Nature: Animal Testing Of Drug Combo Shows Potential For Treating MERS

Coronavirus – Credit CDC PHIL

 

 

# 7743

 

One of the more worrisome aspects of the recent emergence of MERS coronavirus has been the lack of a specific and effective treatment.  Unlike influenza, there are currently no coronavirus-specific antivirals available.

 

Treatment has basically been supportive (e.g. fluids, vasopressors, ventilators and/or ECMO, dialysis, and antibiotics for secondary infections). 

 

Today, in a letter that appears in Nature Medicine, we learn that a drug combination (Interferon-α2b & ribavirin) – which showed promise earlier in the year in in-vitro experiments -  `reduces virus replication, moderates the host response, and improves the clinical outcome’ of rhesus macaques experimentally infected with the MERS coronavirus.

 

While welcome news, a few caveats are in order.

 

• First, the macaque model is not a perfect substitute for humans, as they tend not to be as severely impacted by the MERS virus. 
• Second, treatment was initiated 8 hours post infection, which is an earlier pharmacological intervention than most humans could hope to see. 
• And third, most severe human infections have been seen in people with co-morbidities like COPD, cancer, diabetes, asthma . . . variables this study does not attempt to replicate.

 

Still, this has to be seen as progress. I’ve a link to the Abstract, a brief announcement from NIAID, then a link to Helen Branswell’s article on this announcement.

 

Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques

Darryl Falzarano, Emmie de Wit, Angela L Rasmussen, Friederike Feldmann, Atsushi Okumura,Dana P Scott, Doug Brining, Trenton Bushmaker,  Cynthia Martellaro, Laura Baseler, Arndt G Benecke, Michael G Katze, Vincent J Munster& Heinz Feldmann

ABSTRACT (Excerpt)

The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro⁶; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs.

 

Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.

From NIAID:

Sunday, September 8, 2013

MERS-CoV Treatment Effective in Monkeys, NIH Study Finds

WHAT:

National Institutes of Health (NIH) scientists report that a combination of two licensed antiviral drugs reduces virus replication and improves clinical outcome in a recently developed monkey model of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Their study, which appears as a letter in the Sept. 8 edition of Nature Medicine, expands on work published in April showing that a combination of ribavirin and interferon-alpha 2b stops MERS-CoV from replicating in cell culture. Both antivirals are routinely used together to treat viral diseases such as hepatitis C.

 

In the latest study, investigators at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) infected six rhesus macaques with MERS-CoV and, eight hours later, treated half of them with the two-drug regimen. Compared to the untreated animals, the treatment group showed no breathing difficulties and only minimal X-ray evidence of pneumonia. The treated animals also had lower amounts of virus and less severe tissue damage in the lungs.

 

As of Aug. 30, 2013, the World Health Organization has reported 108 human cases of MERS-CoV infection, including 50 deaths. Given the current lack of treatment options, the authors of this study conclude that combined ribavirin and interferon-alpha 2b therapy should be considered as an early intervention. 

(Continue . . . )

And finally, from Helen Branswell, a detailed and informative report, with comments from Matthew Frieman, Professor of Virology at the University of Maryland medical school in Baltimore.

 

Drug combo helps reduce MERS virus in animals: study

Helen Branswell, The Canadian Press
Published Sunday, September 8, 2013 1:16PM EDT

TORONTO -- New research is adding weight to the idea that a combination of existing drugs may help some patients infected with the new MERS coronavirus.

 

The findings could prove to be important because there is no vaccine to prevent the infection and no drugs specifically designed to mitigate the damage it does in severe cases.

 

Infections with the new virus continue to pile up, particularly in Saudi Arabia.

 

(Continue . . . )

NIH Statement On Lifting Of The H5N1 Research Moratorium

 

# 6883

 

 

Just over a year ago, in response to safety concerns raised by biosecurity experts over certain types of H5N1 research, a group of researchers proposed a temporary (60 day) moratorium on their work. 

 

After more than a year, that self-imposed moratorium was lifted earlier this week (see Scientists Declare End To H5N1 Research Moratorium).

 

Here in the United States, the NIH has yet to put the finishing touches on their framework policies for H5N1 research, and so research here won’t restart immediately.

