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61-447: The PSAF superseded the 2007 linear Pandemic Severity Index (PSI), which assumed 30% spread and measured case fatality rate (CFR) to assess the severity and evolution of the pandemic. The United States Centers for Disease Control and Prevention (CDC) adopted the PSAF as its official pandemic severity assessment tool in 2014, and it was the official pandemic severity assessment tool listed in

122-721: A capsid ), and sometimes covered with a lipid layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own and instead propagate by subjugating a host cell to produce copies of themselves, thus producing the next generation. Researchers working on such " rational drug design " strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects. Compounds isolated from fruiting bodies and filtrates of various mushrooms have broad-spectrum antiviral activities, but successful production and availability of such compounds as frontline antiviral

183-518: A PSI level 3–4 situation. The analogy of "category" levels were introduced to provide an understandable connection to hurricane classification schemes, with specific reference to the aftermath of Hurricane Katrina . Like the Saffir–Simpson Hurricane Scale , the PSI ranges from 1 to 5, with Category 1 pandemics being most mild (equivalent to seasonal flu ) and level 5 being reserved for

244-437: A greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome ( AIDS ). The first experimental antivirals were developed in

305-532: A high frequency of mutations. DNA viruses, such as HPV and herpesvirus, hijack host cell replication machinery, which gives them proofreading capabilities during replication. DNA viruses are therefore less error prone, are generally less diverse, and are more slowly evolving than RNA viruses. In both cases, the likelihood of mutations is exacerbated by the speed with which viruses reproduce, which provides more opportunities for mutations to occur in successive replications. Billions of viruses are produced every day during

366-529: A linear scale. Antiviral drug Antiviral drugs are a class of medication used for treating viral infections . Most antivirals target specific viruses , while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials , a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies . Most antivirals are considered relatively harmless to

427-464: A new pandemic influenza planning tool for use by states, communities, businesses and schools, as part of a drive to provide more specific community-level prevention measures. Although designed for domestic implementation, the HHS has not ruled out sharing the index and guidelines with interested international parties. The index and guidelines were developed by applying principles of epidemiology to data from

488-593: A pandemic – and more upon how severe the epidemic actually is. The main criterion used to measure pandemic severity will be case-fatality rate (CFR), the percentage of deaths out of the total reported cases of the disease. The actual implementation of PSI alerts was expected to occur after the World Health Organization (WHO) announces phase 6 influenza transmission (human to human) in the United States. This would probably result in immediate announcement of

549-453: A researcher might target a critical enzyme synthesized by the virus, but not by the patient, that is common across strains, and see what can be done to interfere with its operation. Once targets are identified, candidate drugs can be selected, either from drugs already known to have appropriate effects or by actually designing the candidate at the molecular level with a computer-aided design program. The target proteins can be manufactured in

610-545: A treatment for hepatitis B. Antiviral resistance can be defined by a decreased susceptibility to a drug caused by changes in viral genotypes. In cases of antiviral resistance, drugs have either diminished or no effectiveness against their target virus. The issue inevitably remains a major obstacle to antiviral therapy as it has developed to almost all specific and effective antimicrobials , including antiviral agents. The Centers for Disease Control and Prevention (CDC) inclusively recommends anyone six months and older to get

671-465: A yearly vaccination to protect them from influenza A viruses (H1N1) and (H3N2) and up to two influenza B viruses (depending on the vaccination). Comprehensive protection starts by ensuring vaccinations are current and complete. However, vaccines are preventative and are not generally used once a patient has been infected with a virus. Additionally, the availability of these vaccines can be limited based on financial or locational reasons which can prevent

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732-409: Is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA. Another target is integrase , which integrate the synthesized DNA into the host cell genome. Examples of integrase inhibitors include raltegravir , elvitegravir , and dolutegravir . Once a virus genome becomes operational in a host cell, it then generates messenger RNA (mRNA) molecules that direct

793-483: Is a group of experimental antiviral drugs initially developed at the Massachusetts Institute of Technology . In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus , Amapari and Tacaribe arenavirus , Guama bunyavirus , H1N1 influenza and rhinovirus , and was additionally found effective against influenza in vivo in weanling mice. It

854-403: Is a long way away. Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern: One antiviral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a sequence of steps to do this, beginning with binding to a specific " receptor " molecule on the surface of the host cell and ending with

915-663: Is a nucleoside analogue, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analogue. An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections. One of these drugs, lamivudine , has been approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase. Another target being considered for HIV antivirals include RNase H —which

