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From Wired at http://www.post-gazette.com/pg/07228/809913-114.stm

 

Scientists Find Key to What Could Make Bird Flu a Human Pandemic

 

By Brandon Keim 1/6/8

 

Scientists have identified a key mechanism necessary for bird flu to morph from a rare but deadly infection into a pandemic that could kill millions of people.

MIT scientists reported in Sunday's issue of Nature Biotechnology that the shape of certain structures in the virus could be key to allowing it to easily pass from human to human. In birds, the shape of the structures match the shape of sugars in the animals' respiratory tracts, allowing the infection to easily latch onto the animals. In humans, those shapes don't match up -- but if the virus morphed so they did, it could lead to a pandemic.

"We’re like a sitting duck, waiting for an H5N1 virus that can attach to us," said Richard Cummings, an Emory University biochemist and influenza cell specialist who did not participate in the study. "This research moves us to the point where we can start anticipating what might happen."

Since its 1997 outbreak in Hong Kong, H5N1 avian influenza has spread rapidly around the world -- first in poultry, then in wild birds. It’s killed millions of fowl in 66 countries, most since 2003. But it has yet to become a common human killer. What H5N1 lacks in human infectiousness, however, it makes up for in lethality: of 348 people in 14 countries infected by H5N1 since 2003, 216 died.

The virus is constantly evolving. Each infected bird population is a giant petri dish of potential mutations. If H5N1 learns to spread among people as well as it spreads in birds, the consequences could be catastrophic. A 1918 influenza pandemic killed 50 million people, and outbreaks in 1957 and 1968 killed another three million.

With H5N1, humans have so far benefited from the differences between cells in our noses and throats and those of birds -- but that could change. With the MIT scientists' discovery, doctors can monitor H5N1 strains for early evidence of human virulence. They may also make precisely targeted vaccines and drugs in advance of outbreaks.

Massachusetts Institute of Technology cell biologist and study co-author Ram Sasisekharan and his colleagues studied two strains of avian influenza, H3N2 and H1N1 -- the latter closely related to the killer 1918 virus -- that spread from birds to people. They found that the viruses connected to particular types of sugar found on the surface of upper respiratory tract cells.

These sugars act like doorknobs. When a single viral particle meets a cell, it grapples with the sugar molecule, using it as entry point for invasion. Once inside the cell, the virus produces copies of itself that soon explode outwards, infecting new cells and becoming airborne with each breath.

Both H3N2 and H1N1 latched onto sugar configurations known as a2-6 sialylated glycans, found exclusively in our upper respiratory tracts. Birds possess slightly different sugars, known as a2-3 sialylated glycans, to which H5N1 connects easily. In order to spread efficiently between people, said Sasisekharan, H5N1 would have to configure itself to our own sugars.

Sasisekharan’s team then identified the unique shapes taken by our a2-6 sialylated glycans, which vary between regions of the respiratory tract. They identified two shapes, roughly resembling an umbrella and a cone, that would be the likely connecting points for a pandemic H5N1 strain.

"People hadn't really thought about the shape of the structures as being so relevant in this regard," Cummings said.

Scientists can now search for evidence of necessary configurations in new strains of H5N1, perhaps stifling them before the transformation is complete. They can also predict the genetic mutations necessary for H5N1 to bind to our sugars, and use the knowledge to develop specifically targeted vaccines and drugs.

"Rather than looking for a needle in a haystack, this lets us focus," Sasisekharan said.

 

 

 

Vaccine will take 3-5 years to complete safety testing

 

 

January 16, 2008. Times Online

Call for more bird flu vaccine as fourth swan dies at Abbotsbury reserve

A fourth swan from the Abbotsbury swannery in Dorset is believed to have been infected with the deadly H5N1 avian flu virus. The result is to be confirmed today by the Department for Environment, Food and Rural Affairs (Defra).

The mute swan was found dead on Friday and sent for testing to the Veterinary Laboratories Agency in Weybridge.

Government vets are not surprised by the further case and believe it is likely that other swans at the important reserve near Chesil Beach may be infected.

It is not known precisely how the virus arrived in the area, though the most plausible explanation is that a duck or similar species arrived from across the Channel during the cold snap before Christmas. The birds at the swannery are fairly static and do not migrate.

