PNAS: Virulence & Transmissibility Of H1N2 Influenza Virus In Ferrets

 

 

 

# 6547

 

Timing is, as they say, everything.

 

And coming on the heels the announcement 10 days ago of three human infections with a swine-origin H1N2 influenza (see Minnesota Reports Swine H1N2v Flu), a study that appears today in PNAS is certainly well timed.

 

The study, conducted at Chungbuk National University South Korea examined viruses circulating in Korean swine (H1N2 & H3N2), and found - for the most part - they were not particularly pathogenic in ferrets.

 

The exception was a triple reassortant H1N2 virus dubbed Sw/1204, that had picked up two notable mutations, and it not only transmitted efficiently, it also caused severe (even fatal) disease in the test animals.

 

The study, is called:

 

Virulence and transmissibility of H1N2 influenza virus in ferrets imply the continuing threat of triple-reassortant swine viruses

Philippe Noriel Q. Pascua, Min-Suk Song, Jun Han Lee, Yun Hee Baek, Hyeok-il Kwon, Su-Jin Park, Eun Hye Choi, Gyo-Jin Lim, Ok-Jun Lee, Si-Wook Kim, Chul-Joong Kim, Moon Hee Sung, Myung Hee Kim, Sun-Woo Yoon, Elena A. Govorkova, Richard J. Webby, Robert G. Webster, and Young-Ki Choi

 

Ed Yong, writing for Nature has the details  on this paper:

 

Need for flu surveillance reiterated

Study of Korean pigs finds virus with pandemic potential.

Ed Yong 10 September 2012

 

 

One to the two mutations discussed in this paper is hemagglutinin (HA) (Asp-225-Gly) – also known as D225G – which is something we’ve looked at a number of times in the past.

 

This mutation involves a single amino acid change in the HA gene at position 225 (H3 numbering) from aspartic acid (D) or Asp to glycine (G), and was first linked to more severe pandemic flu by Norwegian Scientists in 2009.

 

The evidence for the D222G/N  amino acid substitution driving increased virulence, and deep lung infection, has been mixed, however. A few earlier blogs include:

 

Eurosurveillance: Debating The D222G/N Mutation In H1N1

Study: Receptor Binding Changes With H1N1 D222G Mutation

WER Review: D222G Mutation In H1N1

 

The second mutation, called NA-315 (serine to asparagine the in neuraminidase) isn’t as well studied, but is believed to assist the virus in breaking out of infected cells after replicating.

 

As Ed Yong mentions in his article - viruses often have multiple amino acid changes – and we are really just beginning to understand the ramifications of these different genetic combinations. 

 

Whether this particular virus ever ends up posing a public health threat is impossible to say, but it does illustrate these swine reassortant viruses aren’t always mild in mammals.

 

New strains of influenza come about from reassortment; the swapping of genetic material between two different flu strains in a common host. We tend to focus on swine, simply because they are highly susceptible to a variety of influenza viruses, and have a history of producing reassorted viruses.  

 

 

The pandemic virus that emerged in the spring of 2009 was the end product of several influenza strains that had kicked around the world’s swine population for many years, trading bits of genetic material back and forth, until they produced a version capable of jumping to humans.

 

But any host (human, swine, avian, or other mammal) could produce a reassorted virus.

 

For more on the flu risks from swine reassortments, I continue to heartily recommend Helen Branswell’s terrific piece in SciAm  from late 2010 called Flu Factories.

Flu Factories

The next pandemic virus may be circulating on U.S. pig farms, but health officials are struggling to see past the front gate

By Helen Branswell  | December 27, 2010 |

 

And for some of my earlier looks at swine influenza, you may wish to revisit:

 

H3N2v: When Pigs Flu

You Say You Want An Evolution?

The (Swine) Influenza Reassortment Puzzle

»» Read More

PNAS: A Hypothesis On The Effects Of La Niña On Influenza Reassortment

 

 

# 6078

 

 

 

We have an interesting hypothesis being offered today by a pair of well-respected researchers (Jeffrey Shaman of Columbia University's Mailman School of Public Health and Marc Lipsitch of the Harvard School of Public Health), who note that the weather patterns prior to the pandemics of 1918, 1957, 1968 and 2009 all showed the Pacific ocean to be in a La Niña cycle.

 

We know, of course, that correlation doesn’t necessarily imply causation, but an apparent association between two events can often provide a useful starting point for further scientific investigation.

 

And that’s what these researchers are calling for.

 

Whether this correlation is casual, or is simply coincidental, is for now unknown.  

 

For those unfamiliar with the basics of El Niño and La Niña, a very brief overview:

 

The Pacific Ocean cycles between an El Niño pattern (warmer) and a La Niña (colder) than normal water temperatures in the Equatorial Pacific Ocean.

 

These water temperature cycles can have major effects on climate and weather far removed from the Pacific. During La Niña years, for example, the Atlantic Hurricane season is usually more active.

 

 

La Niña (December 2000)

El Niño (December 1997)

Sea surface temperature anomalies (°C)

Photo Credit- NOAA 

 

La Niña's occur every 2 to 7 years, and over the past 62 years 14 have been observed. During that time, we saw 3 pandemics (1957, 1968, 2009).

