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Study of coronavirus variants predicts virus evolving to escape current vaccines

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Study of coronavirus variants predicts virus evolving to escape current vaccines

A new study of the U.K. and South Africa variants of SARS-CoV-2 predicts that current vaccines and certain monoclonal antibodies may be less effective at neutralizing these variants and that the new variants raise the specter that reinfections could be more likely.

The study was published in Nature on March 8, 2021. A preprint of the study was first posted to BioRxiv on January 26, 2021.The study’s predictions are now being borne out with the first reported results of the Novavax vaccine, says the study’s lead author David Ho, MD. The company reported on Jan. 28 that the vaccine was nearly 90% effective in the company’s U.K. trial, but only 49.4% effective in its South Africa trial, where most cases of COVID-19 are caused by the B.1.351 variant.”Our study and the new clinical trial data show that the virus is traveling in a direction that is causing it to escape from our current vaccines and therapies that are directed against the viral spike,” says Ho, the director of the Aaron Diamond AIDS Research Center and the Clyde’56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.””If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to chasing after the evolving SARS-CoV-2 continually, as we have long done for influenza virus,” Ho says. “Such considerations require that we stop virus transmission as quickly as is feasible, by redoubling our mitigation measures and by expediting vaccine rollout.”

After vaccination, the immune system responds and makes antibodies that can neutralize the virus.Ho and his team found that antibodies in blood samples taken from people inoculated with the Moderna or Pfizer vaccine were less effective at neutralizing the two variants, B.1.1.7, which emerged last September in England, and B.1.351, which emerged from South Africa in late 2020. Against the U.K. variant, neutralization dropped by roughly 2-fold, but against the South Africa variant, neutralization dropped by 6.5- to 8.5-fold.

“The approximately 2-fold loss of neutralizing activity against the U.K. variant is unlikely to have an adverse impact due to the large ‘cushion’ of residual neutralizing antibody activity,” Ho says, “and we see that reflected in the Novavax results where the vaccine was 85.6% effective against the U.K. variant.”

Data from Ho’s study about the loss in neutralizing activity against the South Africa variant are more worrisome.

“”The drop in neutralizing activity against the South Africa variant is appreciable, and we’re now seeing, based on the Novavax results, that this is causing a reduction in protective efficacy,” Ho says.

The new study did not examine the more recent variant found in Brazil (B.1.1.28) but given the similar spike mutations between the Brazil and South Africa variants, Ho says the Brazil variant should behave similarly to the South Africa variant.


“We have to stop the virus from replicating and that means rolling out vaccine faster and sticking to our mitigation measures like masking and physical distancing. Stopping the spread of the virus will stop the development of further mutations,” Ho says.

The study also found that certain monoclonal antibodies used now to treat COVID patients may not work against the South Africa variant. And based on results with plasma from COVID patients who were infected earlier in the pandemic, the B.1.351 variant from South Africa has the potential to cause reinfection.

New study contains comprehensive analysis of variants

The new study conducted an extensive analysis of mutations in the two SARS-CoV-2 variants compared to other recent studies, which have reported similar findings.

The new study examined all mutations in the spike protein of the two variants. (Vaccines and monoclonal antibody treatments work by recognizing the SARS-CoV-2 spike protein.)

The researchers created SARS-CoV-2 pseudoviruses (viruses that produce the coronavirus spike protein but cannot cause infection) with the eight mutations found in the U.K. variant and the nine mutations found in the South African variant.

They then measured the sensitivity of these pseudoviruses to monoclonal antibodies developed to treat COVID patients, convalescent serum from patients who were infected earlier in the pandemic, and serum from patients who have been vaccinated with the Moderna or Pfizer vaccine.

Implications for monoclonal antibody treatments

The study measured the neutralizing activity of 18 different monoclonal antibodies — including the antibodies in two products authorized for use in the United States.

Against the U.K. variant, most antibodies were still potent, although the neutralizing activity of two antibodies in development was modestly impaired.