Among the brids that migrate to the UK when there are cold spells on the Continent are mallard, teal, widgeon and pochard as well as gulls.

John Houston, general manager at Abbotsbury Tourism, said that the latest case delayed a return to normal business. “It puts us back to square one in terms of waiting for a 21-day clearance before we are out of the woods,” he said.

“It's disappointing but not totally unexpected this early in the outbreak. It would be wonderful if it disappeared immediately but that's unrealistic. It's going to take a while for it to be contained and weeded out.”

The all-clear will be given only after 21 days have passed without any new bird infected with the virus at the swannery.

Abbotsbury is one of the most popular tourist attractions on the south coast and is due to reopen to the public on March 15 after the winter.

It has been owned by the Ilchester Estate since the 1540s though the swannery was established by Benedictine monks who built a monastery at the site in the 1040s.

There is some relief that there is no evidence of the virus being endemic in wild birds in the area. Similarly, the virus has not been found in any chick on a commerical poultry farm or backyard flock in the area.

The existing control and monitoring zones are to remain in place. There are some 32 premises within the zone, of which 19 are free-range operations, involving a total of 24,588 birds.

In the wider monitoring area there are 34 farms, of which 17 are free-range, with a total of 111,488 chickens.

Fred Landeg, the acting Chief Veterinary Officer, is appealing to anyone in the area who might own a small number of chickens to come forward so that their birds and premises can be checked.

All birds inside the control zone - which extends 15 miles southeast of Abbotsbury and includes Weymouth, Chesil Beach and Portland Bill - must be kept indoors. Owners are also advised to keep poultry away from wild birds in the larger monitoring area, which extends to some 20 miles and includes the town of Dorchester.

Under current government regulations only owners with more than 50 birds must enlist to the official poultry register, but others are encouraged to do so voluntarily.

France has raised the level of alert for a lethal avian flu outbreak as a result of the British outbreak and ordered all birds to be locked indoors in areas near lakes, ponds and the coast. Defra said there were no such plans in Britain.

The new outbreak has renewed calls for the routine vaccination of all free-range, organic and hobby birds against the deadly flu virus.

The Elm Farm Organic Research Centre has been campaigning for such a preventive strategy for more than two years. Defra has a stock of 10 million does of vaccine but so far they have been offered only for use to save rare birds and collections in zoos.

Richard Sanders, senior policy researcher at the centre, said the latest outbreak at Abbotsbury was now “a trigger point” and gave a definite indication the virus was circulating in wild birds.

He urged Defra to release its stocks of H5N1 vaccine to start an orderly programme of preventive treatment.The alternative to vaccination was to lock up all birds a move that was “unacceptable, impractical and with some species such as geese, impossible”, he said.

“When the national mood, as voiced so loudly by Jamie Oliver and Hugh Fearnley-Whittingstall, is for quality, high-welfare poultry production, then we must do everything in our power to protect and grow the sector.”

 

 

TIMESW ONLINE, JAN 4, 08, Nigel Hawkes, Health Editor

 

New vaccinations give scientists hope of conquering flu pandemic

vaccine that could help to control a flu pandemic has shown encouraging results in its first human trials.

The vaccine, made by Acambis, based in Cambridge, should protect against all strains of influenza A, the type responsible for pandemics. Unlike existing vaccines it does not have to be reformulated each year to match the prevalent strains of flu, so it could be stockpiled and used as soon as a pandemic strain emerges. Nor does it need to be grown on fertilised chicken eggs, as the existing vaccines do, but can be produced by cell culture.

The results, announced yesterday by Acambis, show that in human volunteers the Acam-Flu-A vaccine was safe and produced an immune response against its target, a small protein (peptide) called M2e that is found on the surface of all A-strains of the flu virus. The vaccine was also tested on ferrets, which are commonly used in flu research because they are susceptible to human and bird flu.

The ferrets were divided into two groups and either vaccinated with the new vaccine or left unvaccinated. They were then exposed to a large dose of the H5N1 bird flu that has killed millions of chickens and more than 200 people across Asia since 2003. All the unvaccinated ferrets died, but 70 per cent of the vaccinated ones survived.

