Immunity: The antigenic drift of the new coronavirus is 10 times faster than that of the influenza A virus!

Life science On December 14, 2021, Jonathan W.
Yewdell, a researcher at the National Institute of Allergy and Infectious Diseases, published a new article titled "Antigenic drift: Understanding COVID-19" in the Cell Press journal Immunity.
article
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Antigenic drift refers to the evolutionary accumulation of amino acid substitutions in viral proteins that retain variants that favor them as the virus moves through the population due to selection by the host's adaptive immune system
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Antigenic drift can greatly limit the duration of immunity from natural infection and vaccination
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Here, we explain the factors that lead to the rapid antigenic drift of the SARS-CoV-2 spike protein and receptor proteins of other viruses, and discuss the impact of this phenomenon on SARS-CoV-2 evolution and immunity
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Long press the picture to identify the two-dimensional code to read the basic concept of original antigen drift.
On the earth we live in, there are about 1033 kinds of viruses that constitute the entire virus group, which are the most abundant self-replicating entities on the earth
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The genome of the virus is small, but it can replicate rapidly as the virus proliferates, allowing rapid adaptive evolution to occur
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The proteome encoded by the viral genome is relatively simple, but still sufficient to alter the biosynthetic machinery of the host cell and produce up to 1 million progeny viruses in a single day through an infection cycle
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Viral DNA or RNA polymerases are extremely efficient, but this high efficiency sacrifices replication or transcriptional accuracy
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The virus produces 1 nucleotide substitution for every 5000 nucleotides replicated, i.
e.
, the mutation rate per base pair is 2 × 10−4; in comparison, the error rate of human genome replication is 6000 lower times
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Therefore, usually each progeny virus has at least one point mutation per genome
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Genetic variation in viruses is further enhanced by codon deletions and/or insertions and recombination between viral genomes, which is one of the common features of coronaviruses (CoVs), and this process of enhanced variation occasionally occurs in viruses.
and the host genome
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Infected humans can produce 1012 virions, or infectious virus particles, during respiratory viral infection
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For many viruses with high mutation rates, this group includes viruses with mutations at every position in the genome, and even viruses with every possible nucleotide at any two positions
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This growing and strong genetic diversity allows the virus to evolve rapidly under the immune pressure of the host
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Of course, it is important to distinguish this genetic drift from 'antigenic drift' (Fig.
1)
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Genetic drift is an inevitable consequence of the high mutation rate of the virus
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When a small number of viruses (sometimes only one) transmit an infection to a new host, mutations that do not affect viral replication and spread spread randomly and "fixed" in the viral population
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If the amino acid substitution produced by this mutation reduces the antigenicity of the immune target protein, it will lead to an antigenic drift phenotype
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Due to antigenic drift, the efficacy of existing immune agents targeting the drift region of viral proteins is reduced
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In the absence of selection, antigenic mutations are present at very low frequencies in the virus population; however, some viruses are able to evade the host's immune neutralization or the destruction of infected cells by the immune system (immune selection) and thus dominate the population status and replace the original virus
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In contributing to immune escape, antigenic drift disrupts immunity conferred by prior infection or vaccination
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As discussed below, antigenic drift is highly relevant to the evolution of 2019-nCoV, as the virus is still circulating globally
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Therefore, we need to boost the vaccine, and we need to continuously improve the vaccine to match the drifting variation, just like our measures against the flu
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Virus Escape from Host Immunity Every virus must have evolved to evade innate host cell immunity
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Therefore, they not only need to deal with intracellular machinery that restricts their transcription and translation, but also need to escape extracellular proteins that prevent their entry in multicellular organisms
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If a zoonotic virus is to infect a new species, certain hurdles must be overcome, such as binding to host cell receptors, entry of the virus into the cell, escape from innate immunity and spread to the next host
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During the early stages of virus adaptation to a new species, evolution rapidly optimizes viral genes to maximize transmission
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In a pandemic, as tens of thousands of people are successively infected, newly introduced viruses are expected to reach near-optimal genotypes for humans
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The consequences of selection for additional mutations arise when viruses encounter host polymorphisms in innate immunity genes or persistent differences in weather and/or behavioral conditions that affect transmission
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However, the strongest selection pressure after virus adaptation occurs when the virus encounters the adaptive immune system
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For 2019-nCoV and other acute viruses that first infect a host, transmission of the virus is likely to occur before the transmitting host can initiate an effective immune response, that is, a week or more after infection
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Thus, in the early stages of a pandemic, adaptive immune pressure is limited due to the large number of uninfected hosts
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However, as the number of vaccinated or previously infected populations increases, so does the immune pressure, thus increasing the likelihood of selection of variants through immune escape (Fig.
1)
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Figure 1.