Against the South Africa variant, however, the neutralizing activity of four antibodies was completely or markedly abolished. Those antibodies include bamlanivimab (LY-CoV555, approved for use in the United States) that was completely inactive against the South Africa variant, and casirivimab, one of the two antibodies in an approved antibody cocktail (REGN-COV) that was 58-fold less effective at neutralizing the South Africa variant compared to the original virus. The second antibody in the cocktail, imdevimab, retained its neutralizing ability, as did the complete cocktail.

“Decisions of the use of these treatments will depend heavily on the local prevalence of the South Africa and Brazil variants,” Ho says, “highlighting the importance of viral genomic surveillance and proactive development of next-generation antibody therapeutics.”

Reinfection implications

Serum from most patients who had recovered from COVID earlier in the pandemic had 11-fold less neutralizing activity against the South Africa variant and 4-fold less neutralizing activity against the U.K. variant.

“The concern here is that reinfection might be more likely if one is confronted with these variants, particularly the South Africa one,” Ho says.

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Editing without ‘cutting’: Molecular mechanisms of new gene-editing tool revealed

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Joint research led by Yutaro Shuto, Ryoya Nakagawa, and Osamu Nureki of the University of Tokyo determined the spatial structure of various processes of a novel gene-editing tool called “prime editor.” Functional analysis based on these structures also revealed how a “prime editor” could achieve reverse transcription, synthesizing DNA from RNA, without “cutting” both strands of the double helix. Clarifying these molecular mechanisms contributes greatly to designing gene-editing tools accurate enough for gene therapy treatments. The findings were published in the journal Nature.

The 2020 Nobel Prize in Chemistry was awarded to Jennifer Doudna and Emmanuelle Charpentier for developing a groundbreaking yet simple way to edit DNA, the “blueprint” of living organisms. While their discovery opened new avenues for research, the accuracy of the method and safety concerns about “cutting” both strands of DNA limited its use for gene therapy treatments. As such, research has been underway to develop tools that do not have these drawbacks.

The prime editing system is one such tool, a molecule complex consisting of two components. One component is the prime editor, which combines a SpCas9 protein, used in the first CRISPR-Cas gene editing technology, and a reverse transcriptase, an enzyme that transcribes RNA into DNA. The second component is the prime editing guide RNA (pegRNA), a modified guide RNA that identifies the target sequence within the DNA and encodes the desired edit. In this complex, the prime editor works like a “word processor,” accurately replacing genomic information. The tool has already been successfully implemented in living cells of organisms such as plants, zebrafish, and mice. However, precisely how this molecule complex executes each step of the editing process has not been clear, mostly due to a lack of information on its spatial structure.

“We became curious about how the unnatural combination of proteins Cas9 and reverse transcriptase work together,” says Shuto, the first author of the paper.

The research team used cryogenic electron microscopy, an imaging technique that makes observations possible at a near-atomic scale. The method required samples to be in glassy ice to protect them from the potential damage by the electron beams, posing some additional challenges.

“We found the prime editor complex to be unstable under experimental conditions,” explains Shuto. “So, it was very challenging to optimize the conditions for the complex to stay stable. For a long time, we could only determine the structure of Cas9.”

Finally overcoming the challenges, the researchers succeeded in determining the three-dimensional structure of the prime editor complex in multiple states during reverse transcription on the target DNA. The structures revealed that the reverse transcriptase bound to the RNA-DNA complex that formed along the “part” of the Cas9 protein associated with DNA cleavage, the splitting of a single strand of the double helix. While performing the reverse transcription, the reverse transcriptase maintained its position relative to the Cas9 protein. The structural and biochemical analyses also indicated that the reverse transcriptase could lead to additional, undesired insertions.

These findings have opened new avenues for both basic and applied research. So, Shuto lays out the next steps.

“Our structure determination strategy in this study can also be applied to prime editors composed of a different Cas9 protein and reverse transcriptase. We want to utilize the newly obtained structural information to lead to the development of improved prime editors.”