 

Today, the directors of the NIH and NIAID released a joint statement, indicating that decisions should be forthcoming in the next few weeks.

 

 

Statement of Drs. Collins and Fauci concerning intention to lift moratorium

January 25, 2013

One year ago, scientists in the H5N1 influenza research community announced that they would voluntarily suspend certain “gain-of-function” experiments involving highly pathogenic avian influenza (HPAI) H5N1 viruses pending a broad international dialogue about the future direction of this research.

 

That dialogue — which has included experts in the life sciences, public health, biosecurity, biosafety, law, and science policy communities — has been highly productive, with numerous meetings and publications helping to clarify the most critical issues associated with this type of research.

 

Countries where this research is (or might be) conducted have had the opportunity to review their policies and parameters for funding, conducting, and communicating about this research. In this context, the H5N1 influenza research community has announced their intention and support for resuming their research in those countries with final guidelines in place.

 

The Department of Health and Human Services (HHS) has worked in a transparent and collaborative fashion to develop a framework for reviewing funding decisions regarding research that might increase mammalian transmission of HPAI H5N1 viruses by respiratory droplets. We anticipate that the final framework for HHS funding decisions regarding HPAI H5N1 gain-of-function experiments will be complete in the next several weeks. In the meantime, U.S.-funded researchers (both those working in the United States, including those in government laboratories, as well as those working overseas) have agreed not to resume these types of HPAI H5N1 gain-of-function experiments pending finalization of the HHS Framework.

 

Understanding how influenza viruses become human pandemic threats is vitally important to global health preparedness. We applaud the international H5N1 influenza research community for the spirit in which they instituted this extended “pause” on their work, which has provided time for thoughtful consideration of its implications.

Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health

Anthony S. Fauci, M.D.
Director, National Institute of Allergy and Infectious Diseases
National Institutes of Health

ECDC Influenza Virus Characterization

# 6784

 

The only constant with influenza viruses is their ability to change over time. Since immune systems can learn to recognize and defeat previously seen viral infections, they would soon run out of susceptible hosts if they could not continually evolve.

 

Most of the time, these changes are incremental, and are due to a process called Antigenic drift. Drift comes about due to replication errors that are common with single-strand RNA viruses.

 

Over time these minor changes can accumulate to the point that previously infected immune systems will fail to recognize it, giving the virus a fresh supply of hosts. 

 

NIAID has a nice 3-minute video illustrating the process, which you can view on their Youtube Channel or in the box below.

 

 

 

So, while we talk about seasonal A/H3N2 or A/H1N109 as if they are single entities, in truth, there are a good many minor variations on each theme circulating around the world.

 

Within each strain, we can see numerous `clades’, or genetically distinct groups.  We watch the formation, and progress of these clades carefully, since they may eventually require a change in the flu vaccine’s formulation.

 

Roughly once a month the ECDC releases an influenza virus characterization report, providing laboratory analysis of recently collected flu virus samples across Europe. Collection dates only extend through week 39, but this latest ECDC report indicates continued diversity among the viruses in circulation.

 

The vast majority of flu viruses identified (68%) were of the type A/H3N2. Relatively few A/H1N1 viruses were collected.

 

Among the influenza B viruses received, samples were pretty evenly divided between the Victoria lineage (included in last year’s vaccine) and the Yamagata lineage (part of this year’s vaccine).

 

 

Here’s the link to their report, and the abstract.

 

Influenza virus characterisation - Summary Europe, November 2012

Surveillance reports - 14 Dec 2012

Available as PDF in the following languages:

 

ABSTRACT

During the 2011/2012 season, A(H1N1)pdm09, A(H3N2) and B/Victoria and B/Yamagata lineage influenza viruses, with collection dates between 1 January and 30 September 2012 (weeks 1–39), have been detected in ECDC-affiliated countries.

