HHS WORKS TO FIND TESTS FOR INFLUENZA, BETTER RESPONSE TO PANDEMIC

FROM:  U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

HHS pursues detection tests for influenza

Tests for influenza viruses to improve diagnosis and speed pandemic response
Potential tests to help doctors diagnose influenza sooner and more accurately will advance in development under contracts from the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response (ASPR). The tests could help boost influenza pandemic preparedness by increasing diagnostic capabilities in near-patient care settings such as doctors’ offices, clinics, and hospitals.

One award will advance the development of a simple, low-cost molecular test under a 3.5-year, $12.9 million contract with Alere Inc., headquartered in Waltham, Massachusetts. The other award, to InDevR Inc., of Boulder, Colorado, will allow a biochip test to move forward under a two-year, $7.9 million contract with options to extend the contract up to $14.7 million over four years.

The tests use different technologies to detect influenza viruses and offer different levels of information about the viruses detected. Both tests would use swabs taken from a patient’s nasal passage.

Alere will develop its iNAT Influenza A&B test which could yield results within 15 minutes and show whether a patient has an infection caused by a seasonal influenza virus type A or B infection. The company will conduct studies necessary to submit for U.S. Food and Drug Administration clearance or approval, including a Clinical Laboratory Improvement Amendments waiver for iNAT, which would allow the rapid molecular test to be performed in the near-patient settings.

InDevR will develop its FluChip-8G test to identify seasonal influenza viruses and recognize novel flu viruses within four hours in near-patient settings. Currently, this type of detailed genetic testing is conducted in state, federal, or specialty laboratories, and can take days to complete. If successful during the first two years, InDevR will conduct clinical studies necessary to submit for clearance or approval from the FDA and will develop a fully automated version of the test.

“Administering fast and inexpensive tests at the point of care has tangible benefits to personal and public health, particularly in helping doctors prescribe the right therapy immediately,” said Robin Robinson, Ph.D., director of ASPR’s Biomedical Advanced Research and Development Authority (BARDA) whose office will oversee the development programs. “Prescribing medication or other therapies in a more targeted way is good stewardship and will be critical to reducing the risk of antimicrobial resistance.”

Distinguishing viral influenza infections from bacterial infections could aid doctors and patients in choosing the best treatment, and could reduce unnecessary antibiotic use, as antibiotics are ineffective in treating illness caused by viruses. In addition, testing for influenza viruses in doctors’ offices, clinics, and hospitals could improve use of precautions among patients and health care workers to reduce spread of influenza from person to person.

Improved tests available in more settings can alert doctors and public health authorities to community outbreaks of respiratory illness and signal new viruses causing illness. A new influenza virus to which people do not have immunity could potentially spread quickly and have pandemic potential.

To help prepare the United States for pandemics, BARDA also is supporting development of other diagnostic platforms, including a test to identify drug resistance in influenza, as well as new vaccine technology, antiviral drugs, low-cost, portable ventilators and other medical equipment and supplies.

BARDA is seeking additional proposals for advanced development of new drugs and products to diagnosis and treat illness. Proposals are accepted through the broad agency announcement BAA-BARDA-13-100-SOL-19, available on www.fbo.gov.

These new programs are part of BARDA’s comprehensive integrated portfolio approach to the advanced research and development, innovation, acquisition, and manufacturing of vaccines, drugs, diagnostic tools, and non-pharmaceutical products for public health emergency threats. These threats include chemical, biological, radiological, and nuclear agents, pandemic influenza, and emerging infectious diseases.

ASPR leads HHS in preparing the nation to respond to and recover from adverse health effects of emergencies, supporting communities’ ability to withstand adversity, strengthening health and response systems, and enhancing national health security. HHS is the principal federal agency for protecting the health of all Americans and providing essential human services, especially for those who are least able to help themselves. To learn more about HHS, visit hhs.gov.
To learn more about ASPR and preparedness, response and recovery from the health impacts of disasters, visit the HHS public health and medical emergency website, phe.gov. Information about influenza is available at flu.gov.