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Acute sense of touch helps hummingbirds hover near a flower without bumping into it

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Hummingbirds seem like a marvel of nature and engineering: a living creature that can hover near a flower with surgical precision. How do they do this?

Though hummingbirds’ flight mechanics have been well studied, far less is known about how their sense of touch helps these tiny, energetic birds sip nectar from a flower without bumping into it. Most of what scientists know about how touch is processed in the brain comes from studies on mammals, but bird brains are very different from mammal brains.

UCLA-led research published in Current Biology shows that hummingbirds create a 3D map of their body when neurons in two specific spots of the forebrain fire — as gusts of air touch feathers on the leading edge of their wings and skin of their legs. Receptors on their bill, face and head also work toward this end. The air pressure’s intensity, influenced by factors including proximity to an object, is picked up by nerve cells at the base of the feathers and in the leg skin and transmitted to the brain, which gauges the body’s orientation relative to an object.

Zebra finches, also studied by the researchers, have the same general organization with slightly less sensitivity in some areas than hummingbirds, suggesting that these areas help with highly specialized hummingbird flight dynamics. The work adds to knowledge of how animals perceive and navigate in their worlds and can help identify ways to treat them more humanely.

Humans produce a tactile map of the body that progresses from the toes at the center of the brain, down to the legs, back and a much larger area that represents touch to the face and hands. These areas, used for touching and touch tasks, are enlarged in the human brain.

“In mammals, we know that touch is processed across the outer surface of the forebrain in the cortex,” said Duncan Leitch, corresponding author and a professor of integrative biology at UCLA. “But birds have a brain without a layered cortex structure, so it was a wide-open question how touch is represented in their brains. We showed exactly where different kinds of touch activate specific neurons in these regions and how touch is organized in their forebrains.”

Previous studies in which birds were injected with dye showed their brains have one region in the forebrain to process touch to the face and head, and one for touch anywhere else on the body. In owls, for example, touch centers that typically correspond to face touch are devoted solely to talons. But since hummingbirds live very different lives than owls, it didn’t seem likely this would hold true for them.

Leitch and co-authors at Royal Veterinary College and the University of British Columbia were able to observe neurons firing in real time by placing electrodes on hummingbirds and finches, and touching them gently with cotton swabs or puffs of air. A computer amplified the signals from the electrodes and converted them to sound for easier analysis.

The experiments confirmed that touch for the head and body is mapped in different regions of the forebrain and showed for the first time that air pressure activates specific clusters of neurons in these regions. Examination of the wings showed a network of nerve cells that likely sent a signal to the brain when activated by puffs of air on the feathers.

The researchers found particularly large clusters of brain cells that reacted to stimulation of the edges of wings, which they think help the birds adjust flight in a nuanced way. They also discovered that the feet are acutely sensitive to touch and this touch had a large representation in the brain, presumably to help with perching. The researchers speculate these areas may be even larger in parrots and other birds that use their feet to grasp and move objects.

In their study, the researchers identified receptive fields on the birds, in which a touch would trigger a neuron to fire. In hummingbirds, some of these fields — especially on the bill, face and head — were very small, meaning they could sense the lightest touch. Zebra finches had the same but larger receptive fields, suggesting these regions in finches are not quite as sensitive and  probably of greater relevance to hummingbirds that rely on constant, steady precision flight.

“Hummingbirds were often reacting to the slightest thresholds we could give them,” Leitch said.

Learning more about how diverse animals map touch across their body could lead to advances in technologies that use sensors to move about or perform a task, such as prosthetic limbs or autonomous devices. But improvements to animal welfare are perhaps a more immediate outcome of the research.

“If we can understand how animals perceive their sense of touch, we can develop practices that are less disturbing to them,” Leitch said.



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Complete X and Y chromosome sequences of living great ape species determined

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Newly generated, complete “end-to-end” reference genomes for the sex chromosomes of five great ape species and one lesser ape species — produced by an international collaborative team led by researchers at Penn State, the National Human Genome Research Institute and the University of Washington — highlight extremely rapid changes on the male-specific Y chromosome among ape species. These findings shed light on the evolution of sex chromosomes and inform understanding of diseases related to genes on these chromosomes in both apes and humans.