 

Graph Credit- Wikipedia

 

 

We’ve  the Press Release from Columbia University's Mailman School of Public Health, but after a quick visit to the PNAS journal website I wasn’t able to locate the article online. I imagine it will be online shortly.

 

Does the La Niña weather pattern lead to flu pandemics?

 

Public release date: 16-Jan-2012

 

Worldwide pandemics of influenza caused widespread death and illness in 1918, 1957, 1968 and 2009. A new study examining weather patterns around the time of these pandemics finds that each of them was preceded by La Niña conditions in the equatorial Pacific. The study's authors--Jeffrey Shaman of Columbia University's Mailman School of Public Health and Marc Lipsitch of the Harvard School of Public Health—note that the La Niña pattern is known to alter the migratory patterns of birds, which are thought to be a primary reservoir of human influenza. The scientists theorize that altered migration patterns promote the development of dangerous new strains of influenza.

 

The study findings are currently published online in PNAS.

 

To examine the relationship between weather patterns and influenza pandemics, the researchers studied records of ocean temperatures in the equatorial Pacific in the fall and winter before the four most recent flu pandemics emerged. They found that all four pandemics were preceded by below-normal sea surface temperatures—consistent with the La Niña phase of the El Niño-Southern Oscillation. This La Niña pattern develops in the tropical Pacific Ocean every two and seven years approximately.

 

The authors cite other research showing that the La Niña pattern alters the migration, stopover time, fitness and interspecies mixing of migratory birds. These conditions could favor the kind of gene swapping—or genetic reassortment—that creates novel and therefore potentially more variations of the influenza virus.

 

"We know that pandemics arise from dramatic changes in the influenza genome. Our hypothesis is that La Niña sets the stage for these changes by reshuffling the mixing patterns of migratory birds, which are a major reservoir for influenza," says Jeffrey Shaman, PhD, Mailman School assistant professor of Environmental Health Sciences and co-author of the study.

 

Changes in migration not only alter the pattern of contact among bird species, they could also change the ways that birds come into contact with domestic animals like pigs. Gene-swapping between avian and pig influenza viruses was a factor in the 2009 swine flu pandemic.

 

 

For the record, the Pacific is currently in a La Niña cycle, and the forecast is for it to remain so well into the Northern Hemisphere spring of 2012.

 

 

This is an interesting hypothesis, and should promote some fascinating avenues of investigation.

»» Read More

The Birth Of The Flus

 

 

# 5963

 

 

Southeast Asia has long been considered `the cradle of influenza’, an area of the world where influenza viruses circulate year round, more than a billion people live in close proximity, and where humans and farm animals often come into close contact with one another.

 

An ideal breeding ground, and launching pad, for flu pandemics. 

 

During the 20th century, 2 of the 3 influenza pandemics (1957 Asian Flu, 1968 Hong Kong Flu) originated from this region.

 

But new research on the the spread of influenza A, published yesterday in PNAS, indicates that Southeast Asia isn’t the only birthplace of the flu.

 

The dauntingly titled open access study can be found at:

 

 

Temporally structured metapopulation dynamics and persistence of influenza A H3N2 virus in humans

Published online before print November 14, 2011, doi: 10.1073/pnas.1109314108 PNAS November 14, 2011

Justin Bahl, Martha I. Nelson, Kwok H. Chan, Rubing Chen, Dhanasekaran Vijaykrishna, Rebecca A. Halpin, Timothy B. Stockwell, Xudong Lin, David E. Wentworth, Elodie Ghedin, Yi Guan, J. S. Malik Peiris, Steven Riley, Andrew Rambaut, Edward C. Holmes, and Gavin J. D. Smith

 

(EXCERPT)

Although the virus population that migrated between Southeast Asia and Hong Kong persisted through time, this was dependent on virus input from temperate regions and these tropical regions did not maintain a source for annual H3N2 influenza epidemics.

 

We further show that multiple lineages may seed annual influenza epidemics, and that each region may function as a potential source population. We therefore propose that the global persistence of H3N2 influenza A virus is the result of a migrating metapopulation in which multiple different localities may seed seasonal epidemics in temperate regions in a given year.

 

Such complex global migration dynamics may confound control efforts and contribute to the emergence and spread of antigenic variants and drug-resistant viruses.

 

 

The entire study is available online, but for those of us who find the finer details of Bayesian phylogeographic analysis of viral migration above our pay grade, we’ve a press release from Duke University Medical Center that helps summarize this paper.

 

Study finds tropical areas aren't the only source of seasonal flu

DURHAM, N.C. and SINGAPORE – A commonly held theory says that flu virus originates every year in Southeast and Eastern Asia, making this region the source of seasonal flu epidemics in other parts of the world.

 

However, researchers at Duke-NUS Graduate Medical School in Singapore have found that influenza virus in tropical areas isn't the only global source of flu epidemics. The international team of scientists involved in the work found that any one of the urban centers they studied could act as a source for a flu epidemic in any other locality.

 

"We found that these regions are just one node in a network of urban centers connected by air travel, through which flu virus circulates and causes a series of local epidemics that overlap in time," said Gavin Smith, PhD, senior author and Associate Professor in the Program in Emerging Infectious Diseases at Duke-NUS.

