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Ex vivo replication of SARS-CoV-2 and transmission in vivo

The distinction may have been obtained in various ways by the SARS-CoV-2 strain that has become most prevalent around the globe. Changes in transmissibility, antigenicity, and pathogenicity are possibilities. According to a new report, the performance of the prevalent strain comes down to improved transmissibility and speed of replication.

By announcing a gain in SARS-CoV-2 transmissibility, the study isn't exactly a cause for celebration, but matters could have been worse. Less susceptibility to antibody drug neutralisation or a greater propensity to cause serious disease could have been shown by the most common SARS-CoV-2 strain. The research, which appeared in Science on November 12, did not support any of these grim possibilities.

Perhaps more encouragingly, the study indicates that the most prevalent SARS-CoV-2 strain, which arose in Europe, is possibly no less vulnerable to vaccine-induced immunity than is the strain that originated in China.

Analysis from the University of North Carolina (UNC) at Chapel Hill and the University of Wisconsin-Madison is presented in the report, entitled 'SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo' At these institutions, scientists engineered a version of SARS-CoV-2 containing a replacement of D614G in the spike glycoprotein of the virus. It is this substitution that distinguishes the most common strain of SARS-CoV-2. The researchers then performed a series of experiments in human cells and animal models to compare the characteristics of the engineered variant with those of the ancestral form.

In primary human airway epithelial cells, the variant exhibits more successful invasion, replication, and competitive fitness, but retains similar morphology and in vitro neutralisation properties compared with the ancestral wild-type virus, the authors of the study wrote. Infection of transgenic mice and Syrian hamsters with human angiotensin-converting enzyme 2 (ACE2) of both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease.' The D614G version, however, transmits considerably quicker and displays improved competitive fitness in hamsters than the wild-type virus.

The researchers also tested the neutralisation properties of the variant and the ancestral form of convalescent human serum samples and SARS-CoV-2 neutralising monoclonal antibodies, finding no substantial difference.

"Ralph S. Baric, PhD, co-corresponding author of the study and professor of epidemiology at the UNC-Chapel Hill Gillings School of Global Public Health, said The D614G virus outcompetes and outgrows the ancestral strain by about 10-fold and replicates extremely effectively in primary nasal epithelial cells, which are a potentially significant site for person-to-person transmission. Bacic, also a professor of microbiology and immunology at the UNC School of Medicine, has spent more than three decades researching coronaviruses and has been an integral part of the development of remdesivir, the first FDA-approved COVID-19 treatment.

Researchers conclude that the coronavirus D614G strain dominates because it increases the capacity of the spike protein to open cells for the virus to join. The D614G mutation helps the virus to infect cells more effectively, but also tends to change the conformation of the spike protein, possibly making the virus more susceptible to neutralisation of antibodies. (These crown-like spikes give the coronavirus its name.)

Baric Lab scientists, including first author Yixuan J. Hou, collaborated with Yoshihiro Kawaoka, PhD, and Peter Halfmann, PhD, both virologists at the University of Wisconsin-Madison, for the new research.

In this location, the original spike protein had a 'D' and it was replaced by a 'G," said Kawaoka, a professor at the University of Wisconsin-Madison and the other corresponding author of the analysis. "It has already been mentioned in many articles that this mutation makes the protein more functional and more effective in getting into cells."

However the earlier work relied on a pseudotyped virus that contained, but was not authentic, the receptor-binding protein. Baric's team replicated a matched pair of mutant SARS-CoV-2 viruses using reverse genetics, which encoded D or G at position 614 and compared basic property analysis using cell lines, primary respiratory human cells, and mouse and hamster cells.

Kawaoka contributed to the studies on the hamster. With one virus or the other, hamsters were inoculated. Eight uninfected hamsters were placed in cages next to the infected hamsters the next day. There was a separator between them so that they did not touch, however air could flow through the cage.

On day two researchers started searching for replication of the virus in the uninfected animals. Via airborne transmission, both viruses transmitted between animals, but the timing was different.

With the mutant virus, within two days, the researchers saw transmission to six out of eight hamsters, and to all hamsters by day four. They saw no transmission on day two with the initial virus, but all of the exposed animals were infected by day four.

"We have shown that the mutant virus transmits better than the original] virus in the air, which may explain why the virus dominates humans," said Kawaoka.

The researchers have looked at the pathology of the strains of the two coronaviruses. They presented exactly the same viral load and symptoms once hamsters become infected. (The hamsters lost marginally more weight when sick with the mutated strain.) This means that while the mutant virus is much better at infecting hosts, it does not cause dramatically worse disease.

In human studies, researchers warn that the outcomes of pathology can not hold true. "SARS-CoV-2 is a totally new human pathogen and it is difficult to predict its evolution in human populations," Baric said. New variants, such as the recently discovered mink SARS-CoV-2 cluster 5 variant in Denmark that also encodes D614G, are constantly emerging.

The author further explain that "We must continue to control and understand the impact of these new mutations on disease severity, transmission, host range, and susceptibility to vaccine-induced immunity," he stressed, "to optimise public health safety.

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