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CDC SAYS FLU SEASON HARD FOR YOUNGER PEOPLE

FROM:  CENTERS FOR DISEASE CONTROL AND PREVENTION 
CDC Reports Flu Hit Younger People Particularly Hard This Season
Vaccination lowered risk of having to go to the doctor by about 60 percent for people of all ages

This influenza season was particularly hard on younger- and middle-age adults, the Centers for Disease Control and Prevention reported in today’s Morbidity and Mortality Weekly Report. People age 18-64 represented 61 percent of all hospitalizations from influenza—up from the previous three seasons when this age group represented only about 35 percent of all such hospitalizations. Influenza deaths followed the same pattern; more deaths than usual occurred in this younger age group.

A second report in this week’s MMWR showed that influenza vaccination offered substantial protection against the flu this season, reducing a vaccinated person’s risk of having to go to the doctor for flu illness by about 60 percent across all ages.
“Flu hospitalizations and deaths in people younger- and middle-aged adults is a sad and difficult reminder that flu can be serious for anyone, not just the very young and old; and that everyone should be vaccinated,” said CDC Director Tom Frieden, M.D., M.P.H. “The good news is that this season's vaccine is doing its job, protecting people across all age groups."

U.S. flu surveillance data suggests that flu activity is likely to continue for a number of weeks, especially in places where activity started later in the season. Some states that saw earlier increases in flu activity are now seeing decreases. Other states are still seeing high levels of flu activity or continued increases in activity.

While flu is responsible for serious illness and death every season, the people who are most affected can vary by season and by the predominant influenza virus. The currently circulating H1N1 virus emerged in 2009 to trigger a pandemic, which was notable for high rates of hospitalization and death in younger- and middle-aged people. While H1N1 viruses have continued to circulate since the pandemic, this is the first season since the pandemic they have been predominant in the U.S. Once again, the virus is causing severe illness in younger- and middle-aged people.

Approximately 61 percent of flu hospitalizations so far this season have occurred among persons aged 18-64 years. Last season, when influenza A (H3N2) viruses were the predominant circulating viruses, people 18 to 64 years accounted for only 35 percent of hospitalizations. During the pandemic season of 2009-2010, people 18 to 64 years old accounted for about 56 percent of hospitalizations.
Hospitalization rates have also been affected. While rates are still highest among people 65 and older (50.9 per 100,000), people 50 to 64 years now have the second-highest hospitalization rate (38.7 per 100,000), followed by children 0-4 years old (35.9 per 100,000). During the pandemic, people 50 to 64 years also had the second-highest hospitalization rate. Note that hospitalization rates are cumulative and thus will continue to increase this season.

Influenza deaths this season are following a pattern a similar to the pandemic.  People 25 years to 64 years of age have accounted for about 60 percent of flu deaths this season compared with 18 percent, 30 percent, and 47 percent for the three previous seasons, respectively. During 2009-2010, people 25 years to 64 years accounted for an estimated 63 percent of deaths.

"Younger people may feel that influenza is not a threat to them, but this season underscores that flu can be a serious disease for anyone," said Dr. Frieden. "It's important that everyone get vaccinated. It's also important to remember that some people who get vaccinated may still get sick, and we need to use our second line of defense against flu: antiviral drugs to treat flu illness. People at high risk of complications should seek treatment if they get a flu-like illness. Their doctors may prescribe antiviral drugs if it looks like they have influenza."

People at high risk for flu complications include pregnant women, people with asthma, diabetes or heart disease, people who are morbidly obese and people older than 65 or children younger than 5 years, but especially those younger than 2 years. A full list of high risk factors and antiviral treatment guidance is available on the CDC website. More information about flu vaccine and how well it works also is available.