 

The study was published the week of Nov. 14 in the online Early Edition of the Proceedings of the National Academy of Sciences.

 

The research team chose to study influenza A because it is much more prevalent than both influenza B and C. Influenza is a significant cause of human illness and death worldwide – the World Health Organization estimates that 250,000 to 500,000 influenza A related deaths occur per year worldwide, and about 49,000 deaths occur in the United States.

 

The team obtained RNA sequences of virus samples from 2003 to 2006 in Australia, Europe, Japan, New York, New Zealand and Southeast Asia, as well as some more recently sequenced viruses from Hong Kong. The virus populations from tropical Southeast Asia and Hong Kong showed relatively low levels of genetic diversity and no seasonal fluctuations in comparison with annual temperate-area epidemics.

 

The analysis used time and space parameters to reveal high rates of viral migration among the urban centers tested. Although the virus population that migrated between Southeast Asia and Hong Kong persisted through time, the pattern of infections also depended on virus input from temperate regions that have distinct seasons. None of the temperate and tropical regions they examined was the source of all of the new flu strains in a given year.

 

The scientists showed that multiple lineages of a virus could seed annual flu epidemics, and that each region could function as a potential source population.

(Continue . . . )

 

 

Six weeks before the 2009 H1N1 pandemic virus emerged in Mexico, I wrote  blog called:

 

Sunday, March 08, 2009

How The Next Pandemic Will Arrive

# 2876

There is a lot we don't currently know about the next pandemic.  We don't know when it will arrive.  We don't know what virus will cause it.  And we don't know how bad it will be.

 

But there is one thing almost certain.

 

It will arrive in most countries by airplane.

The video above, which as been making the rounds for several months, was made by ZHAW (Zürcher Hochschule für Angewandte Wissenschaften) or The Zurich University of Applied Sciences.

(Continue . . .)

 

 

Before the advent and explosion in international air travel, the tropical regions of Southeast Asia probably played a much bigger role in the the creation, incubation, and spread of influenza viruses. 

 

With man’s help, influenza today has become an accomplished world traveler. No longer are we protected by vast oceans and long transit times.

 

New strains and viral reassortments that a few decades ago might have sputtered and died out unnoticed in some remote region of the world, or have been detected and quarantined aboard slow moving ships, can now hop a plane and find new hosts in a matter of hours.

 

Something we saw as recently as the 2009 H1N1 pandemic, which began not in Asia, but in the Americas.

 

Further proof that as the world evolves and become more complex, so does the threat from emerging infectious diseases.

»» Read More

PNAS: Reassortment Potential Of Avian H9N2

 

 

 

# 5675

 

All that is required to spark a pandemic is for a novel influenza virus to emerge that mankind has little or no resistance to, for it to cause significant morbidity and mortality, and for it to adapt to human physiology so that it transmits efficiently.

 

The H5N1 virus fulfills these first two criteria, but fails on the third. 

 

For now, anyway.

 

But there are many other influenza viruses circulating in birds, pigs, and other species that have the potential to either mutate - or more likely - reassort (swap gene segments with another flu strain) and adapt to human hosts.

 

Below you’ll find a chart lifted and edited from CIDRAP’s excellent overview Avian Influenza (Bird Flu): Implications for Human Disease  showing non-H5N1 avian flu infections in humans over the past decade.

 

 

Since surveillance is – at best - haphazard (or even non-existent) in many parts of the world, how often these types of novel infections really occur is unknown.  

 

Despite rare known human infections, these viruses need to acquire genetic changes before they could spark a pandemic. Which is why we concern ourselves with their ability to reassort with other – already humanized – flu strains.

 

Reassortment (or Shift), happens when two different influenza viruses co-infect the same host and swap genetic material.

 

 

Influenza A viruses have 8 gene segments (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, NS2)

.

Which means that any two compatible influenza viruses could conceivably – and under the right conditions – generate 256 different combinations by swapping one or more of their 8 (potentially) interchangeable gene segments.

 

The key words being “under the right conditions”.

 

 

Last February in PNAS: Reassortment Of H1N1 And H9N2 Avian viruses we saw research from Chinese scientists that created – using reverse genetics – 128 reassorted viruses from the avian H9N2 virus and the (formerly pandemic) H1N1 virus.

 

In mouse testing, they found half of the hybrid viruses were biologically `fit’ as far as replication goes, and 8 hybrids were significantly more pathogenic than either of their parental viruses.

 

 

Today, again from PNAS, we have a new study that once again looks at the reassortment potential of the avian H9N2 virus and H1N1.

 

This time, research was done using ferrets, whose respiratory physiology is closer to human than are mice.

 

Compatibility of H9N2 avian influenza surface genes and 2009 pandemic H1N1 internal genes for transmission in the ferret model

J. Brian Kimble, Erin Sorrell,  Hongxia Shao,  Philip L. Martin, and Daniel Roberto Perez

Abstract

In 2009, a novel H1N1 influenza (pH1N1) virus caused the first influenza pandemic in 40 y. The virus was identified as a triple reassortant between avian, swine, and human influenza viruses, highlighting the importance of reassortment in the generation of viruses with pandemic potential.