976-469: Is a set of drugs based on ribozymes , which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable them. A ribozyme antiviral to deal with hepatitis C has been suggested, and ribozyme antivirals are being developed to deal with HIV. An interesting variation of this idea

1037-419: Is currently widespread in seasonal H1N1 strains. The genetic makeup of viruses is constantly changing, which can cause a virus to become resistant to currently available treatments. Viruses can become resistant through spontaneous or intermittent mechanisms throughout the course of an antiviral treatment. Immunocompromised patients, more often than immunocompetent patients, hospitalized with pneumonia are at

1098-513: Is partly trial and error, it can be a relatively slow process until an adequate molecule is produced. A very early stage of viral infection is viral entry , when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets a specific type of lymphocyte known as "helper T cells", and identifies these target cells through T-cell surface receptors designated " CD4 " and " CCR5 ". Attempts to interfere with

1159-550: Is similar in most strains of rhinoviruses and enteroviruses , which can cause diarrhea, meningitis , conjunctivitis , and encephalitis . Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable. Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers reported in Nature Communications in 2016. Rhinoviruses are

1220-412: Is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual. One possible advantage of the therapeutic approach of blocking viral entry (as opposed to the currently dominant approach of viral enzyme inhibition) is that it may prove more difficult for the virus to develop resistance to this therapy than for

1281-406: Is the use of genetically modified cells that can produce custom-tailored ribozymes. This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by generating specialized proteins that block viral replication at various phases of the viral life cycle. Interference with post translational modifications or with targeting of viral proteins in

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1342-423: Is to identify viral proteins, or parts of proteins, that can be disabled. These "targets" should generally be as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects and toxicity. The targets should also be common across many strains of a virus, or even among different species of virus in the same family, so a single drug will have broad effectiveness. For example,

1403-453: Is to synthesize antibodies , protein molecules that can bind to a pathogen and mark it for attack by other elements of the immune system. Once researchers identify a particular target on the pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. A monoclonal drug is now being sold to help fight respiratory syncytial virus in babies, and antibodies purified from infected individuals are also used as

1464-555: Is to target the processes that synthesize virus components after a virus invades a cell. One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA , but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of reverse transcriptase (RNA to DNA) than with "normal" transcriptase (DNA to RNA). The first successful antiviral, aciclovir ,

1525-711: The United States Department of Health and Human Services (HHS) on February 1, 2007, the PSI was designed to resemble the Saffir-Simpson Hurricane Scale classification scheme. The index was replaced by the Pandemic Severity Assessment Framework in 2014, which uses quadrants based on transmissibility and clinical severity rather than a linear scale. The PSI was developed by the Centers for Disease Control and Prevention (CDC) as

1586-405: The hepatitis B and C viruses, and influenza A and B viruses. Viruses use the host's cells to replicate and this makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and antiviral drugs is due to viral variation. The emergence of antivirals is the product of

1647-448: The 1960s, mostly to deal with herpes viruses , and were found using traditional trial-and-error drug discovery methods. Researchers grew cultures of cells and infected them with the target virus. They then introduced into the cultures chemicals which they thought might inhibit viral activity and observed whether the level of virus in the cultures rose or fell. Chemicals that seemed to have an effect were selected for closer study. This

1708-583: The CDC's National Pandemic Strategy at the time of the COVID-19 pandemic . Historically, measures of influenza pandemic severity were based on the case fatality rate. However, the case fatality rate might not be an adequate measure of pandemic severity during a pandemic response because: To account for the limitations of measuring the case fatality rate alone, the PSAF rates severity of a disease outbreak on two dimensions: clinical severity of illness in infected persons; and

1769-587: The COVID-19 pandemic in the "very high severity" quadrant. This preliminary assessment ranks the COVID-19 pandemic as the most severe pandemic since the 1918 influenza pandemic. Pandemic Severity Index The pandemic severity index ( PSI ) was a proposed classification scale for reporting the severity of influenza pandemics in the United States. The PSI was accompanied by a set of guidelines intended to help communicate appropriate actions for communities to follow in potential pandemic situations. Released by

1830-422: The PSI has been "drawing generally high marks from public health officials and others, but they say the plan spells a massive workload for local planners". One MD praised that the PSI were "a big improvement over the previous guidance"; while historical influenza expert and author John M. Barry was more critical of the PSI, saying not enough emphasis was placed on basic health principles that could have an impact at