A significant problem with conventional vaccines is that they attack parts of the flu virus that can change rapidly. Each season the World Health Organisation identifies the three strains that are circulating, normally two A-strains and one B, and the vaccine is made to order to provide protection against them. It is always a race against time, because millions of eggs have to be produced to grow the vaccine and if it is not used it is out of date by the following season.

Acambis’s approach was to identify some aspect of the virus that is unchanging. Pandemics are invariably caused by A-strains of flu; B-strains, which are found only in humans, may cause epidemics but have never caused pandemics.

The company identified a peptide, M2e, on the surface of all A-strains and developed a vaccine that targeted it. When an individual is vaccinated the vaccine teaches the immune system to recognise and be alert to the peptide so that as soon as flu arrives the body’s protective systems swing into action against it. To improve the vaccine’s effectiveness, it was combined in the trial with adjuvants, chemicals that ginger up the immune system and improve its ability to learn. The adjuvant called QS-21, made by Antigenics, proved to be the best. When this was added, 90 per cent of those vaccinated had antibodies against the M2e peptide.

Michael Watson, the executive vice-president for research and development at Acambis, said: “If there was an immediate threat of pandemic flu, it would be possible to complete the trials and market the vaccine within three years. Without such a threat, it will likely take longer, perhaps five years.

“The beauty of the vaccine is its simplicity. It could be used in several different ways. First, we could produce a pre-pandemic vaccine that we know would be effective against A-strains. If a bird flu strain such as H5N1 turned into a pandemic strain we could get the vaccine out of storage and use it. Alternatively we could use it as soon as we got the slightest inkling of a pandemic strain emerging. Or it could be used instead of the normal vaccine for protecting against seasonal flu, with a vaccine against B-strains added. That would depend on how effective it was, which we will only know after further trials.”

The fate of millions

— Flu viruses can drift and shift. Drift refers to the continual small changes that dictate the annual reformulation of the flu vaccine to ensure that it works. Shift happens rarely and unpredictably, and produces pandemics

— There were three shifts in the 20th century, causing pandemics in 1918, 1957 and 1968. Some virologists fear that another is overdue

— Pandemic strains strike human beings unprepared, and spread fast. The 1918 pandemic killed 20 million, some say 40 million

— Shifts occur when avian strains infect human beings, or avian and human strains share genes, as may be happening in Asia

— Since the H5N1 avian strain first appeared in 2003, a few hundred cases have been transmitted to humans. About half of those have died, but this is not yet a pandemic strain, and may never become one

 

 

 

 

 

India, Bangladesh Try to Halt Bird Flu

CALCUTTA, India (AP) — India and Bangladesh searched for new cases of bird flu Thursday as authorities pressed ahead with plans to slaughter hundreds of thousands of birds in a bid to keep the outbreak from spreading, officials said.

No human cases have been reported since the latest outbreak of bird flu was first discovered earlier this week. But nearly 56,000 birds have died from the disease in eastern India, where authorities have begun slaughtering another 400,000 animals, most of them chickens. In Bangladesh, officials say about 20 birds have died and another 1,700 have been slaughtered.

Bangladeshi authorities say the outbreak in that country, which has so far been limited to a single poultry farm, is the H5N1 strain of the disease. In India, where the outbreak is more widespread, authorities say they are still conducting tests to determine what strain of bird flu killed the animals.

The outbreaks are in adjacent areas of the neighboring countries.

There was also uncertainty in India on Thursday about an undetermined number of new bird deaths in areas near the center of the outbreak in a rural region in the southwestern part of India's West Bengal state. Bangladeshi authorities were also searching for other cases of bird deaths.

While bird flu seemed to be the obvious culprit in the new deaths in West Bengal, the state's animal husbandry minister, Anisur Rahman, cautioned the symptoms indicated Newcastle disease, known locally as Ranikhet, a fatal respiratory virus that is not known to attack humans.

"But we are not taking chances and have sent samples to laboratories for testing for bird flu," he told The Associated Press.

Apart from slaughtering birds in areas where bird flu has been confirmed, health workers were also going door-to-door, looking for people with high fevers or breathing trouble, he said.

An outbreak of the H5N1 virus hit western India in 2006, but India declared the country bird flu-free after slaughtering hundreds of thousands of chickens. No human cases were reported. A smaller outbreak in northeastern India was contained last year.