Flu Vaccine Best Tool Available

In the flu vaccine effectiveness (VE) study, CDC looked at data from 2,319 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness (Flu VE) Network from December 2, 2013 to January 23, 2014. They found that flu vaccine reduced the risk of having to go to the doctor for flu illness by an estimated 61 percent across all ages. The study also looked at VE by age group and found that the vaccine provided similar levels of protection against influenza infection across all ages. VE point estimates against influenza A and B viruses by age group ranged from 52 percent for people 65 and older to 67 percent for children 6 months to 17 years. Protection against the predominant H1N1 virus was even slightly better for older people; VE against H1N1 was estimated to be 56 percent in people 65 and older and 62 percent in people 50 to 64 years of age. All findings were statistically significant.

The interim VE estimates this season are comparable to results from studies during other seasons when the viruses in the vaccine have been well-matched with circulating influenza viruses and are similar to interim estimates from Canada for 2013-14 published recently.

While flu vaccine can vary in how well it works, vaccination offers the best protection currently available against influenza infection. CDC recommends that everyone 6 months and older get an annual flu vaccine.

“We are committed to the development of better flu vaccines, but existing flu vaccines are the best preventive tool available now. This season vaccinated people were substantially better off than people who did not get vaccinated. The season is still ongoing. If you haven’t yet, you should still get vaccinated," said Dr. Frieden.

MUTATION AND DENGUE FEVER

Photo:  Mosquito.  Credit:  NSF/Wikipedia.

FROM: NATIONAL SCIENCE FOUNDATION"Defective" Virus Leads to Epidemic of Dengue Fever


It's 2001 in Myanmar (formerly known as Burma), a country in Southeast Asia. Almost 200 people have died, and more than 15,000 are ill--all having contracted dengue fever.

Dengue is a disease transmitted by mosquitoes and caused by four types of dengue virus. Infection may not result in symptoms, or may cause mild, flu-like illness--or hemorrhagic fever.

Dengue virus infects some 50-100 million people annually in Southeast Asia, South America and parts of the United States.

In 1998, a pandemic of dengue resulted in 1.2 million cases of dengue hemorrhagic fever in 56 countries.

In Myanmar, dengue is endemic. The disease has occurred there in three- to five-year cycles since the first recorded outbreak in 1970. Each one has been more deadly.

What caused the widespread infection in Myanmar in 2001, a disease that resulted from one type of dengue virus, DENV-1? For more than a decade, researchers have been working to solve the puzzle.

All viruses not created equal

Could the DENV-1 in Myanmar have been different in some way, perhaps "defective"?

Defective viruses result from genetic mutations or deletions that eliminate essential functions. They're generated in viruses with high mutation rates, but were believed to be unimportant.

But it now appears that defective viruses may be able to play a critical role in the spread of disease.

In a paper published this week in the journal PLoS Pathogens, scientists funded by the National Science Foundation (NSF) report a significant link between one such defective virus and the high rate of transmission of DENV-1 in Myanmar in 2001.

"The idea has always been that defective viruses are either meaningless or detrimental," says James Lloyd-Smith, an ecologist and evolutionary biologist at University of California, Los Angeles.

"We've found the opposite--that the defective virus is actually helping the normal, functional virus. It's bizarre and hard to believe, but the data are the data."

"We've shown that the defective virus not only goes with the normal virus, but increases the transmission of that virus," says scientist Ruian Ke, also of UCLA.

While defective viruses can't complete their life cycle on their own, if they're able to get into the same cell with a non-defective virus, they can "hitch-hike" with the non-defective one and propagate.

Deadly outbreak of DENV-1

The research team--James Lloyd-Smith; Ruian Ke; John Aaskov, a virologist at Queensland University of Technology in Brisbane, Australia; and Edward Holmes, a biologist at the University of Sydney--found that the presence of a defective DENV-1 virus may have led to a spike in dengue fever cases in Myanmar during 2001-2002.

"The causes of epidemics are much more complicated than we thought," says Sam Scheiner, NSF program director for the joint NSF-National Institutes of Health Ecology and Evolution of Infectious Diseases (EEID) Program. At NSF, EEID is funded by the Directorates for Biological Sciences and Geosciences.