 

Previously, we showed that a reassortant virus composed of wild-type avian H9N2 surface genes in a seasonal human H3N2 backbone could gain efficient respiratory droplet transmission in the ferret model.

 

Here we determine the ability of the H9N2 surface genes in the context of the internal genes of a pH1N1 virus to efficiently transmit via respiratory droplets in ferrets. We generated reassorted viruses carrying the HA gene alone or in combination with the NA gene of a prototypical H9N2 virus in the background of a pH1N1 virus.

 

Four reassortant viruses were generated, with three of them showing efficient respiratory droplet transmission. Differences in replication efficiency were observed for these viruses; however, the results clearly indicate that H9N2 avian influenza viruses and pH1N1 viruses, both of which have occasionally infected pigs, have the potential to reassort and generate novel viruses with respiratory transmission potential in mammals.

 

The entire study is available online, and open access. 

 

As noted in the abstract above, these authors had previously successfully created laboratory reassortments between seasonal H3N2 and H9N2.  

 

The fact that these hybrid viruses can be created in the laboratory doesn’t automatically mean they would be generated in the field by a co-infected host.

 

Only that it is possible.

 

And with 256 possible combinations, these 4 hybrids might not even represent the most `fit’ reassortments.

 

But research like this continues to show the potential for the H9N2 virus to move towards a more `humanized’ pathogen. And with H1N1 and H9N2 both known to be circulating in pigs in Asia, there are ample opportunities for them to co-infect the same host. 

 

A few notable H9N2 stories from the past include:

• In December 2008 I ran a blog featuring an interview in which world famous Hong Kong virologist Malik Peiris cautioned that the H9N2 virus may be circulating far more commonly than we believe. Revisiting A Malik Peiris Interview On H9N2

• In January of 2010, in H9N2: The Other Bird Flu Threat, I wrote about the World Health Organization  recommending the creation of a candidate vaccine virus for H9N2. According to the latest vaccine update from the WHO, work continues on that candidate vaccine virus.

• And just this past November, in Study: The Continuing Evolution Of Avian H9N2, we looked at computer modeling that suggested that the H9N2 virus moving towards becoming more `human-adapted’.

 

Unlike the H7 and H5 avian flu strains, poultry (and swine) infections by the H9N2 virus are not required to be reported to the OIE.  

 

As we saw in 2009, sometimes a pandemic virus will emerge from an unexpected source, and with a surprising lineage. While the world was waiting for an H5 bird flu to emerge from Asia, we were blindsided by a H1N1 swine flu from North America.

 

All of which highlights the importance of establishing better global surveillance of humans, and farm animals, for the next emerging influenza virus. 

 

Regardless of its strain.

»» Read More

PNAS: Challenging Drug Resistance Conventional Wisdom

 

 

# 5641

 

 

 

Proving you should never judge a study by it’s title, today we’ve an absolutely intriguing article that appears in today’s early edition of PNAS (Proceedings of the National Academy of Sciences) called:

 

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Andrew F. Reada, Troy Dayc, and Silvie Huijbena

 

The authors – using malarial resistance as an example – suggest that some of the tactics used today to try to conserve the effectiveness of our drug arsenal may actually be driving the evolution of resistant pathogens.

 

In this article they question several conventional treatment wisdoms including:

 

• whether the standard advice -  that patients must `finish a drug course even after they feel better’ – is always the best strategy to prevent the creation of resistant organisms.
• whether it is always necessary (or even desirable) to hit an infection hard and fast with mono or combo therapy in order to effect a cure.

 

Heresy?

 

Perhaps.

 

But these authors are not advocating that we suddenly abandon our current antibiotic and drug strategies, only that we need to examine them closely to see if, and when, they really make sense.

 

And they suggest that what is appropriate for one type of pathogen, or in one part of the world at a given point in time, may not be the best course for another.

 

While they present a lot of detail (you are going to want to read the entire 7-page article), the basic premise is pretty simple. 

 

Resistant organisms are generally believed to be less biologically fit than their wild type ancestors, which is why we aren’t (yet, anyway) hip deep in resistant organisms.

 

As long as they share a host with a more `fit’ and competitive strain, they are rarely able to establish a toehold and proliferate.

 
But when you start applying heavy drug therapy, killing off only the drug sensitive strains, that small population of resistant pathogens can suddenly swell.

 

It’s almost a Nietzschian concept, really.  

 

Whatever doesn’t completely kill off a pathogen, makes the resistant strains stronger.

 

 

Of course, the issues are a great deal more complicated than I’ve outlined here. Rather than go in greater detail, I’ll simply suggest you read the article in its entirety.

 

The authors suggest that these concepts could apply across a wide range of resistance issues; everything from bacteria, parasites, and viruses to insecticide and cancer chemotherapy resistance. 

 

 

This article is one of many printed this week that results from:

 

. . . the Arthur M. Sackler Colloquium of the National Academy of Sciences, “In the Light of Evolution V: Cooperation and Conflict,” which was held January 7–8, 2011, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA.

The complete program and audio files of most presentations are available on the NAS Web site at www.nasonline.org/SACKLER_cooperation.

»» Read More

PNAS: Reassortment Of H1N1 And H9N2 Avian viruses

 

 

# 5345

 

 

We’ve a study published today in PNAS that is shedding new light on the possibility of seeing a biologically `fit’ and virulent novel virus emerge from a reassortment between the H9N2 avian flu and the (former) pandemic H1N1 swine flu.

