New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

As an RNA virus, the new coronavirus (SARS-CoV-2) is more unstable and prone to mutation than THE DNA virus. The question of virus evolution follows: Has SARS-CoV-2 evolved to be more human-adapted? Is it more contagious? Is it more toxic? However, viral mutations are influenced by a variety of factors, such as natural selection, random genetic drift, or recent epidemiological characteristics, which make it difficult for scientists to distinguish whether virus mutations are adaptive or accidental, making it more difficult to determine whether individual mutations will alter the outcome of an infection or pandemic.

Up to now, the research and controversy surrounding the new coronavirus D614G mutation is the most controversial. White House health adviser Anthony Fauci also said July 2, local time, that the new coronavirus has mutated, may make it easier to spread the pathogen. On the same day, researchers from the world-famous Los Alamos National Laboratory, the Duke Human Vaccine Institute and Department of Surgery, the University of Sheffield in the United Kingdom published a study in the top academic journal Cell online, entitled “Change Tracking in SARS-CoV-2: Spike that D614G the sos infectivity of the coVID-19 virus”. Their findings suggest that THE SARS-CoV-2 mutant strain carrying the S protein D614G has become the most common form of the global pandemic.

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

The team’s dynamic tracking of the frequency of variation showed that the G614 showed repeated growth patterns at multiple geographic levels, such as national, regional, and city. The transition from D614 to G614 will occur even if the D614 has previously been identified as the dominant region. They argue that the consistency of this model is highly statistical, suggesting that the G614 variant may have an adaptive advantage.

The team also found that higher viral loads suggested a higher level of nucleic acid in the upper respiratory tract virus than before the mutation. But the paper also notes, “We found no significant association between D614G and the severity of the disease.” “The research team also suggested that the G614 mutant pseudovirus was associated with higher infectiousness, and quantitative analysis showed that the virus particles carrying G614 mutations had significantly higher infectious titer than the corresponding D614, increasing by 2.6 to 9.3 times, and confirmed in a variety of cell types.

Research teams from Los Alamos National Laboratory continue to monitor other mutations in the S protein at the regional and global levels and are regularly updated on the public website (cov.lanl.gov).

Bette Korber, a computational biologist at Los Alamos National Laboratory who studies molecular biology and population genetics of HIV, has made a significant contribution to the availability of an effective HIV vaccine, one of which is currently being tested in humans in Africa. In 2004, Korber received the Ernest Orlando Lawrence Award, the highest recognition of scientific achievements from the U.S. Department of Energy.

It is worth mentioning that on April 40, the research team had pioneered the publication of their study on the preprinted platform bioRxiv, entitled “The saper Spike pipeline sthes the impression of the a more transmissible form of SARS-CoV-2”. Then, on May 5, they updated and released the second edition.

Since their research was published, it has sparked a wide range of discussions among scientists in the field. At the time of the preprint, some sceptics had suggested that it was too early to judge that any strain was more contagious. Some have even suggested that the G614 mutant strain is spreading so far-reachingly and widely because it happens to infect areas where no action was taken in the early stages of the pandemic. Perhaps researchers will need to do more to determine whether any strains are more contagious than others, and whether the virus may mutate faster than vaccines.

“There’s a lot of speculation here that they haven’t been tested.” Dr. Peter Hotez of the Vaccine Development Center at Texas Children’s Hospital in Houston said.

Dr. Bill Hanage of Harvard’s Chen Zengxi School of Public Health believes that a single mutation is unlikely to have any effect. Hanage writes that it’s important to remember that any drug or vaccine has to be tested to fight any virus that is spreading. “It’s lucky that the virus can find escape mutations on all these vaccines so early.” He also believes that since few people have any natural immunity to the virus, there is little or no pressure on the choice of escape mutations.

It is worth noting that the peer-reviewed, officially published version of the paper published in Cell has changed significantly from the previous preprinted version, reducing speculative views and adding a large amount of experimental data. Three scholars from the Yale School of Public Health, the Harvard School of Public Health, and the Melman School of Public Health in Columbia published another article in the journal Cell, reviewing the study by Korber of Los Alamos National Laboratory, entitled “Making Sense of the issue: what D614G means for the COVID-19 remain s “。

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

The three scholars note that new research by Korber et al. is at the heart of the debate. “They provide convincing data showing amino acid changes in the early stages of the pandemic, the virus S protein D614G, which now dominates the world.” But the key question, they say, is: Is this the result of natural selection and what does it mean for the COVID-19 pandemic?

They argue that the data provided by Korber et al. do not prove that G614 is more contagious or easily transmittable than the D614 virus. “There are still many questions about the potential impact of D614G on the COVID-19 pandemic, if any.”

“Early Warning”: Tracking the Evolution of the New Crown Virus S Protein

Previous studies have suggested that coronaviruses have a genetic proofing mechanism, while THE Diversity of SARS-CoV-2 sequences is very low, however, natural selection can still play a role in rare but beneficial mutations.

Similarly, antigen drift causes the flu virus to accumulate mutations during the flu season, and the complex interaction between immune resistance mutations and adaptability allows antibody resistance to develop in the population, which also drives the need to develop new flu vaccines every few seasons. Longer flu seasons increase the chances of choosing stress.

So-called antigen drift, refers to the virus by altering their own genes, so that the protein sequence and structure change, so that the original immunity of people can not identify. The paper notes that while SARS-CoV-2 shows some seasonal signs of abating, the persistence of pandemics may allow the virus to accumulate immune-related mutations even when vaccines are developed.

It is known that antigen drift exists in the common cold coronavirus OC43, 229E, and even SARS-CoV-1Z. Although there is no evidence of antigen drift in SARS-CoV-2, SARS-CoV-2 may also acquire mutations with adaptive advantages and immune resistance as a result of widespread human-to-human transmission.

