New H7N9 influenza is not good

Kawaoka gives a slide presentation to a group of media representatives touring the Influenza Research Institute (IRI) at UW–Madison in February 2017. The high-security research facility was closed down for annual decontamination, cleaning and maintenance. PHOTO: JEFF MILLER

In 2013, an influenza virus that had never before been detected began circulating among poultry in China. It caused several waves of human infection and in late 2016, the number of people to become sick from the H7N9 virus suddenly started to rise. As of late July 2017, nearly 1,600 people had tested positive for avian H7N9. Nearly 40 percent of those infected had died.

In early 2017, Yoshihiro Kawaoka, professor of pathobiological sciences at the University of Wisconsin–Madison School of Veterinary Medicine, received a sample of H7N9 virus isolated from a patient in China who had died of the flu. He and his research team subsequently began work to characterize and understand it. The first of those results are published today (Oct. 19, 2017) in Cell Host & Microbe.

For the first time, Kawaoka says, his team has identified an influenza virus strain that is both transmissible between ferrets (the best animal model proxy for human influenza infections) and lethal, both in the animal originally infected and in otherwise healthy ferrets in close contact with these infected animals.

“This is the first case of a highly pathogenic avian virus that transmits between ferrets and kills them,” Kawaoka says. “That’s not good for public health.”

Everyone in the influenza field knew it was only a matter of time before the virus became pathogenic in chickens, which is to say that it became capable of causing disease, but Kawaoka says it took several years. It was initially hard to detect because, unlike some other influenza viruses such as H5N2 — which is highly lethal in chickens and caused significant outbreaks on poultry farms across the U.S. and elsewhere in 2015 — H7N9 was not killing the chickens it infected.

Instead, it remained silent, passing unknown from chicken to chicken and, occasionally, infecting humans that came into contact with the birds.

Influenza viruses are well known for their propensity to adapt. With each new infection of a host, small changes take place within the genomes of influenza viruses. Sometimes these mutations occur in key regions and lead to significant alterations to the original virus, rendering it capable of infecting new hosts, making hosts sick, causing greater illness, and becoming resistant to the drugs typically used to treat them.

Kawaoka and his team observed this within the sample isolated from the deceased patient, who while alive had been treated with the common flu drug Tamiflu. Using a technique to read the genetic identity of the virus population that had infected the patient, Kawaoka’s team learned the virus had started to mutate: The sample contained a population of H7N9 virus that was sensitive to Tamiflu and a population that was resistant.

So the team created two viruses virtually identical to those isolated from the patient, one sensitive to Tamiflu and the other bearing the mutation that conferred resistance to the drug. Comparing this to a low-pathogenic version of the H7N9 virus that Kawaoka and others had previously studied, the research team assessed how well each virus grows in human respiratory cells, where most influenza viruses take up residence in the body. They found that each grew efficiently, though the resistant strain was less effective than the other two.

The team also found that each virus infects and causes illness, to varying degrees, in several animal models for influenza — mice, ferrets and macaques.

To test whether the virus was transmissible between mammals, the researchers set up experiments in which ferrets were housed alone in individual cages separated by a barrier that allowed respiratory droplets to pass from one cage to the next. In each pair, one ferret was deliberately infected with the virus while the other was placed into the cage healthy.

Each of the three virus types were transmitted from infected ferrets to the previously uninfected animals. Two of three ferrets infected with the nonresistant strain of H7N9 — the strain currently circulating in China — died, as did the animals to which they passed the virus.

“Without additional mutations, the virus transmitted and killed ferrets,” says Kawaoka, noting that further alterations to the virus may not be necessary to make it a potential public health threat, though human-to-human transmission has thus far remained limited.

The team also confirmed the drug-resistant H7N9 did not respond to oseltamivir, the active agent in Tamiflu. It did respond to another drug called a protease inhibitor, but Kawaoka says it is a drug currently approved only in Japan and only for use in pandemic situations.

“I don’t want to cause alarm,” Kawaoka says, but “it’s only a matter of time before the resistant virus acquires a mutation that allows it to grow well, (rendering it) more likely to be lethal at the same time it is resistant.”

However, Kawaoka and his team are currently unable to better understand what mutations may enable this transition, at least in the United States, where a moratorium on work that might cause a pathogen to take on a new function not currently known in nature has been in place for several years.