Gene and antigenic drift Antigenic drift of the 2019-nCoV spike All viral genes are derived from a very small number of common ancestral genes
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As a result, all viral proteins can genetically differentiate and retain their original functions, and given enough time, they can evolve proteins that escape immune or other selective pressures
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Therefore, the key to the antigenic drift of viral target proteins lies in the evolution speed of the virus in the process of host transmission
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For any given protein in any given virus, antigenic drift is related to multiple factors (Figure 2)
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These factors include: (1) the inherent mutation rate of the viral polymerase and the number of viruses that an individual produces that may spread outward
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(2) The ability of viral proteins to accept amino acid substitutions that reduce antibody binding while maintaining viral fitness and enhancing its fitness through penetrance changes
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This can vary widely between different proteins
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For example, measles virus receptors and fusion proteins are antigenically conserved and do not readily tolerate random amino acid insertions
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However, the antigenic variable regions of influenza virus HA and NA are more tolerant to random mutation and insertion of amino acids
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(3) The number of viruses that initiate infection
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This number can be anywhere from 1 to 100 or so virions
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If there are enough transmission events, even with just a few viruses, selection for single amino acid substitutions will occur
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If there are more viruses, this selection will increase proportionally
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(4) The amount of virus produced during infection
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More replication means more mutations to choose from
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(5) The nature of the immune selection pressure, especially the extent to which the condition of "Goldilocks" is satisfied, that is, a moderate immune response focused on one (or possibly two) antigenic sites
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Figure 2.
Factors affecting the rate of antigenic drift Until recently, the antigenicity of human coronaviruses was considered to be stable, unlike the typical virus that undergoes antigenic drift, seasonal influenza virus, whose two target proteins (HA and NA) will accumulate 1 to 1.
5 amino acid substitutions per year, almost all substitutions are on the protein surface, and many substitutions are still in established antigenic sites
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Drift in H3 HA has allowed us to update our flu vaccine 16 times over 22 years
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Over 32 years, the 229E seasonal coronavirus spike exhibits 46 substitutions, many of which are located in regions likely to be recognized by neutralizing antibodies
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HA and seasonal coronavirus spikes differ in the evolution of N-linked glycans
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The 229E spike virus has 24 predicted N-linked glycans that are fully conserved over 32 years of human evolution
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During the same 32 years of evolution, H3 HA added 3 carbohydrates in the antigenic region
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In the brief evolution of human beings, the spike of the new coronavirus has shown astonishingly rapid evolution
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In less than a year, the delta variant spike that is now sweeping the globe (isolated in October 2020) has accumulated 1-nucleotide deletions and 9-nucleotide substitutions
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Like 229E, its N-linked polysaccharide sites have been highly conserved, with only 1,236 (0.
2%) of 519,035 delta isolates showing changes in sugar sites (almost all single-site deletions)
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The recently discovered omicron mutation, which appears to be the predominant circulating strain in South Africa, has a 35 amino acid change in its spike
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This rate of evolution (replacement of each residue per year) is approximately 10 times higher than that of influenza virus HA and is unprecedented in an acute virus, prompting serious consideration of reformulation of vaccines that induce T cells to respond to more coronavirus proteins reaction
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Current evidence suggests that although spike antigen drift promotes 2019-nCoV reinfection, infection and vaccine-induced antibody and T-cell responses can still provide robust immunity to delta-mutant severity and death, even if this immunity Not perfect
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The extent to which this applies to the Omicron variant remains to be determined
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Depending on the situation with seasonal coronaviruses and other human respiratory viruses, individuals may contract COVID-19 every few years as immunity wanes after infection and/or vaccination, but severe illness will not be a common outcome
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The extent to which repeated booster vaccines are still required to prevent moderate to severe disease in different high-risk groups remains an open question
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Results from monitoring vaccination rates in different regions should provide answers in the coming years
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A review concludes that the high mutation rate of many viruses enables them to evolve rapidly, thereby increasing transmission between individuals
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Human adaptive immunity against viruses can exert high selective pressures that trigger antigenic drift of T cells and antibody epitopes
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For acute viruses, antigenic drift is essentially limited to the selection of the virus by antibodies, that is, mutation of viral surface proteins
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These mutations reduce the number of antibodies that can stop the virus from spreading
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Mutations can reduce the binding of the antibody by changing the amino acids of the epitope, limit the exposure of the epitope to the antibody, or enable the addition of polysaccharides that prevent the antibody from accessing its epitope
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Mutations are subject to their effects on protein function, whereas epimutations can mitigate the effects of the same or other viral proteins
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Viruses exhibit considerable variation in the rate of antigenic mutation based on a variety of factors
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Compared with other acute viruses, the antigenic drift speed of 2019-nCoV is astonishing, and may even be 10 times faster than the HA of influenza A virus
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If this situation continues unabated in the next few years, we may need to update the vaccine regularly
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Predicting antigenic drift may not be possible, so vaccine selection needs to be empirical, taking into account the currently dominant circulating strains, and serious consideration should be given to expanding vaccines to induce responses against multiple spike proteins
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Related paper information The original text of the paper was published in Immunity, a journal of CellPress.