Bird flu was first detected in Bangladesh in February 2007 at a poultry farm near the capital. Since then, authorities have slaughtered more than 300,000 chickens — including 19,000 killed during another outbreak earlier this month — at about 90 farms across the country. Nearly 360,000 eggs have been destroyed.

Bird flu has killed at least 217 people worldwide since it began ravaging Asian poultry stocks in late 2003. It remains hard for people to catch, but experts fear it will mutate into a form that spreads easily among humans, potentially sparking a pandemic. So far, most human cases have been linked to contact with infected birds.

What keeps us safe for now (unlike the birds) is that a strain of the H5N1 virus does not have the ability to spread from person to person.

 

Bird Flu Passed From Son to Father, W.H.O. Says

New York Times, June 23, 06 by Elisabeth Rosenfthal

 

An Indonesian man who died of H5N1 bird flu caught it from his 10-year-old son, the first laboratory-confirmed case of human-to-human transmission of the disease, according to a World Health Organization investigation of an unusual family cluster of bird-flu cases.

The investigators also found that the virus mutated slightly when the son had the disease, although not in any way that would allow it to pass more readily among people. Flu viruses like H5N1 mutate constantly, although most of the mutations are insignificant biologically; that appears to be have been the case in the Indonesian cluster.

"Yes, it is slightly altered, but in a way that viruses commonly mutate," said Dick Thompson, a spokesman for the World Health Organization n Geneva, describing the findings, which were not publicly released. "But that didn't make it more transmissible, or cause more severe disease."

The greater importance of the slightly modified virus is that it allowed researchers from the organization and the United States Centers for Disease Control to document for the first time that the virus almost certainly passed from the son directly to his father.

In previous cases where human-to-human transmission was suspected, scientists were not able to say for sure, either because test samples from the patients were not available or because the virus in the patients was the same as that found in poultry in the area.

Scientists say the H5N1 virus, which has killed hundreds of millions of birds worldwide, does not spread easily to humans or among them. But they have worried that it might, through normal biological processes, acquire the ability to do so, potentially setting off a devastating human pandemic.

More than 200 people have contracted bird flu around the world, almost all of them after very close contact with infected birds.

International health officials have been in Indonesia for much of the past month, investigating a family outbreak that affected seven relatives in a remote region of Sumatra. Six of the seven died.

Although Indonesia has been struggling all year to control a series of bird flu outbreaks in poultry, the family on Sumatra had no known direct contact with sick birds, although the first death in the family was a woman who sold vegetables in a market that also sold birds.

Scientists have suspected that H5N1, though an avian virus, could also spread from person to person in rare cases if there were prolonged close contact.

The family members in the cluster had a banquet in late April, when the vegetable merchant was already ill and coughing heavily. Some spent the night in the same small room with her. Some members also cared for their relatives when they were sick.

In hospitals, doctors and nurses generally wear masks when treating people who may have bird flu.

The first five family members to fall ill had identical strains of H5N1, one that is common in animals in Indonesia. But the virus mutated slightly in the sixth victim, the 10-year-old boy, and he apparently passed the mutated virus to his father. The presence of that mutation allowed the lab to confirm the route of transmission.

Still, Mr. Thompson said there was no evidence that the mutated virus is any better adapted to human infection than before. In fact, the World Health Organization has been following 54 neighbors and family members who lived near the family for a month, and none has contracted the virus.

 

 

 

May 27, 2008

Scientists identify second H7 strain of bird flu that could cause pandemic

 

The H5N1 strain of bird flu that has killed 241 people is not the only one that could trigger a pandemic, according to research in America. A few H7 strains of the flu virus have started to evolve some of the traits they would need to infect people easily, scientists have discovered.

The findings, from a team led by Terrence Tumpey, of the US Centres for Disease Control and Prevention (CDC) in Atlanta, show that while there is no immediate indication that H7 flu is about to acquire potentially damaging mutations, it is critical that global surveillance and research covers this virus class as well as the more obvious H5N1, scientists said.

The H5N1 strain has been regarded as the most deadly strain since it appeared in Asia in 2003. Although it has a death rate of more than 60 per cent, it has not yet acquired the ability to move from person to person, which would be a prerequisite for a pandemic.