“We can’t do the experiments to find out why,” Kawaoka says. “We really need to understand why H7N9 is lethal and transmissible, and what is different in this one resistant H7N9. If we knew that, because there are multiple viruses circulating, we could narrow down efforts to those that are lethal and transmissible.”

He recently published a commentary in the Proceedings of the National Academy of Sciences, co-authored with two colleagues who are also experts in influenza, in which they explain the challenges this moratorium creates for understanding the potential of viruses like H7N9 to become pandemic.

“Results from (gain-of-function) studies would almost certainly help in understanding the pandemic potential of influenza viruses and produce public health benefits, such as the prioritization and development of pre-pandemic vaccines and antiviral drugs,” the authors write. Fundamental (gain-of-function) research on transmissibility, host-range restriction, drug resistance, immunogenicity, pathogenicity, and replicative ability would also benefit global public health.”

The H7N9 virus is likely to continue to mutate as it infects humans, resulting in adaptations that enhance the viruses’ pathogenicity or ability to pass from person to person, Kawaoka adds. In other words, nature is already performing its own gain-of-function experiments, with potentially serious consequences.

It has, however, become a bit easier recently to detect when poultry are infected with H7N9, thereby allowing people to limit their exposure. That’s because the virus has begun to kill birds in China, too. But unlike in the U.S., where farmers cull their flocks to limit the spread of infectious disease, China relies on vaccines. This worries Kawaoka, given how well the virus has been shown to grow.

For now, he says: “We should improve our surveillance.”

Learn more: H7N9 influenza is both lethal and transmissible in animal model for flu

 

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A quick-acting, long-lasting, multi-strain vaccine against pandemic influenza A that lasts for 10 years?

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A seasonal flu shot is a bit like a local weather forecast: Based on the conditions elsewhere and the direction of the prevailing wind, a meteorologist can give the public a pretty good idea of what to expect in the near future. Experts who track influenza’s intercontinental travels basically do the same thing.

“Epidemiologists monitor what strains of influenza are circulating in Southeast Asia. … they usually choose three or four of them, and they predict what the prevailing circulating strains will be,” said David Putnam, associate professor in the Nancy E. and Peter C. Meinig School of Biomedical Engineering.

“Usually they’re right, but sometimes they’re wrong,” Putnam said, “and it changes every year because proteins in the virus mutate.”

But certain proteins in the influenza virus remain constant year after year. And Putnam and Matt DeLisa, the William L. Lewis Professor of Engineering in the Robert Frederick Smith School of Chemical and Biomolecular Engineering, are taking one of those conserved proteins, Matrix-2 (M2), and packaging it in a nanoscale, controlled-release “capsule” in an attempt to create a quick-acting, long-lasting, multi-strain vaccine against pandemic influenza A.

The capsule is a bacterial outer membrane vesicle (OMV), which DeLisa and Putnam have developed collaboratively for several years. The OMV is a membrane-based nanostructure, in this case engineered from nonpathogenic E. coli, whose outer surface mimics the cell from which it originated.

Their paper, “A Single Dose and Long-Lasting Vaccine Against Pandemic Influenza Through the Controlled Release of a Heterospecies Tandem M2 Sequence Embedded Within Detoxified Bacterial Outer Membrane Vesicles,” appears in the journal Vaccine. First author is Hannah Watkins, Ph.D. ’17, now a postdoctoral researcher at the Massachusetts Institute of Technology.

The influenza A virus is a moving target. It changes year to year, and can morph into a pandemic – infectious across a large region – strain that can put the general population at risk. The Putnam-DeLisa team is leveraging the versatility of OMVs, which have shown promise against other deadly pathogens, to create a single-shot vaccine.

The M2 protein is found evolutionarily in the influenza sequence in birds, pigs and humans, so the group took two sequences from birds, one from pigs and one from humans, and assembled them into one multitarget antigen.

“So even if, say, the human strain mutates,” Putnam said, “we know where it came from and it’s going to look like the other two. We kind of covered all the bases.”

In testing, mice infected with the influenza A virus developed high antibody counts just four weeks after vaccination, compared with eight weeks from a typical multishot (prime/boost) vaccine regimen. And the protection was long-lasting: After six months, all of the test mice given the OMV vaccine survived a lethal influenza A infection.