• Type A viruses predominated over type B.
• A(H3N2) viruses predominated over A(H1N1)pdm09 viruses.
• A(H1N1)pdm09 viruses continued to show genetic drift from the vaccine virus, A/California/07/2009, but the vast majority remained antigenically similar to it.
• Antigenic drift of A(H3N2) viruses compared to the A/Perth/16/2209 vaccine virus resulted in a recommendation to change to an A/Victoria/361/2011-like component for the 2012/2013 influenza season.
• B/Victoria lineage viruses fell within the B/Brisbane/60/2008 genetic clade and were antigenically similar to reference cell-propagated viruses of the B/Brisbane/60/2008 genetic clade.
• Recent B/Yamagata-lineage viruses fell into two genetic clades in approximately equal proportions: clade 3 represented by the recommended vaccine component for the 2012/2013 influenza season, B/Wisconsin/1/2010, and clade 2 represented by B/Estonia/55669/2012. Viruses in each clade are antigenically distinguishable.

 

 

The split between clade 2 and clade 3 of the Yamagata B virus lineage bears watching, and A/H3N2 shows the most variety with samples falling into 5 distinct genetic groups.

 

The good news, despite this growing diversity among flu viruses, is that the majority of those collected in Europe through week 39 still appear antigenically similar to this year’s vaccine strains.

NIAID Video: Tracking Ebola In The Congo

 

 

# 6601

 

Once again, Ebola has been in the news this summer with outbreaks both in Uganda (see here & here) and the Democratic Republic of The Congo (see here and here).

 

While the Uganda outbreak appears to be over, the DRC outbreak continues (see Crof’s recent report DR Congo: Ebola toll rises to 36).

 

Today the National Institute of Allergy and Infectious Diseases (NIAID) has posted a short (3 minute) video on their Youtube Channel that provides a fascinating look at the attempts of researchers to unravel the secrets of this hemorrhagic virus as they probe deep in the jungle.

 

 

 

Many government agencies maintain a presence on YouTube, where you can find tons of informative videos ranging from short PSAs to podcasts to full length webinars.

 

A few examples include:

 

CDCStreamingHealth

Federal Emergency Management Agency

NIAID

NIH Vodcast Episodes

Public Health Emergency (PHE)

USFoodandDrugAdmin

Health & Human Services

 

And last, but not least, the World Health Organization also maintains a Youtube Channel.

 

World Health Organization

 

Resources well worth checking out.

NIAID Video: How Influenza Pandemics Occur

 

 

 

# 6581

 

NIAID, the National Institute of Allergy and Infectious Diseases, has recently released a 3 1/2 minute video that explains, very nicely, the emergence and potential spread of new influenza viruses.

 

The NIAID Youtube Channel is a terrific resource, with more than 2 dozen informative videos, covering a variety of medical and research topics.

This video is somewhat similar to the NIAID video I highlighted last April (see NIAID Video: Antigenic Drift).

 

Well worth a look.

 

NIAID Video: Antigenic Drift

 

 

# 6288

 

 

NIAID, part of the NIH, has just released a short (3 minute) video that nicely illustrates how flu viruses change antigenically over time, and eventually mutate so that the current flu vaccine no long is effective.

 

 

 

As the seasonal H3N2 virus that has been covered in the flu vaccine over the past 3 years has begun to accumulate changes like the ones discussed in this video, in the fall a new H3N2 strain will be incorporated in the flu shot.

 

There are currently 18 videos on the NIAID Youtube site, and links to others on other channels.

Well worth taking a look.

NIH: Any Combo Of Prime-Boost Flu Vaccine Protects Toddlers

 

 

# 5759

 

 

Children 6 months of age or older, who have never received a flu vaccine before, are recommended to receive a priming vaccine and a booster – one month apart – the first time.

 

For children over the age of 6 months, the TIV flu shot may be used, and for healthy children 24 months or older, the LAIV nasal spray may be substituted.

 

Until now, a lack of clinical studies have left some doubts as to whether a combination of the TIV flu shot and LAIV nasal vaccine would perform equally as well.

 

From the NIH today, we’ve a report on clinical trials conducted at Saint Louis University, along with investigators at Vanderbilt University in Nashville, and the Cincinnati Children's Hospital – funded by NIAID -that looks at the immune responses in toddlers who received one of four different flu shot combinations:

 

• two injections of a TIV vaccine
• two LAIV nasal spray vaccines
• A LAIV nasal spray followed by a TIV shot
• a TIV shot followed by the LAIV nasal spray

 

The good news . . . particularly for children at least 2 years of age with an aversion to needles . . . is that two sprays of the LAIV vaccine appear to produce the same level of antibody response as two flu shots.