 

Researchers in China – using reverse genetics – created 127 hybrid viruses in the laboratory and tested them on mice for compatibility, replication ability, and virulence.

 

They found that half of the hybrid viruses were biologically `fit’ as far as replication goes, and 8 hybrids were significantly more pathogenic than either of their parental viruses.

 

A link to the study, followed by excerpt from the abstract, and then I’ll return with more.

 

High genetic compatibility and increased pathogenicity of reassortants derived from avian H9N2 and pandemic H1N1/2009 influenza viruses

Yipeng Sun,Kun Qin, Jingjing Wang, Juan Pu, Qingdong Tang, Yanxin Hu, Yuhai Bi,Xueli Zhao, Hanchun Yang, Yuelong Shu, and Jinhua Liu

Abstract

H9N2 influenza viruses have been circulating worldwide in multiple avian species and repeatedly infecting mammals, including pigs and humans, posing a significant threat to public health. The coexistence of H9N2 and pandemic influenza H1N1/2009 viruses in pigs and humans provides an opportunity for these viruses to reassort.

<SNIP>

Our results indicate that some avian H9-pandemic reassortants could emerge with a potentially higher threat for humans and also highlight the importance of monitoring the H9-pandemic reassortant viruses that may arise, especially those that possess the PA gene of H1N1/2009 origin.

 

 

When it comes to pathogenicity of flu viruses, mice are reasonably good test subjects  . . . but are not necessarily the best physiological surrogates for humans.

 

The authors of this study are quoted in the media as saying their next step is to repeat these experiments with ferrets and guinea pigs, lab animals that have more human-like respiratory systems.

 

We’ve discussed reassortment many times before, so those familiar with the concept may wish to skip ahead.

 

Shift, or reassortment, happens when two different influenza viruses co-infect the same host swap genetic material.

Influenza A viruses have 8 gene segments (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, NS2).

 

Which means that any two compatible influenza viruses could conceivably – and under the right conditions – generate more than 250 different combinations by swapping one or more of their 8 (potentially) interchangeable gene segments.

 

The key words being “under the right conditions”.

 

If it were easy, or a common occurrence, we’d be up to our hip boots in new, reassorted viruses all the time.

 

But it happens often enough that we recognize it as a real threat.   Shift is how new pandemic strains are born, and it was precisely the mechanism that created the 2009 `swine’ flu strain.

 

 

While the novel H1N1 `swine flu’ virus needs no introduction, the H9N2 avian virus is less well known. It is endemic in poultry across Asia, and while rare, we have seen a handful human infections. 

 

How often humans are really infected is unknown, since surveillance and testing among poultry farmers in China is practically non-existent.

 

 

A few notable H9N2 stories from the past include:

 

• In December 2008 I ran a blog featuring an interview in which world famous Hong Kong virologist Malik Peiris cautioned that the H9N2 virus may be circulating far more commonly than we believe. Revisiting A Malik Peiris Interview On H9N2

• A little over a year ago, in H9N2: The Other Bird Flu Threat, I wrote about the World Health Organization  recommending the creation of a candidate vaccine virus for H9N2. According to the latest vaccine update from the WHO, work continues on that candidate vaccine virus.

• And just this past November, in Study: The Continuing Evolution Of Avian H9N2, we looked at computer modeling that suggested that the H9N2 virus moving towards becoming more `human-adapted’.

 

Today’s PNAS study, like many others before it  . . .

 

EID Journal: H1N1 Reassortment Possibilities

mBio: A/H1N1 Potential For Mutation

PNAS: H3N2 And H5N1 Reassortment)

 

. . .  point out the potential for nature’s laboratory to come up with new, and potentially devastating, flu strains through genetic reassortment. Granted, less virulent hybrid flu strains are also a possibility.

 

While we may not be able to stop the next pandemic from happening - knowing which dangerous hybrids to look for, and conducting aggressive global surveillance - may help us detect the next outbreak at the earliest possible moment.

And a few extra week’s warning could make all the difference between having a vaccine in time to mitigate the pandemic’s peak, or having it arrive after the worst had passed.

»» Read More

PNAS: Human Networking & Infectious Disease Spread

 

# 5140

Note: Fixed broken link.

 

 

A truly ingenious piece of research, published yesterday in PNAS, that uses wireless technologies to chart the opportunities an airborne virus has to spread in a closed, heavily populated environment, like a high school.

 

The authors wired 655 students, 73 teachers, 55 staff, and 5 others with tiny remote sensors (called motes) that detected each time any of them came within 3 meters of another individual.

 

The movements, contacts (including duration), and clustering of individuals were recorded every 20 seconds over the period of a single school day in January, and during that time they collected 762,868 CPIs (Close Proximity Interactions).

 

They then ran a series of computer simulations, assigning each student (1 student at a time) as an index case with an infectious respiratory virus, and using thousands of computer runs, determined whether or not secondary transmission would occur.

 

Although no secondary transmission occurs in 2/3rds of the simulation runs - were a virus circulating in the community - multiple introductions would be expected, raising the odds of ongoing transmission.