Six months is approximately 25 percent of the typical life expectancy for a mouse, so Putnam thinks it is likely that this OMV-based vaccine would be long-lasting for humans, too.

“Even if we have to give a booster shot every 10 years, like tetanus, that’s still very good,” he said. “Theoretically it should last a long time.”

Additionally, since the vaccine cocktail is encapsulated in a bacterial vesicle, there’s no need for an adjuvant – an agent that’s added to most vaccines to boost the body’s immune response. The immune response is enhanced by the bacteria from which the OMV is derived.

“As a result, formulating and manufacturing of controlled-release OMVs should be more cost-effective,” DeLisa said.

Learn more: A new kind of influenza vaccine: One shot might do the trick

 

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A novel voltage-based biosensor for the influenza virus that is almost 100 times more sensitive than conventional tests

Fig: Human Influenza Virus Recognition by Sugar-modified Conducting Polymers

A research team at Tokyo Medical and Dental University(TMDU) builds a novel voltage-based biosensor for the influenza virus that is almost 100 times more sensitive than conventional tests, and can distinguish between human and avian strains

Researchers have developed a new, rapid biosensor for the early detection of even tiny concentrations of the human influenza A (H1N1) virus. Such early-stage diagnosis is crucial for averting a potential pandemic outbreak, as antiviral medication must be administered in a timely fashion. Conventional tests for detecting the flu virus are often slow and expensive, and can miss early viral infections. In contrast, the new biosensor measures tiny changes in voltage in an electrically conductive polymer to quickly detect virus concentrations almost 100 times smaller than the limit of currently available kits. The work was done at the Tokyo Medical and Dental University (TMDU), in a collaboration between the Institute of Biomaterials and Bioengineering and the Department of Molecular Virology.

Conductive polymers are a class of carbon-based molecules that conduct electricity, but can also be used in biological environments. They are very attractive materials for biosensor applications because researchers can easily attach biomolecules to the polymers, which allow them to bind with specific targets, such as flu viruses. In this study, poly(3,4-ethylenedioxythiophene) (PEDOT) was modified with a functional group that binds with the H1N1 human influenza virus, but not avian flu strains. “Conducting polymers have several advantages over inorganic counterparts,” explains corresponding author Yuji Miyahara. “These include the ability to conduct both electrical and ionic carriers, mechanical flexibility, low cytotoxicity, low-cost production by casting or printing, and tunable properties via chemical synthesis or doping.”

A new conducting polymer was developed for detecting specific interaction of trisaccharide with hemagglutinin in the envelope of the human influenza A virus (H1N1) by electrical manners.

To construct the biosensor, the polymer film was placed between two electrodes. When a solution containing H1N1, which carries a tiny positive charge on its exterior shell, was added, some of the viruses stuck to the polymer and increased the voltage measured by the electrodes. This electrical method allows the sensor to detect the presence of miniscule amounts of the virus. Viral loads are often measured in hemagglutination units (HAU). The new sensor can detect viral concentrations as small as 0.013 HAU. By comparison, commercially available kits that use immunochromatographic tests only work for concentrations greater than about 1.13 HAU. This represents an almost 100-fold increase in sensitivity. Study coauthor Shoji Yamaoka stressed the clinical applications of the device. “We developed a conducting polymer-based sensor that can recognize a specific virus, which makes it a good candidate for wearable monitoring and point-of-care testing.”

The article, “Specific Recognition of Human Influenza Virus with PEDOT Bearing Sialic Acid-Terminated Trisaccharides” was published in ACS Applied Materials & Interfaces at DOI: 10.1021/acsami.7b02523

Summary:

A research team at Tokyo Medical and Dental University(TMDU) built a novel biosensor for the rapid detection of human influenza A virus using a modified poly(3,4-ethylenedioxythiophene) conducting polymer. The voltage-sensing detector was almost 100 times more sensitive than conventional tests, and distinguished between human and avian flu strains. The use of this biosensor may provide point-of-care testing and help prevent the outbreak of flu pandemics.

Learn more:“A Lightning-Fast Flu Virus Detector”

 

 

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Universal flu vaccine designed by scientists

via engineering.stanford.edu

via engineering.stanford.edu

An international team of scientists have designed a new generation of universal flu vaccines to protect against future global pandemics that could kill millions.

