change the nature or behaviour of the virus.
So far, only two isolates from India have been genetically sequenced. Both are from coronavirus patients in Kerala who had arrived from China’s Wuhan in late January. The strains are nearly identical to the ones sequenced in Wuhan and cannot be identified as a separate “Indian strain”.
Anu Raghunathan, a scientist at the Council of Scientific and Industrial Research’s (CSIR) National Chemical Laboratory in Pune, told ThePrint that the researchers of the aforementioned study used computational biology to analyse the genomic data from different strains around the world.
The initial attempt of the team from the International Centre for Genetic Engineering and Biology, New Delhi, at analysing the virus strain is not sufficient to conclude that all Indian strains would have only “one unique mutation”, said Raghunathan.
The mutations themselves are composed of changes in base pairs.
The novel corona virus’s genome is made up of 30,000 base pairs, while a human genome contains over 3 billion. The small numbers make it easy for scientists to track changes and new lineages as they evolve.
To understand what these mutations mean for India, the country will have to sequence a much larger set of the viral isolates from the patients here.
Rakesh K. Mishra, director of CSIR’s Centre for Cellular and Molecular Biology in Hyderabad, told ThePrint that his institute has the capacity to run the genome sequencing of the isolates from at least 500 people within a couple of weeks. This can help scientists decide the correct course of action for treating the disease.
For example, if a virus mutates too fast, vaccines being developed now will potentially become useless, and pharmaceuticals will have to constantly keep up with the mutations by developing new vaccines all the time, a financially unviable prospect.
How viruses mutate
Regularly switching up the genetic code is an essential part of how a virus evolves. Some viruses, such as the coronaviruses that cause flu, change their genetic code extremely rapidly. This is the main reason why it’s so difficult to find a vaccine for coronaviruses. They evolve quickly, making vaccines defunct.
The flu vaccine, now available and recommended especially for older people, needs to be taken annually for this reason. By the time the next season comes along, the vaccine is no longer effective on the circulating form of the virus.
Coronaviruses are ribonucleic acid (RNA) viruses, containing just RNA strands (single or double) as its genetic material. They have about 26,000 to 32,000 bases or RNA “letters” in their length.
RNA viruses mutate continuously. Such a mutation is what made SARS-CoV-2’s jump from animals to humans possible.
The virus multiplies inside living organism’s cells by creating copies for the RNA. However, the process it uses to make these copies is not perfect, and often introduces tiny errors in the sequence of ‘letters’ — much like a game of Chinese whispers.
The errors that do not help the survival of the virus eventually get eliminated, while other mutations get embedded. It is these mistakes that help scientists track how the virus travelled around different geographic locations.
For example, by genetically sequencing over 2,000 isolates of samples from different countries, scientists tracked how the novel coronavirus spread to different countries, and how the virus evolved and geographically mutated in different areas.
The word ‘mutations’ often conjures images of humans with superpowers — thanks to Hollywood movies — but it doesn’t mean the virus acquires superpowers. The genetic changes are normal in the evolution of the virus. In some cases, the changes are extremely rapid because the replication is not rigorous or thorough.
The only problem with mutations is the problem of development of vaccines, which would require constant upgrade.
The coronavirus mutation
The novel coronavirus, unlike its cousins, mutates slowly . It seems to have a proofreading mechanism in place that reduces the error rate and slows down the speed of mutation. But the mutations are completely random.
“One mutation that supports the virus replication and transmission from human to human or any other host sustains whereas the virus that cannot infect many eventually dies out,” explained Shweta Chelluboina, clinical virologist at the Interactive Research School for Health Affairs in Pune.
“ These are random events and such a phenomenon has caused the outbreak in the first place. The new coronavirus had mutated successfully enough that it jumped from animal to human, allowing it to infect many with still no containment in sight ,” said Chelluboina.
There were reports earlier about how the novel coronavirus has mutated into two strains so far — the original S-type which originated in Wuhan, and the subsequent L-type that evolved from the S-type and is more prevalent in countries like the US. Scientists at the Peking University’s School of Life Sciences and the Institut Pasteur of Shanghai announced these findings.
The L-type is the more “aggressive” one, and spreads rapidly but is no more or less virulent than the S-type. The researchers urged everyone to take preventive measures because the mutation indicates that more could be coming.
But these aren’t really two ‘strains’ as such. A strain is a genetic variant characterised by different forms of surface proteins. But the L-type and the S-type are not quite different enough to call them strains just yet. They are just mutations, referred to as types, according to the study.