 

And when a child receives at least one of their vaccines via the LAIV nasal spray, they produced a wider array of immune T cells, which may help protect against other flu strains.

 

This from NIH News.

 

 

Any Prime-Boost Mix of Injected or Spray Flu Vaccine Shields Toddlers

Broadest Immune Response from Nasal Spray Vaccine, NIH-Funded Study Finds

Children younger than 3 years old receive the same protective antibody response from the recommended two doses of licensed seasonal influenza vaccines regardless of whether the two doses are injected by needle, inhaled through a nasal spray or provided through one dose of each in any order, according to researchers funded by the National Institutes of Health. Doctors usually give young children two matching vaccines, and one goal of the study was to determine whether giving two different types of vaccines works just as well.

Daniel Hoft, M.D., Ph.D., conducted a trial of influenza vaccines in young children.
Credit: Saint Louis University

 

<SNIP>

 

The researchers found that all four dosing patterns were safe and induced similar levels of protective antibodies. However, when the investigators looked at responses from the T-cell arm of the immune system, a striking difference emerged. They could not detect influenza-specific T cells in children who received only TIV, according to Dr. Hoft. But, he added, “The kids who received at least one dose of LAIV nasal spray vaccine produced significant amounts of three important T-cell subtypes that are likely to confer additional protection beyond that afforded by antibodies alone.”

 

Previous studies have demonstrated that children are better protected against influenza infection and disease by LAIV than by TIV, Dr. Hoft noted. However, few studies have examined the T-cell responses elicited by LAIV when given to very young children who have little prior natural exposure to seasonal influenza viruses. Distinguishing T-cell responses due to vaccination from those arising after natural exposure to influenza virus becomes more difficult as a child ages, he explained. Because the children in the trial were all younger than 3 years old, the researchers could be confident that spikes in levels of the three T-cell subtypes they detected were likely due to the vaccinations.

 

Children who received only one dose of LAIV had T-cell responses similar to those who received two, and the order of vaccine types did not make a significant difference in the size of the T-cell response. However, because LAIV has sometimes been associated with increased incidence of wheezing in the youngest recipients, the results of this trial suggest that the best regimen for kids younger than 24 months may be TIV followed by LAIV, Dr. Hoft said. Larger clinical trials are required to confirm the safety and efficacy of such an approach, he added. 

 

(Continue . . . )

 

The results are published today in the Journal of Infectious Diseases, and the abstract may be read at:

 

Live and Inactivated Influenza Vaccines Induce Similar Humoral Responses, but Only Live Vaccines Induce Diverse T-Cell Responses in Young Children

Daniel F. Hoft, Elizabeth Babusis, Shewangizaw Worku, Charles T. Spencer, Kathleen Lottenbach, Steven M. Truscott, Getahun Abate, Isaac G. Sakala, Kathryn M. Edwards, C. Buddy Creech, Michael A. Gerber, David I. Bernstein, Frances Newman, Irene Graham, Edwin L. Anderson and Robert B. Belshe

NIH: Phase I Trials Of A Dengue Vaccine

 

 

 

# 4797

 

 

Dengue Fever has received a fair amount of coverage here in this blog, and has become a major component of Crofsblog over the past few years. 

 

Mainstream media coverage of this disease has grown in recent months as well, in the wake of the emergence of a handful of Dengue cases in Key West, Florida.

 

The global burden of Dengue is immense, with 2.5 billion people – two fifths of the world's population – at risk of infection.

 

The World Health Organization  estimates there may be as many as 50 million dengue infections each year.

 

Currently, there is no specific treatment, and no vaccine available.   But that may be changing.

 

The NIH has announced the start of Phase I human clinical trials of a tetravalent Dengue vaccine developed by researchers at NIAID, and undergoing study at the Johns Hopkins Bloomberg School of Public Health.

 

Two other vaccine candidates are also under study.  Even if these trials prove successful, a commercially available Dengue vaccine is still a number of years away.

 

Excepts from the NIH press release are below.  Follow the link to read the entire report.