The vaccine could give protection for up to 88% of known flu strains worldwide in a single shot, spelling the end of the winter flu season. The collaboration involving the universities of Lancaster, Aston and Complutense in Madrid have applied ground-breaking computational techniques to design the vaccine in a study published in the leading journal Bioinformatics.

The researchers have devised two universal vaccines;

  • a USA-specific vaccine with coverage of 95% of known US influenza strains
  • a universal vaccine with coverage of 88% of known flu strains globally

Dr Derek Gatherer of Lancaster University said: “Every year we have a round of flu vaccination, where we choose a recent strain of flu as the vaccine, hoping that it will protect against next year’s strains. We know this method is safe, and that it works reasonably well most of the time.

“However, sometimes it doesn’t work – as in the H3N2 vaccine failure in winter 2014-2015 – and even when it does it is immensely expensive and labour-intensive. Also, these yearly vaccines give us no protection at all against potential future pandemic flu.” Previous pandemics include the “Spanish flu” of 1918, and the two subsequent pandemics of 1957 and 1968, which led to millions of deaths.

Even today, the World Health Organisation says that annual flu epidemics are estimated to cause up to half a million deaths globally. Dr Gatherer said: “It doesn’t have to be this way. Based on our knowledge of the flu virus and the human immune system, we can use computers to design the components of a vaccine that gives much broader and longer-lasting protection.”

Dr Pedro Reche of Complutense University said: “A universal flu vaccine is potentially within reach. The components of this vaccine would be short flu virus fragments – called epitopes – that are already known to be recognized by the immune system. Our collaboration has found a way to select epitopes reaching full population coverage.

Dr Darren Flower of Aston University said: “Epitope-based vaccines aren’t new, but most reports have no experimental validation. We have turned the problem on its head and only use previously-tested epitopes. This allows us to get the best of both worlds, designing a vaccine with a very high likelihood of success.”

The team are now actively seeking partners in the pharmaceutical industry to synthesize their vaccine for a laboratory proof-of-principle test.

Learn more: Universal flu vaccine designed by scientists

 

 

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A new weapon in war against flu pandemics and pneumonia

The new antibody in a test tube

The new antibody in a test tube

Patent-pending antibody allows easier tracking of treatment effectiveness

Scientists from NTU Singapore, the world’s No. 1 young university, have developed an antibody which boosts the survival chances for patients suffering from influenza and pneumonia.

Proven effective in lab tests, the antibody is now being made suitable for use in humans. The scientists are also using the new antibody to develop a diagnostic kit which can help doctors accurately track the recovery progress of flu and pneumonia patients.

The patent-pending antibody has generated much interest globally. Two biotech multi-national corporations, Abcam based in the United Kingdom and Adipogen International based in the United States, have won the rights to license the antibody. The two multinational companies will produce the antibody for sale to global organisations doing research in vaccine and drug development.

The breakthrough finding was published in the latest issue of the prestigious international peer-reviewed journal Cell Reports.

Influenza epidemics, such as the deadly 1918 Spanish Flu which killed over 50 million people or the severe acute respiratory syndrome (SARS) outbreak in 2002, are of big concern to governments and the general populace worldwide.

The World Health Organisation estimated that influenza results in about 3 to 5 million cases of severe illness worldwide each year, with about 250,000 to 500,000 deaths annually.

Pneumonia is the leading cause of death in children worldwide accounting for 15 per cent of all deaths for children under 5 years old, and is among the top 10 leading causes of death in the United States.

This new antibody was developed by NTU Singapore’s Associate Professor Andrew Tan, who led an interdisciplinary team of scientists from Singapore.

“While it will take up to eight years to develop the antibody into a useable treatment for human patients, we are currently developing a diagnostic kit which should be commercialised in about three years,” said Assoc Prof Tan.

“The kit will help doctors diagnose the severity of pneumonia and the efficacy of the prescribed treatment. This is done by detecting the concentration of a particular protein called ANGPTL4, which is present in samples taken from patients suffering from upper respiratory tract infections.”

Read more: NTU Singapore develops new weapon in war against flu pandemics and pneumonia

 

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