1891-495: The binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective. HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor (differing depending on

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1952-603: The binding of these antisense segments to these target sections blocks the operation of those genomes. A phosphorothioate antisense drug named fomivirsen has been introduced, used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus , and other antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is morpholino antisense. Morpholino oligos have been used to experimentally suppress many viral types: Yet another antiviral technique inspired by genomics

2013-424: The cascade, and cleave a variety of cellular proteins, thereby killing the cell. Rifampicin acts at the assembly phase. The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named zanamivir (Relenza) and oseltamivir (Tamiflu) that have been recently introduced to treat influenza prevent

2074-632: The cell is also possible. Some viruses include an enzyme known as a protease that cuts viral protein chains apart so they can be assembled into their final configuration. HIV includes a protease, and so considerable research has been performed to find " protease inhibitors " to attack HIV at that phase of its life cycle. Protease inhibitors became available in the 1990s and have proven effective, though they can have unusual side effects, for example causing fat to build up in unusual places. Improved protease inhibitors are now in development. Protease inhibitors have also been seen in nature. A protease inhibitor

2135-402: The cell type). Approaches to blocking this virus/cell fusion have shown some promise in preventing entry of the virus into a cell. At least one of these entry inhibitors—a biomimetic peptide called Enfuvirtide , or the brand name Fuzeon—has received FDA approval and has been in use for some time. Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent

2196-514: The community level, adding "I'd feel a lot more comfortable with a lot more research [supporting them]". During the initial press releases in 2007, the CDC acknowledge that the PSI and the accompanying guidelines were a work in progress and will likely undergo revision in the months following their release. In 2014, after the 2009 swine flu pandemic , the PSI was replaced by the Pandemic Severity Assessment Framework , which uses quadrants based on transmissibility and clinical severity rather than

2257-458: The course of an infection, with each replication giving another chance for mutations that encode for resistance to occur. Multiple strains of one virus can be present in the body at one time, and some of these strains may contain mutations that cause antiviral resistance. This effect, called the quasispecies model , results in immense variation in any given sample of virus, and gives the opportunity for natural selection to favor viral strains with

2318-573: The cumulative incidence of infection instead of the scaled measure of transmissibility. During its development, the PSAF was applied to past influenza pandemics and epidemics, resulting in the following assessments: A team of Brazilian researchers preliminarily assessed the severity of the COVID-19 pandemic using the PSAF in April 2020 based on Chinese data as at 11 February 2020. In their preliminary assessment, they rate COVID-19's scaled transmissibility at 5 and its scaled clinical severity at 4 to 7, placing

2379-438: The difference may be in the timing of using these measures and whether they're coordinated in an effective way for us to really gain the benefits of them. During the onset of a growing pandemic, local communities cannot rely upon widespread availability of antiviral drugs and vaccines (See Influenza research ). The goal of the index is to provide guidance as to what measures various organizations can enact that will slow down

2440-458: The effectiveness of herd immunity, making effective antivirals a necessity. The three FDA-approved neuraminidase antiviral flu drugs available in the United States, recommended by the CDC, include: oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab). Influenza antiviral resistance often results from changes occurring in neuraminidase and hemagglutinin proteins on the viral surface. Currently, neuraminidase inhibitors (NAIs) are

2501-413: The following as potential measures of clinical severity: The original developers of the PSAF provided a model for the number of hypothetical deaths in the United States 2010 population of an influenza pandemic using the PSAF. While the axes of the PSAF are scaled measures of transmissibility and clinical severity, this model uses the case-fatality ratio instead of the scaled measure of clinical severity and

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2562-577: The highest risk of developing oseltamivir resistance during treatment. Subsequent to exposure to someone else with the flu, those who received oseltamivir for "post-exposure prophylaxis" are also at higher risk of resistance. The mechanisms for antiviral resistance development depend on the type of virus in question. RNA viruses such as hepatitis C and influenza A have high error rates during genome replication because RNA polymerases lack proofreading activity. RNA viruses also have small genome sizes that are typically less than 30 kb, which allow them to sustain

2623-407: The history of the last three major flu pandemics and seasonal flu transmission, mathematical models, and input from experts and citizen focus groups. Many "tried and true" practices were combined in a more structured manner: We also realize as we look back through history is what cities did – 44 cities did, is that many of these measures ultimately every city adopted at some point or another, and

2684-406: The host, and therefore can be used to treat infections . They should be distinguished from virucides , which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees . Most of the antiviral drugs now available are designed to help deal with HIV , herpes viruses ,