 

The researchers also looked at the effects on transmission due to different vaccination strategies (random, students, teachers).

 

There’s a lot in this open access paper, which is admittedly heavy on math and statistics. Luckily we’ve a press release, a short audio podcast, and the abstract to give us the highlights.

 

First, the study and abstract (slightly reparagraphed for readability).

 

A high-resolution human contact network for infectious disease transmission

10.1073/pnas.1009094108

 

Marcel Salathé, Maria Kazandjieva, Jung Woo Lee, Philip Levis, Marcus W. Feldman, and James H. Jones

Abstract

The most frequent infectious diseases in humans—and those with the highest potential for rapid pandemic spread—are usually transmitted via droplets during close proximity interactions (CPIs). Despite the importance of this transmission route, very little is known about the dynamic patterns of CPIs.

 

Using wireless sensor network technology, we obtained high-resolution data of CPIs during a typical day at an American high school, permitting the reconstruction of the social network relevant for infectious disease transmission.

 

At 94% coverage, we collected 762,868 CPIs at a maximal distance of 3 m among 788 individuals. The data revealed a high-density network with typical small-world properties and a relatively homogeneous distribution of both interaction time and interaction partners among subjects.

 

Computer simulations of the spread of an influenza-like disease on the weighted contact graph are in good agreement with absentee data during the most recent influenza season. Analysis of targeted immunization strategies suggested that contact network data are required to design strategies that are significantly more effective than random immunization. Immunization strategies based on contact network data were most effective at high vaccination coverage.

 

You can listen to a brief interview with one of the authors (Marcel Salathé) HERE.

 

And a press release, from the National Science Foundation, provides the basics.

 

Human networking theory gives picture of infectious disease spread

High school students' interactions provide new look at disease transmission

It's colds and flu season, and as any parent knows, colds and flu spread like wildfire, especially through schools.

 

New research using human-networking theory may give a clearer picture of just how, exactly, infectious diseases such as the common cold, influenza, whooping cough and SARS can spread through a closed group of people, and even through populations at large.

 

With the help of 788 volunteers at a high school, Marcel Salathé, a biologist at Penn State University, developed a new technique to count the number of possible disease-spreading events that occur in a typical day.

 

This results are published in this week's issue of the journal Proceedings of the National Academy of Sciences.

 

The research was funded by the National Science Foundation (NSF) and the National Institutes of Health (NIH).

(Continue . . . )

 

 

My thanks to Carol@SC and Jane on the Flu Wiki  for the head’s up on these links.

»» Read More

Towards A Universal Flu Vaccine

 

 

 

# 4991

 

 

It’s the Holy Grail of flu researchers; a universal flu shot that could protect against a wide range of flu viruses, and give protection that would last for years.

 

And based on research published yesterday in PNAS, researchers are inching slowly closer to that goal. 

 

The study is dauntingly titled:

 

Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes

1. Taia T. Wang, Gene S. Tan, Rong Hai, Natalie Pica, Lily Ngai,Damian C. Ekiert, Ian A. Wilson,Adolfo García-Sastre, Thomas M. Moran, and Peter Palese

 

And the Abstract – which describes the testing of a synthetic peptide that binds to the stalk of a cross-variety of influenza hemagglutinins in mice – is probably for nonscientists –  a bit of tough sledding.

 

Luckily, we’ve a pair of articles available online that shed a good deal more light on the subject, and in language that is easier to understand.

 

First, from Scientific American, we’ve an interview with co-author Peter Palese –  a familiar name in influenza research - and Professor of microbiology and head of the Department of Microbiology at the Mount Sinai School of Medicine in New York.

 

How Close Is a Universal Influenza Vaccine That Could Provide Lifelong Immunity with One Shot?

The rapidly mutating strains of flu virus have so far thwarted efforts to develop a vaccine that could knock out all varieties with a single injection, but recent advances suggest a synthetic solution. The head of Mount Sinai School of Medicine's microbiology department explains

 

Second, an article by Lauren Gravitz at MIT’s Technology Review, with comments by such notables as Robert Webster, Gary Nabel at NIH, and Terrance Tumpey at the CDC  titled:

 

A Long-lasting Universal Flu Vaccine

Advance could eliminate the need for shots each year for evolving strains.

By Lauren Gravitz

 

Both are good reads.

 

The short version, however, is that researchers have created a synthetic peptide which binds to a slow-to-mutate portion of the viral hemagglutinin that is common across many strains of influenza.

 

This experimental vaccine produced (in mice, at least) varying immune responses against the H1N1, H5N1, and H3N2 viruses . . . with protection that ranged from mild to robust.

 

 

But as the saying goes, if you are sick . . . and you are a mouse . . . there’s a lot that modern science can do for you.

 

What works in mice, however, doesn’t always translate into a viable treatment for humans.  

 

The levels of protection achieved from this vaccine apparently weren’t potent enough  across all subtypes to serve as a stand-alone universal vaccine, but this work is still in its early stages.

 

And even if this technique eventually proves efficacious in humans, it is a long road from testing it on lab mice to having a human-approved drug.

 

But this is real progress, offers a tantalizing avenue for further research,  and gives hope to the idea that someday a universal vaccine might become a reality.