 

 

FOR IMMEDIATE RELEASE
Monday, August 9, 2010

Human Clinical Trial of NIH-developed Dengue Vaccine Begins

After more than a decade of development at the National Institutes of Health, a vaccine to prevent infection by the mosquito-borne dengue virus has begun human clinical testing. The vaccine was developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and is undergoing clinical study at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

 

<BIG SNIP>

 

In this Phase I trial, study volunteers who have never been exposed to dengue were randomly assigned to receive one of the candidate tetravalent vaccine formulations or a placebo. The candidate vaccines are live-attenuated, or created by making the live virus harmless or less virulent.

 

Evaluation of a second candidate combination vaccine has been initiated at the University of Vermont in Burlington, and trials of the third candidate will begin shortly thereafter at Johns Hopkins. These early clinical trials are designed to test the vaccine’s safety and ability to stimulate immune responses in healthy adults ages 18 to 50. After a baseline assessment, participants will receive one dose of the assigned vaccine or placebo. At follow-up study visits over the next six months, the researchers will assess their health and dengue symptoms and collect blood and urine samples for analysis. After determining which tetravalent vaccine is most promising, the researchers will test that candidate in a trial in a new group of volunteers in Brazil, where dengue has become highly prevalent.

 

The next stage of testing, a Phase II trial, will involve more participants and will test for differences in preliminary signs of effectiveness between people who have been exposed to dengue and those who have not, as well as the need for a booster shot within a few months of the initial vaccination. “If everything goes well after that stage, we hope to start the final phase of human testing in three to four years,” says Dr. Durbin.

 

For more information, visit NIAID’s Dengue Fever Web portal.

 

 

For some additional blogs on Dengue in Florida, and the Caribbean, you might wish to visit:

 

Healthmap.org: Charting Dengue’s Progress

Puerto Rico Dengue Update

Making Themselves At Home

ASTMH: Dengue and Insect-Borne EIDs In The US

Dengue Reports From The Caribbean

NIH: Progress Towards A Universal Flu Vaccine

 

 

 

# 4729

 

 

For vaccinologists, coming up with a universal flu shot – one that didn’t have to be reformulated with new antigens every year – is the holy grail.   

 

It would mean that over time you could conceivably inoculate much of the world’s population against influenza, instead of having to `start over’ with that Sisyphean task every year.

 

Like with the Tetanus vaccine, lifelong protection would only require periodic booster shots.

 

While that lofty goal is still a number of years away, researchers at the NIAID have taken a big step towards turning it into reality. 

 

They are working on a two-step process that combines a novel DNA vaccine to prime the immune system followed by a `regular’ flu shot.  

 

The result is an immune response against a wide spectrum of influenza viruses.

 

First excerpts from the NIH press release, then a link to a great summary by Maggie Fox of Reuters.

 

 
Thursday, July 15, 2010
2 p.m. EDT

 

NIH Scientists Advance Universal Flu Vaccine

A universal influenza vaccine — so-called because it could potentially provide protection from all flu strains for decades — may become a reality because of research led by scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

 

In experiments with mice, ferrets and monkeys, the investigators used a two-step immunization approach to elicit infection-fighting antibodies that attacked a diverse array of influenza virus strains. Current flu vaccines do not generate such broadly neutralizing antibodies, so they must be re-formulated annually to match the predominant virus strains circulating each year.

 

The research, led by NIAID scientist Gary J. Nabel, M.D., Ph.D., appears online ahead of print July 15 in Science Express.

 

"Generating broadly neutralizing antibodies to multiple strains of influenza in animals through vaccination is an important milestone in the quest for a universal influenza vaccine," says NIAID Director Anthony S. Fauci, M.D. "This significant advance lays the groundwork for the development of a vaccine to provide long-lasting protection against any strain of influenza. A durable and effective universal influenza vaccine would have enormous ramifications for the control of influenza, a disease that claims an estimated 250,000 to 500,000 lives annually, including an average of 36,000 in the United States."

 

In parallel experiments with mice, ferrets and monkeys, Dr. Nabel and his colleagues first primed the animals’ immune systems with a vaccine made from DNA encoding the influenza virus hemagglutinin (HA) surface protein. After being primed with DNA vaccine, the mice and ferrets received a booster dose of the 2006-2007 seasonal influenza vaccine or a vaccine made from a weakened cold virus (an adenovirus) containing HA flu protein. Monkeys were boosted with the seasonal flu vaccine only.