There has been only one case in which it is considered probable that the virus was transmitted from person to person, and analysis of the virus’s genetic structure has not yet revealed mutations that would allow it to infect people more easily. It is generally caught from close contact with infected birds, in which it is endemic in some parts of the world, particularly in Asia.

The H7 family of flu viruses also primarily affects birds. A deadly version of the H7N7 strain hit poultry in the Netherlands in 2003, and a less severe form, H7N2, broke out in the UK last year. Between 2002 and 2004 several outbreaks of H7N3 and H7N2 have been reported.

In each of these incidents a few human cases of infection have been reported. One vet died during the Dutch outbreak and about 80 people suffered conjunctivitis, an eye infection that is not life-threatening.

The UK outbreak also led to cases of conjunctivitis and a few mild respiratory infections.

Dr Tumpey’s analysis of a 2003 case in New York has shown, however, that the H7N2 virus responsible is capable of replicating in the respiratory tract of mammals. This quality is unusual among avian viruses, and indicates that it could possibly be transmissible from person to person.

A study with ferrets - a standard animal model of flu in humans - also revealed that this H7N2 strain could be passed from animal to animal.

This suggests that the virus could be acquiring an ability to bind to sugars found on the cells of the human windpipe. This happened during all three of the 20th-century flu pandemics, which occurred in 1918, 1957 and 1968. “These findings suggest that the H7 class of viruses are partially adapted to recognise the receptors that are preferred by the human influenza virus,” Dr Tumpey said.

“The finding … underscores the necessity for continued surveillance and study of these viruses as they continue to resemble viruses with pandemic potential.”

Each of the three flu pandemics of the last century was caused by a humanised strain of flu. The Spanish Flu of 1918-19, which killed up to 40 million people, was caused by an H1N1 virus. The 1957-58 Asian Flu was caused by an H2N2 strain, and the 1968-69 Hong Kong Flu by an H3N2 strain.

Both strains can jump from birds to humans but only the H7 virus has been shown to spread from person to person, raising concern that it could unite with the deadlier H5N1 strain and cause a global pandemic.

"The fact that two viruses - one with a proven track record of transmitting easily into people and another with a mortality rate of between 50 and 80 percent - are circulating in Asia at the same time is something to keep a very close eye on," William L. Aldis, the World Health Organization representative in Thailand, told The Associated Press.

If H7 and H5N1 came into contact and exchanged genetic material, it could create an "organism with H5 lethality and H7 transmissibility," said Aldis.

H7 caused eye inflammation and flu-like symptoms in dozens of people in the Netherlands, but there have been no reports of human infections of any strain of bird flu in secretive North Korea. Health workers have killed some 219,000 birds on three farms near the capital, Pyongyang.

 

Summary information follows about these three prominent subtypes of avian influenza A viruses:

Influenza A H5

  • Potentially nine different subtypes
  • Can be highly pathogenic or low pathogenic
  • H5 infections have been documented among humans, sometimes causing severe illness and death

Influenza A H7

  • Potentially nine different subtypes
  • Can be highly pathogenic or low pathogenic
  • H7 infection in humans is rare, but can occur among persons who have direct contact with infected birds; symptoms may include conjunctivitis and/or upper respiratory symptoms

Influenza A H9

  • Potentially nine different subtypes
  • Documented only in low pathogenic form
  • At least three H9 infections in humans have been confirmed

 

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Page last modified October 14, 2005

 

 

Key Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus

Human infection with avian influenza viruses

There are many different subtypes of type A influenza viruses. These subtypes differ because of changes in certain proteins on the surface of the influenza A virus (hemagglutinin [HA] and neuraminidase [NA] proteins). There are 16 known HA subtypes and 9 known NA subtypes of influenza A viruses. Many different combinations of HA and NA proteins are possible. Each combination represents a different subtype. All known subtypes of influenza A viruses can be found in birds.

Usually, “avian influenza virus” refers to influenza A viruses found chiefly in birds, but infections with these viruses can occur in humans. The risk from avian influenza is generally low to most people, because the viruses do not usually infect humans. However, confirmed cases of human infection from several subtypes of avian influenza infection have been reported since 1997. Most cases of avian influenza infection in humans have resulted from contact with infected poultry (e.g., domesticated chicken, ducks, and turkeys) or surfaces contaminated with secretion/excretions from infected birds. The spread of avian influenza viruses from one ill person to another has been reported very rarely, and has been limited, inefficient and unsustained.