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Clipping Dengue’s Wings

 

 

 

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While I’m mindful of the the Law of Unintended Consequences, which always seems positioned to remind mankind that it’s not nice to fool with Mother Nature, scientists have come up with a unique way – they believe – will help control mosquito borne Dengue fever.

 

Essentially, they plan to release genetically altered male Aedes Aegypti mosquitoes that would produce flightless female offspring, a trait not carried forward by the males.

 

Since female mosquitoes are the ones that bite and transmit Dengue, grounding them would go a long way towards reducing the disease.  

 

Whether this sparks protests from `mosquito’s rights’ advocacy groups remains to be seen. 

 

This report from the BBC.

 

 

'Lame' mosquitoes to stop dengue

The dengue virus is spread by infected female Aedes aegypti mosquitoes

Scientists are breeding a genetically altered strain of mosquito in an effort to curb the spread of dengue fever.

 

The dengue virus is spread by the bite of infected female mosquitoes and there is no vaccine or treatment.

 

Experts say the illness affects up to 100 million people a year and threatens over a third of the world's population.

 

Scientists hope their genetically altered males will mate with females to create female offspring that will inherit a gene limiting wing growth.

 

The study is published in Proceedings of the National Academy of Sciences.

The scientists say their approach offers a safe, efficient alternative to harmful insecticides and could be used to stop other diseases spread by mosquitoes, like malaria.

 

They estimate that if released, the new breed could sustainably suppress the native mosquito population in six to nine months.

(Continue . . . )

 

 

For those who would like more than the BBC condensed version, here is the PNAS abstract, and a link to the entire open access article.

 

 

 

Female-specific flightless phenotype for mosquito control

Guoliang Fu Rosemary S. Lees  Derric Nimmo Diane Aw Li Jin  Pam Gray Thomas U. Berendonk Helen White-Cooper Sarah Scaife Hoang Kim Phuc Osvaldo Marinotti Nijole Jasinskiene Anthony A. James Luke Alphey

Abstract

Dengue and dengue hemorrhagic fever are increasing public health problems with an estimated 50–100 million new infections each year. Aedes aegypti is the major vector of dengue viruses in its range and control of this mosquito would reduce significantly human morbidity and mortality. Present mosquito control methods are not sufficiently effective and new approaches are needed urgently.

 

A “sterile-male-release” strategy based on the release of mosquitoes carrying a conditional dominant lethal gene is an attractive new control methodology. Transgenic strains of Aedes aegypti were engineered to have a repressible female-specific flightless phenotype using either two separate transgenes or a single transgene, based on the use of a female-specific indirect flight muscle promoter from the Aedes aegypti Actin-4 gene.

 

These strains eliminate the need for sterilization by irradiation, permit male-only release (“genetic sexing”), and enable the release of eggs instead of adults. Furthermore, these strains are expected to facilitate area-wide control or elimination of dengue if adopted as part of an integrated pest management strategy.

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PNAS: H3N2 And H5N1 Reassortment

 

 

 

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The concern for a good many years has been that the highly pathogenic (and deadly) H5N1 bird flu virus would someday find a way to adapt more fully to humans, and spark a devastating pandemic.  

 

Thus far, H5N1’s saving grace is that it transmits poorly among humans.  A mutation, or a reassortment of the virus, could alter its transmissibility.  

 

And that could change everything overnight.  

 

Flu Viruses are made up of 8 gene segments, and when two flu viruses infect the same cell in a host simultaneously, they can sometimes swap genetic material and create a new hybrid virus.

 

 

This is called reassortment, and this is how some pandemic viruses have been created in the past.

 

 

In a study released today in PNAS, scientists have taken the H5N1 virus and a seasonal H3N2 virus and have produced (using reverse genetics) all 254 possible reassortant combinations of the two, and have tested them for pathogenicity on mice.

 

 

First the abstract to the study (slightly reformatted for readability), followed by a link to a PhysOrg.com story on the study:

 

Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence

Chengjun Li Masato Hatta Chairul A. Nidom Yukiko Muramoto Shinji Watanabe Gabriele Neumann Yoshihiro Kawaoka

Edited by Robert G. Webster, St. Jude Children’s Research Hospital, Memphis, TN, and approved December 14, 2009 (received for review November 5, 2009)

Abstract

The spread of avian H5N1 influenza viruses around the globe has become a worldwide public health concern. To evaluate the pathogenic potential of reassortant viruses between currently cocirculating avian H5N1 and human H3N2 influenza viruses, we generated all the 254 combinations of reassortant viruses between A/chicken/South Kalimantan/UT6028/06 (SK06, H5N1) and A/Tokyo/Ut-Sk-1/07 (Tok07, H3N2) influenza viruses by reverse genetics.

 

We found that the presence of Tok07 PB2 protein in the ribonucleoprotein (RNP) complex allowed efficient viral RNA transcription in a minigenome assay and that RNP activity played an essential role in the viability and replicative ability of the reassortant viruses. When the pathogenicity of 75 reassortant H5 viruses was tested in mice, 22 were more pathogenic than the parental SK06 virus, and three were extremely virulent.

 

Strikingly, all 22 of these viruses obtained their PB2 segment from Tok07 virus. Further analysis showed that Tok07 PB1 alone lacked the ability to enhance the pathogenicity of the reassortant viruses but could do so by cooperating with Tok07 PB2.