“The Y chromosome is important for human fertility, and the X chromosome harbors genes critical for reproduction, cognition and immunity,” said Kateryna Makova, Verne M. Willaman Chair of Life Sciences, professor of biology at Penn State and leader of the research team. “Our study opens doors for many future investigations of sex chromosomes, how they evolved, and diseases associated with them. The living non-human great ape species we studied are all endangered. The availability of their complete sex chromosome sequences will facilitate studies of their sex-specific dispersal in the wild and of their genes important for reproduction and fertility.”

Such reference genomes act as a representative example that are useful for future studies of these species. The team found that, compared to the X chromosome, the Y chromosome varies greatly across ape species and harbors many species-specific sequences. However, it is still subject to purifying natural selection — an evolutionary force that protects its genetic information by removing harmful mutations.

The new study appears May 29 in the journal Nature.

“Researchers sequenced the human genome in 2001, but it wasn’t actually complete,” Makova said. “The technology available at the time meant that certain gaps weren’t filled in until a renewed effort led by the Telomere-to-Telomere, or T2T, Consortium in 2022-23. We leveraged the experimental and computational methods developed by the Human T2T Consortium to determine the complete sequences for the sex chromosomes of our closest living relatives — great apes.”

The team produced complete sex chromosome sequences for five species of great apes — chimpanzee, bonobo, gorilla, Bornean orangutan and Sumatran orangutan, which comprise most great ape species living today — as well as a lesser ape, siamang. They generated sequences for one individual of each species. The resulting reference genomes act as a map of genes and other chromosomal regions, which can help researchers sequence and assemble the genomes of other individuals of that species. Previous sex chromosome sequences for these species were incomplete or — for the Bornean orangutan and siamang — did not exist.

“The Y chromosome has been challenging to sequence because it contains many repetitive regions, and, because traditional short-read sequencing technology decodes sequences in short bursts, it is difficult to put the resulting segments in the correct order,” said Karol Pál, postdoctoral researcher at Penn State and a co-first author of the study. “T2T methods use long-read sequencing technologies that overcome this challenge. Combined with advances in computational analysis, on which we collaborated with Adam Phillippy’s group at the NHGRI, this allowed us to completely resolve repetitive regions that were previously difficult to sequence and assemble. By comparing the X and Y chromosomes to each other and among species, including to the previously generated human T2T sequences of the X and the Y, we learned many new things about their evolution.”

High variability on the Y chromosome

“Sex chromosomes started like any other chromosome pair, but the Y has been unique in accumulating many deletions, other mutations and repetitive elements because it does not exchange genetic information with other chromosomes over most of its length,” said Makova, who is also the director of the Center for Medical Genomics at Penn State.

As a result, across the six ape species, the research team found that the Y chromosome was much more variable than the X over a variety of characteristics, including size. Among the studied apes, the X chromosome ranges in size from 154 million letters of the ACTG alphabet — representing the nucleotides that make up DNA — in chimpanzee and human to 178 million letters in gorilla. In contrast, the Y chromosome ranges from 30 million DNA letters in siamang to 68 million letters in Sumatran orangutan.

The amount of DNA sequence shared between species was also more variable on the Y. For example, about 98% of the X chromosome aligns between human and chimpanzee, but only about a third of the Y aligns between them. The researchers found that this is in part because the Y chromosome is more likely to be rearranged or have portions of its genetic material duplicated.

Additionally, the percentage of the chromosome occupied by sequences that are repeated is highly variable on the Y. Whereas, depending on the species, 62% to 66% of the X chromosomes are occupied by repetitive elements, 71% to 85% of the Y chromosomes are occupied by them. These percentages are higher on both the X and the Y than in other chromosomes in the human genome.