2745-410: The immune system to attack a range of pathogens. One of the best-known of this class of drugs are interferons , which inhibit viral synthesis in infected cells. One form of human interferon named "interferon alpha" is well-established as part of the standard treatment for hepatitis B and C, and other interferons are also being investigated as treatments for various diseases. A more specific approach

2806-429: The lab for testing with candidate treatments by inserting the gene that synthesizes the target protein into bacteria or other kinds of cells. The cells are then cultured for mass production of the protein, which can then be exposed to various treatment candidates and evaluated with "rapid screening" technologies. Viruses consist of a genome and sometimes a few enzymes stored in a capsule made of protein (called

2867-465: The most common cause of the common cold; other viruses such as respiratory syncytial virus , parainfluenza virus and adenoviruses can cause them too. Rhinoviruses also exacerbate asthma attacks. Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree. A second approach

2928-461: The most frequently prescribed antivirals because they are effective against both influenza A and B. However, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent NAI binding. This was seen in the H257Y mutation, which was responsible for oseltamivir resistance to H1N1 strains in 2009. The inability of NA inhibitors to bind to the virus allowed this strain of virus with

2989-583: The most noticeable impact if implemented uniformly by organizations and governments across the US. While unveiling the PSI, Dr. Martin Cetron, Director for the Division of Global Migration and Quarantine at the CDC, reported that early feedback to the idea of a pandemic classification scale has been "uniformly positive". The University of Minnesota 's Center for Infectious Disease Research and Policy (CIDRAP) reports that

3050-415: The most severe "worst-case" scenario pandemics (such as the 1918 Spanish flu ). The report recommends four primary social distancing measures for slowing down a pandemic: These actions, when implemented, can have an overall effect of reducing the number of new cases of the disease; but they can carry potentially adverse consequences in terms of community and social disruption. The measures should have

3111-400: The progression of a pandemic, easing the burden of stress upon community resources while definite solutions, like drugs and vaccines, can be brought to bear on the situation. The CDC expects adoption of the PSI will allow early co-ordinated use of community mitigation measures to affect pandemic progression. The index focuses less on how likely a disease will spread worldwide – that is, become

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3172-426: The release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains. Rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. Some antivirals of this sort do not focus on a specific pathogen, instead stimulating

3233-502: The resistance mutation to spread due to natural selection. Furthermore, a study published in 2009 in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir stockpiles with additional antiviral drugs including zanamivir. This finding was based on a performance evaluation of these drugs supposing the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the oseltamivir-resistance (His274Tyr) mutation, which

3294-413: The severity. The framework gives commentary on the strengths and limitations of various measures of clinical severity and transmissibility as well as guidelines for scaling them. It also provides examples of assessing past pandemics using the framework. The original documentation for the PSAF includes the following as potential measures of transmissibility: The original documentation for the PSAF includes

3355-488: The synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factors . Several antivirals are now being designed to block attachment of transcription factors to viral DNA. Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug, based on "antisense" molecules. These are segments of DNA or RNA that are designed as complementary molecule to critical sections of viral genomes, and

3416-408: The transmissibility of the infection in the population. Each dimension can be measured using more than one measure, which are scaled to facilitate comparison. Having multiple measures for each dimension offers flexibility to choose a measure that is readily available, accurate, and representative of the impact of the pandemic. It also allows comparison across measures for a more complete understanding of

3477-413: The virus "uncoating" inside the cell and releasing its contents. Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell before they can uncoat. This stage of viral replication can be inhibited in two ways: This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies

3538-408: The virus to mutate or evolve its enzymatic protocols. Inhibitors of uncoating have also been investigated. Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating. Pleconaril works against rhinoviruses , which cause the common cold , by blocking a pocket on the surface of the virus that controls the uncoating process. This pocket

3599-486: Was a very time-consuming, hit-or-miss procedure, and in the absence of a good knowledge of how the target virus worked, it was not efficient in discovering effective antivirals which had few side effects . Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did researchers begin to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their reproductive cycle. The general idea behind modern antiviral drug design

3660-484: Was isolated from the shiitake mushroom ( Lentinus edodes ). The presence of this may explain the Shiitake mushrooms' noted antiviral activity in vitro . Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription. DRACO ( double-stranded RNA activated caspase oligomerizer )

3721-402: Was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. DRACO effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases . The procaspases transactivate via cleavage, activate additional caspases in

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