“Focusing on this risk now may capture important evolutionary shifts in the virus, which is important to ensure the effectiveness of vaccine and immunotherapy interventions when they enter the clinic,” the team said. “

Currently, most of the global vaccines against SARS-CoV-2 target the S protein, resulting in protective neutralizing antibodies. S protein-mediated virus and host cell binding and invasion, it is composed of S1 domain and S2 domain two parts, respectively, mediated receptor binding and membrane fusion.

Most SARS-CoV-2 immunogens and testing reagents are S protein sequences based on Wuhan reference sequence, and first-generation antibody therapy was developed based on early pandemic infections and evaluated using Wuhan reference sequence proteins. However, the team suggests that changes in the transmission of viruses from person to person may change the phenotype of the virus and the effectiveness of immune-based interventions.

Therefore, the team considered it necessary to propose an “early warning” strategy to assess the evolution of The S protein during the pandemic. That was after the new crown outbreak, the Los Alamos National Laboratory HIV database team turned to new crown research, using the Global Shared Influenza Data Initiative (GISAID) database as a baseline for SARS-CoV-2 sequence data in the database, and developed a bio-information analysis software to track the increasein frequency of SARS-CoV-2 S protein amino acid variation in many geographic regions.

The transition from D614 to G614 took place in Europe and is now the main form of the world

For the study, the team analyzed 28,576 S protein sequences in the GISAID database (as of May 29). Since the S protein mutation is still small, the team set a low threshold for S protein mutations and was considered a “point of interest” that could be further tracked. When the team found a 0.3% difference in S protein sequence s with the Wuhan reference sequence, they monitored how often they increased over time in geographic regions and reoccurred in different geographic regions.

In this study, they showed the results of the first amino acid variant, D614G. The change of S protein D614G amino acid was caused by the G-A nucleotide mutation at 23403 bits of the Wuhan reference strain, which was the only mutation tracked by the research team in the first S protein mutation report in early March that met their low threshold setting.

At the time, the form of The G614 was rare in the world, but it became more prominent in Europe, and GISAID tracked down the D614G branch and named it “G-branch”. The D614G mutation is almost always accompanied by three other mutations: the C-T mutation of 5’UTR (corresponding to 241 bits of the Wuhan reference sequence), the C-T silent mutation at 3037 bits, and the 14408-bit C-T mutation (which causes RNA-dependent RNA polymerase RdRp amino acid changes).

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

The happy, which consists of these four genetic mutations, is now the main form of the world. By 1 March, 10 per cent were found in 997 series worldwide, 67 per cent in 14,951 series between 1 March and 31 March and 78 per cent in 12,194 series from 1 April to 18 May.

This means that within a month, the strain carrying the D614G S protein mutation became the global dominant form of SARS-CoV-2. The paper points out that the transition from D614 to G614 first took place in Europe, then in North America and Oceania, and then in Asia.

The study noted that the earliest sequence ssubject of the D614G GISAID G branch 4 mutant monoptopitype was discovered in China and Germany in late January, carrying three of the four mutations that define the branch, with only An RdRp P323L replacement. The team analyzed that this could be the ancestral form of the G-branch. One of the early Wuhan sequences and one of the early Thai sequences had D614G mutations without the other three mutations;

The first sequence satwithn with all four mutations was first detected by the team in Italy on February 20. Within a few days, the hapnotype was sampled in many European countries.

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

The team also studied at a structural level. D614 is located on the surface of the S proteogenic polymer and can come into contact with adjacent protopolymers. The study cites the previous cryogenic cryoscopic mirror structure, which states that the side chains of adjacent protopolymerS D614 and T859 form a hydrogen bond between the protopolymer, combining the remains of one protobody S1 domain and the remains of another protobody’s S2 domain.

The mutation of G614 will eliminate this side-chain hydrogen bond, which may increase the flexibility of the main chain and change the interaction between the protopolymer. In addition, this replacement can regulate the glycogenization of nearby N616-bit points, affect the dynamics of the near-protopolymer near-end spatial fusion peptides, or will have other effects.

There was no significant association between D614G and disease severity

The team also looked at clinical data from 999 PATIENTs with COVID-19 in Sheffield, England, to analyze the effects of mutations on the severity of the disease.

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

They found that higher viral load indications were associated with higher levels of nucleic acid in the upper respiratory tract virus in patients compared to pre-mutation strains. But the paper also notes, “We found no significant association between D614G and the severity of the disease.” “D614G is less statistically significant in relation to hospitalization (p-0.66), although it has critical significance with ICU (p-0.047). Regression analysis further confirmed that G614 was not associated with higher hospitalization levels.

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

However, the team suggested that the G614 mutant pseudovirus was associated with higher infectiousness. The quantitative analysis of the study showed that the virus carrying the G614 mutation had significantly higher infectious titness than the corresponding D614, increasing by 2.6 to 9.3 times, and was confirmed in a variety of cell types.

New Crown D614G Mutation Sweeps the World: Infectious Over 2.6X, Independent of Toxicity

The team also tested whether d614G mutations would also be neutralized by polyclonal antibodies. The study used the rehabilitation period serum of six San Diego residents (possibly infected in early March to mid-March, when both D614 and G614 were circulating) and whose serum had a neutral or better effect on the virus with G614 than carrying the D614 pseudovirus.

“While we don’t know what kind of virus these people are infected with, these preliminary data suggest that, despite increased adaptability in cell culture, the g614-carrying virus is not inherently more resistant to the neutrality of the recovery period serum,” the paper said. “

The team notes that the highly contagious nature of the G614 mutation may be a sufficient cause of its rapid spread and persistence, but other factors should also be considered.