“Human influenza virus” usually refers to those subtypes that spread widely among humans. There are only three known A subtypes of influenza viruses (H1N1, H1N2, and H3N2) currently circulating among humans. It is likely that some genetic parts of current human influenza A viruses came from birds originally. Influenza A viruses are constantly changing, and they might adapt over time to infect and spread among humans.

During an outbreak of avian influenza among poultry, there is a possible risk to people who have contact with infected birds or surfaces that have been contaminated with secretions or excretions from infected birds.

Symptoms of avian influenza in humans have ranged from typical human influenza-like symptoms (e.g., fever, cough, sore throat, and muscle aches) to eye infections, pneumonia, severe respiratory diseases (such as acute respiratory distress), and other severe and life-threatening complications. The symptoms of avian influenza may depend on which virus caused the infection.

Studies done in laboratories suggest that some of the prescription medicines approved in the United States for human influenza viruses should work in treating avian influenza infection in humans. However, influenza viruses can become resistant to these drugs, so these medications may not always work. Additional studies are needed to demonstrate the effectiveness of these medicines.

Avian Influenza A (H5N1)

Influenza A (H5N1) virus – also called “H5N1 virus” – is an influenza A virus subtype that occurs mainly in birds, is highly contagious among birds, and can be deadly to them. H5N1 virus does not usually infect people, but infections with these viruses have occurred in humans. Most of these cases have resulted from people having direct or close contact with H5N1-infected poultry or H5N1-contaminated surfaces.

Avian influenza A (H5N1) outbreaks

For current information about avian influenza A (H5N1) outbreaks, see our Outbreaks page.

Human health risks during the H5N1 outbreak

Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of detected cases of severe disease and death in humans. However, it is possible that those cases in the most severely ill people are more likely to be diagnosed and reported, while milder cases go unreported. For the most current information about avian influenza and cumulative case numbers, see the World Health Organization (WHO) avian influenza website.

Of the human cases associated with the ongoing H5N1 outbreaks in poultry and wild birds in Asia and parts of Europe, the Near East and Africa, more than half of those people reported infected with the virus have died. Most cases have occurred in previously healthy children and young adults and have resulted from direct or close contact with H5N1-infected poultry or H5N1-contaminated surfaces. In general, H5N1 remains a very rare disease in people. The H5N1 virus does not infect humans easily, and if a person is infected, it is very difficult for the virus to spread to another person.

While there has been some human-to-human spread of H5N1, it has been limited, inefficient and unsustained. For example, in 2004 in Thailand, probable human-to-human spread in a family resulting from prolonged and very close contact between an ill child and her mother was reported. In June 2006, WHO reported evidence of human-to-human spread in Indonesia. In this situation, 8 people in one family were infected. The first family member is thought to have become ill through contact with infected poultry. This person then infected six family members. One of those six people (a child) then infected another family member (his father). No further spread outside of the exposed family was documented or suspected.

Nonetheless, because all influenza viruses have the ability to change, scientists are concerned that H5N1 virus one day could be able to infect humans and spread easily from one person to another. Because these viruses do not commonly infect humans, there is little or no immune protection against them in the human population. If H5N1 virus were to gain the capacity to spread easily from person to person, an influenza pandemic (worldwide outbreak of disease) could begin. For more information about influenza pandemics, see PandemicFlu.gov.

No one can predict when a pandemic might occur. However, experts from around the world are watching the H5N1 situation in Asia and Europe very closely and are preparing for the possibility that the virus may begin to spread more easily and widely from person to person.

 

 

There are 4 principle anti-influenza drugs, Amantadine, Rimantadine, Zanamivir, and Oseltamivir.  The first two effect the replication of influenza A, and the latter two effect both A and B. Resistance occurs in some avian and swine influenza viruses including H5N1.  Rimantadine has significantly less side effects than Amantadine (which run as has as 33%).  High plasma levels of Amantadine are associated with serious neurotoxic reactions.  These drugs when given early reduce the course of influenza by about 1 day.  They also are 70-90% effective at inhibiting the disease in those who have been exposes (such as by a family member) and have not been vaccinated.  Resisant variants of the virus have been recovered in 30% of those treated by the 5th day.              

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