To explain the lower population of S-type, the authors of the study suggested that human-adopted measures of curbing contact contained the S-type to the Wuhan region, and allowed the L-type to spread elsewhere uncontained. While the S-type emerged around the time the virus jumped from animals to humans, the L-type emerged soon after that within humans, the team suggested.
Experts think there is also a definite sampling bias for the L-type, which was just sampled more, and uniformly, resulting in higher representation. The mutations were discovered in a preliminary study, as cautioned by the authors as well, and was performed on a limited population of 103 samples.
A recent paper claims that #SARSCoV2 split into L and S strains with L leading to more severe #COVID19. This is most likely a statistical artifact due to intense early sampling of the "L" group in Wuhan, resulting in higher apparent CFR in this group. [1/3]
&mdash Richard Neher (@richardneher) March 4, 2020
The study is not peer-reviewed yet, and as most Covid-related studies are under the open community, is a pre-print for now. It was uploaded on 4 March.
“These findings strongly support an urgent need for further immediate, comprehensive studies that combine genomic data, epidemiological data, and chart records of the clinical symptoms of patients with coronavirus disease 2019 (Covid-19),” said the study.
The science is evolving rapidly, as more and more genome data is collected from around the world.
Newer research data gathered from genetic sequences uploaded to open source website NextStrain.org indicate that anywhere from eight to 18 different sequences of the coronavirus are making their way around the globe, according to researchers who have genetically sequenced over 1,400 isolates from around the world. These are extremely tiny differences within the viruses in their nucleotide sequences, and none of the sequenced groups seem to be growing any more or less lethal than others.
Most importantly, none of them are new ‘strains’ despite their coverage as such in the media and subsequent clarifications by Nextstrain, who have the data for 2,243 SARS-CoV-2 genomes, of which 1,150 have minor mutations.
This article by @USATODAY misleadingly states that there are "8 strains of coronavirus" circulating. Because of this our @nextstrain inbox is today full of questions like "if you get one strain of Covid-19 and recover, do you have immunity to the other seven?". 1/13 pic.twitter.com/y9OW8Mdnsd
&mdash Trevor Bedford (@trvrb) March 30, 2020
On Nextstrain, nearly every virus reveals a slightly different genome. But there are very few mutations and none are strong or vital enough to affect the way the virus spreads, attacks, or lives. The sequences are all named by location where they were first sequenced.
“It is very common that during an outbreak, especially during a global pandemic, the genome sequence of earlier isolates from one particular geographical location will differ from that of the later isolates collected elsewhere,” said Sreejith Rajasekharan, virologist and post doc at the International Center for Genetic Engineering and Biotechnology (ICGEB) in Trieste, Italy, over an email.
“This is what is observed in the current pandemic as well. The first sequence collected from positive patients in Rome, Italy was from a Chinese tourist. This and the one collected after, from an Italian citizen returning from China resemble those that were isolated in China,” said Rajasekharan.
“However, the ones isolated later in Lombardia and Friuli Venezia Giulia regions (in Italy) match the European clad and not the one from China.”
The mutations in the virus are like moving targets, which can’t be hit because they keep changing their genetic sequence.
“Genome sequencing on a large scale can tell us whether viral isolates are different in different countries from what we saw from China. So this will help us decide whether the treatments being contemplated in those places will be applicable for our strains or not,” Rakesh Mishra said.
It will also help decide if the different strains vary so much that developing vaccines may not be viable, Mishra said.
“Some behaviours are unique in different strains like how we know that aged people are at high risk but we saw in India young people have also died,” said Chelluboina. “Some variations in the virus cause the virus to behave in a certain way.”
The sequencing will provide a fundamental understanding of how to address the problem — without it, the treatments are based on what is known of other viruses — which may or may not work for the novel coronavirus, and also likely take up a long time.
“That is why it is important to understand the sequence of the virus in local infections to know which countries have a similar virus, so that we can attempt to better predict the outcome,” added Chelluboina.
However, Rajasekharan added, “The general public needs not be concerned in this regard as the genome of SARS-CoV-2 is quite stable, and therefore the rate of mutation is low.”
The novel coronavirus will continue to mutate and pose a challenge to researchers developing a vaccine. N onetheless, the idea of viruses mutating is not something that needs to worry people in terms of their health when it comes to Covid-19.
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