How the Y has survived

“We found the ape Y to be shrinking, accumulating many mutations and repeats, and losing genes,” Makova said. “So why hasn’t the Y chromosome disappeared, as some previous hypotheses suggested? In collaboration with Sergei Kosakovsky Pond from Temple University and others, we found that the Y chromosome still has a number of genes evolving under purifying selection — a type of natural selection that keeps gene sequences intact. Many of these genes are important for spermatogenesis. This means that the Y chromosome is unlikely to disappear any time soon.”

The researchers found that many genes on the Y chromosome seem to use two strategies to survive. The first takes advantage of genetic redundancy — the presence of multiple copies of the same gene on a chromosome — so that intact copies of the gene can compensate for copies that might acquire mutations. The team quantified this genetic redundancy by completing the landscape of multi-copy gene families on ape sex chromosomes for the first time.

The second survival strategy takes advantage of palindromes, where the sequence of letters in the DNA alphabet is followed by the same, but inverted sequence, for example, ACTG-GTCA. When located within a palindrome, genes benefit from the palindrome’s ability to correct mutations.

“We found that the Y chromosome can exchange genetic information with itself between the repeated sequences of the two palindrome arms, which fold so that the inverted sequences align,” Pál said. “When two copies of the same gene are located within palindromes, and one copy is hit by a mutation, the mutation can be rescued by the genetic exchange with another copy. This can compensate for the Y’s lack of genetic information exchange with the other chromosomes.”

The research team obtained the complete sequences of palindromes on ape sex chromosomes also for the first time, as they were previously difficult to sequence and study. They found that palindromes are particularly abundant and long on the ape Y chromosome, yet they are usually only shared among closely related species.

In collaboration with Michael Schatz and his team at Johns Hopkins University, the researchers also studied the sex chromosomes of 129 individual gorillas and chimpanzees to better understand the genetic variation within each species and search for evidence of natural selection and other evolutionary forces acting on them.

“We obtained substantial new information from previously studied gorilla and chimpanzee individuals by aligning their sex chromosome sequencing reads to our new reference sequences,” said Zachary Szpiech, assistant professor of biology at Penn State and an author of the paper. “While increasing the sample size in the future will be very helpful to improve our ability to detect signatures of different evolutionary forces, this can be ethically and logistically challenging when working with endangered species, so it is critical that we can get the most out of the data we do have.”

The researchers explored a variety of factors that could explain variation on the Y chromosome within gorillas and within chimpanzees, and this analysis revealed additional signatures of purifying selection on the Y. This confirms the role of this type of natural selection on the Y, as was discovered in their previous analyses of genes.

“The powerful combination of bioinformatic techniques and evolutionary analyses that we used allows us to better explain the evolutionary processes acting on sex chromosomes in our closest living relatives, great apes,” said Christian Huber, assistant professor of biology at Penn State and an author of the paper. “Additionally, the reference genomes we produced will be instrumental for future studies of primate evolution and human diseases.”

In addition to Makova, Pál, Szpiech and Huber, the research team at Penn State includes Kaivan Kamali, computational scientist in the departments of biology and of biochemistry and molecular biology; Troy LaPolice, graduate student in bioinformatics and genomics; Paul Medvedev, professor of computer science and engineering and of biochemistry and molecular biology; Sweetalana, research assistant in the department of biology; Huiqing Zeng, research technologist in biology; Xinru Zhang, graduate student in bioinformatics and genomics; Robert Harris, assistant research professor of biology, now retired; Barbara McGrath, associate research professor of biology, now retired; and Sarah Craig, associate research professor of biology, currently a program officer at the National Institutes of Health. The co-authors also included Penn State alumni Monika Cechova, currently a postdoctoral fellow at the University of California Santa Cruz, and Melissa Wilson, currently an associate professor at Arizona State University.

In addition to Makova, the team was co-led by co-corresponding study authors Adam Phillippy, senior investigator at NHGRI, and Evan Eichler, professor of Genome Sciences at the University of Washington. A full list of authors for this paper is available here.

Funding from the National Institutes of Health supported this research.



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