In addition to EEID, the research was supported by NSF's Advancing Theory in Biology Program.

"Pathogens can depend on the presence of other microbial species or, as in this case, other varieties of the same species," says Scheiner. "Understanding these interactions is critical for predicting when the next epidemic might occur--and how to prevent it."

In the study, Ke designed a mathematical model to learn how the defective DENV-1 virus interacted with the normal virus.

Aaskov and Holmes collected genetic sequences from the defective viruses from 15 people sampled over an 18-month period in Myanmar. All were infected with DENV-1 virus; nine were also infected with the defective version.

Ke discovered that the lineage of defective viruses emerged between June 1998 and February 2001; it spread through the population until at least 2002.

The following year, the lineage appeared in the South Pacific island of New Caledonia, carried there by a mosquito or a person.

The scientists analyzed the genetic sequences of the defective and normal viruses to estimate how long the defective virus had been transmitting in the human population.

"We can see from the gene sequence of the defective version that it's the same lineage, and is a continued propagation of the virus," says Lloyd-Smith.

"From 2001 to 2002, it went from being quite rare to being in all nine people we sampled that year," says Lloyd-Smith. "Everyone sampled who was getting dengue fever was getting the defective version along with the functional virus.

"It rose from being rare to being very common in just one year."

Most surprisingly, say the scientists, the combination of the defective virus with the normal virus was "more fit" than the normal dengue virus alone.

"What we've shown is that this defective virus, which everyone had thought was useless or even detrimental to the fitness of the functional virus, actually appears to have made it better able to spread," Lloyd-Smith says.

Ke calculated that the defective virus makes it at least 10 percent more transmissible. "It was spreading better with its defective cousin tagging along than on its own," says Lloyd-Smith.

It takes two (viruses) to tango

The functional virus and defective virus travel in unison. The two transmit together in an unbroken chain.

"That's not just a matter of getting into the same human or the same mosquito--they need to get into the same cell inside that human or mosquito in order to share their genes, and for the defective version to continue hitchhiking," says Lloyd-Smith.

"We're gaining insights into the cellular biology of how dengue is infecting hosts. It must be the case that frequently there are multiple infections of single cells."

The defective virus appeared one to three years before the major epidemics in 2001 and 2002.

"One could imagine that if you build an understanding of this mechanism, you could measure it, see it coming and potentially get ahead of it," says Lloyd-Smith.

Defective viruses: disease transmitters beyond dengue?

Might defective viruses play a role in the transmission of the flu, measles and other diseases?

"There are a few signs that this phenomenon may be happening in other viruses," Lloyd-Smith says.

"We may be cracking open the book on the possible interactions between normal, functional viruses and the defective ones that people thought were just dead-ends.

"These supposedly meaningless viruses may be having a positive effect--positive for the virus, not for us.

"There's great variation from year to year in dengue epidemics in various locations, but we don't understand why. This is a possible mechanism."

Why would a defective virus increase transmission of a disease?

Lloyd-Smith offers two hypotheses.

One is that the presence of the defective virus with the functional virus in the same cell makes the functional virus replicate better within the cell by an unknown mechanism.

"It might give the virus flexibility in how it expresses its genes, and may make it more fit and better able to reproduce under some circumstances," Lloyd-Smith says.

A second idea is that the defective virus may be interfering with the disease-causing virus, making the disease less intense.

People then have a milder infection, and because they don't feel as sick, they're more likely to go out of their homes and spread the disease.

In conducting the research, Lloyd-Smith and Ke combined genetic sequence analyses with sophisticated mathematical models and bioinformatics.

"We were able to show that this defective virus transmitted in an unbroken chain across this population in Myanmar for a year-and-a-half," Lloyd-Smith says.

"Without gene sequencing, we wouldn't have been able to establish that."

The biologists hope their work will help turn the tide of the next deadly outbreak of dengue in Myanmar--and in other tropical countries around the globe.