 

Our data demonstrate that reassortment between an avian H5N1 virus with low pathogenicity in mice and a human virus could result in highly pathogenic viruses and that the human virus PB2 segment functions in the background of an avian H5N1 virus, enhancing its virulence.

Our findings highlight the importance of surveillance programs to monitor the emergence of human H5 reassortant viruses, especially those containing a PB2 segment of human origin.

 

This study has an impressive pedigree that includes such familiar names as Yoshihiro Kawaoka, C.A. Nidom, and no less than Dr. Robert Webster.

 

The `surprise’ in this research was the production of multiple hybrid strains that were even more virulent (in mice) than H5N1 alone.

 

This report from PhysOrg.com.

Virus hybridization could create pandemic bird flu

February 22, 2010

Genetic interactions between avian H5N1 influenza and human seasonal influenza viruses have the potential to create hybrid strains combining the virulence of bird flu with the pandemic ability of H1N1, according to a new study.

 

In laboratory experiments in mice, a single gene segment from a human seasonal flu virus, H3N2, was able to convert the avian H5N1 virus into a highly pathogenic form. The findings are reported the week of Feb. 22 in the online early edition of the Proceedings of the National Academy of Sciences.

 

"Some hybrids between H5N1 virus and seasonal influenza viruses were more pathogenic than the original H5N1 viruses. That is worrisome," says Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison and senior author of the new study.

 

The H5N1 bird flu virus has spread worldwide through bird populations and has caused 442 confirmed human cases and 262 deaths, according to the World Health Organization. To date, however, bird flu has not been able to spread effectively between people.

 

"H5N1 virus has never acquired the ability to transmit among humans, which is why we haven't had a pandemic. The worry is that the pandemic H1N1 virus may provide that nature in the background of this highly pathogenic H5N1 virus," says Kawaoka, a professor of pathobiological sciences at the UW-Madison School of Veterinary Medicine.

 

(Continue . . . )

 

 

Unknown is how likely any of these combinations is to occur naturally; outside of the lab. 

 

Nature, of course, has a huge and extensive laboratory, that is open for business 24/7.

 

However remote, one would do well to consider the wisdom of betting against the possibility.

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Evidence That H1N1 Really Is Novel

 

 

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A fascinating report today (of course, press releases are designed to be fascinating . . . ) that outlines research at the University of California – Berkeley that shows that the genetic makeup of the H1N1 virus’s polymerase is different from any human-adapted influenza viruses studied to date.

 

The polymerase is an important segment in the influenza virus responsible for the virus's replication.  

 

Previously known human-adapted influenza viruses all made a specific mutation in their polymerase to enable them to replicate efficiently in a human host.  

 

The novel H1N1 virus didn’t.   It retains an avian-adapted polymerase.

 

Instead it made a completely different mutation that allows the avian polymerase to replicate in a mammalian host. 

 

As these researchers remind us, the H1N1 virus may not be through mutating and adapting to humans.    

 

I’ve only reproduced part of this press release. Follow the link to read it in its entirety.   Warning:  Some of it is for hardcore science geeks.

 

 

H1N1 influenza adopted novel strategy to move from birds to humans

Bird influenza viruses have a variety of strategies to cross the species barrier and spread

The 2009 H1N1 influenza virus used a new strategy to cross from birds into humans, a warning that it has more than one trick up its sleeve to jump the species barrier and become virulent.

 

In a report in this week's early online edition of the journal Proceedings of the National Academy of Sciences, University of California, Berkeley, researchers show that the H1N1, or swine flu, virus adopted a new mutation in one of its genes distinct from the mutations found in previous flu viruses, including those responsible for the Spanish influenza pandemic of 1918, the "Asian" flu pandemic in 1957 and the "Hong Kong" pandemic of 1968.

 

Previous influenza strains that crossed from birds into people had a specific point mutation in the bird virus's polymerase gene that allowed the protein to operate efficiently inside humans as well. The polymerase transcribes the virus's RNA, allowing the host to express viral genes, and also copies the viral genome, needed to make new viruses.

 

The 2009 H1N1 virus retains the bird version of the polymerase, but has a second mutation that seems to suppress the ability of human cells to prevent the bird polymerase from working.

 

"We were quite shocked when we looked at the swine flu virus, which was clearly replicating in people and other mammalian systems, yet had a polymerase that looked like it was derived from a bird virus, which should not function too well in a human cell type," said UC Berkeley post-doctoral fellow Andrew Mehle of the Department of Molecular and Cell Biology. "The other mutation within the polymerase seems to compensate and allow the enzyme to function."

 

The researchers also discovered another strategy – one not yet adopted by any known flu virus – by which influenza virus can increase its virulence even more. When a particular human subunit is substituted for one of the three protein subunits that make up the bird polymerase, the new combination makes the polymerase more efficient in human cells.

 

"This is an extremely rare mutation and a rare combination, which suggests that there may be other ways that haven't emerged yet that these viruses are going to continue to evolve," said Jennifer Doudna, UC Berkeley professor of molecular and cell biology and an investigator in the Howard Hughes Medical Institute.

(Continue . . . )

 

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