 

This prime-boost vaccine stimulated an immune response to the stem of the lollipop-shaped hemagglutinin of influenza virus. Unlike HA’s head—which mutates readily, allowing the virus to become unrecognizable to antibodies—the stem varies relatively little from strain to strain. In principle, Dr. Nabel explains, antibodies generated against the stem of HA should be able to recognize and neutralize multiple flu strains.

 

Although the DNA in the priming vaccine was derived from a 1999 circulating flu virus, all the animals made antibodies capable of neutralizing virus strains from several other years. Mice and ferrets produced antibodies not only against virus strains dating from before 1999, including a strain that emerged in 1934, but also against strains that emerged in 2006 and 2007.

 

Moreover, although the prime-boost vaccines were both made from H1 subtypes of influenza A virus, the antibodies they generated neutralized other influenza subtypes, including H5N1 (avian influenza) virus. This indicates that a prime-boost strategy potentially could confer immunity to many or all subtypes of influenza A, says Dr. Nabel.

 

In another set of experiments, the scientists measured how well the prime-boost vaccine protected mice and ferrets from infection with deadly levels of flu virus. Three weeks after receiving the boost, 20 mice were exposed to high levels of 1934 flu virus, and 80 percent survived. Mice receiving DNA only, seasonal flu vaccine only or a sham prime-boost vaccine all died.

 

The researchers saw similar results when they tested several prime-boost combinations in ferrets, which are considered a good animal model for predicting flu vaccine efficacy in humans. All four ferrets that received a DNA prime-seasonal boost were protected from infection with a 2007 virus strain, while all six ferrets that received the DNA prime-cold virus boost combination were protected from the 1934 influenza virus.

(Continue . . . )

 

 

From the always terrific Maggie Fox, Science and Health editor for Reuters, we get an excellent overview of the story.  

 

Follow the link to read it in its entirety.

 

Two-step vaccine may offer "universal" flu jab

By Maggie Fox, Health and Science Editor

WASHINGTON | Thu Jul 15, 2010 7:20pm EDT

WASHINGTON (Reuters) - A two-step flu vaccine using DNA to "prime" the immune system and then a traditional seasonal influenza vaccine may be able to protect against all strains of the virus -- providing a long-sought "universal" flu vaccine, U.S. researchers said on Thursday.

(Continue . . .)

 

 

One of the great benefits the world is reaping from our  concerns over a future severe flu pandemic are the advancements in medical and scientific research that has inspired.

 

Ten years ago, despite its deadly toll each year, few scientists were working on influenza. 

 

Today, it is a hot field of research.

 

While the advances above aren’t quite ready for `prime time’, they represent a promising new pathway towards the ultimate goal of a universal vaccine.

NIAID: 2009 H1N1 Vaccine Protects Mice Against 1918 Flu Virus

 

 

# 4949

 

 

For quite some time we’ve recognized that many of those born before – say, 1957 – have some level of immunity against the 2009 H1N1 pandemic virus.  The belief has been that those who were around in the 1940s and 1950s were exposed to a similar virus.

Last August, we learned of research out of Vanderbilt University, that showed that survivors of the 1918 pandemic still retained antibodies against that virus, and that they were protective against the 2009 pandemic virus.

 

 

Survivors of 1918 Flu Pandemic Immune 90 Years Later

By Steven Reinberg

Monday, August 18, 2008; 12:00 AM

SUNDAY, Aug. 17 (HealthDay News) -- People who lived through the 1918 flu pandemic that killed 50 million worldwide are still producing antibodies to the virus 90 years later, researchers report.

(Continue . . . )

 

 

Now scientists working with mice and the 1918 Spanish Flu virus have discovered that this cross-protection works both ways – that the vaccine developed against the 2009 virus is protective (in mice, anyway) against the Spanish flu virus.

 

While vaccines against the 2007 strain of seasonal H1N1 provided some immunity, unvaccinated mice and mice only vaccinated against H3N2 all died when challenged by the 1918 virus.

Mice vaccinated against the 2009 pandemic H1N1 all survived that challenge. 

 

This press release appears to builds on similar research described in another press release by the NIH last March entitled 1918 and 2009 Pandemic Influenza Viruses Lack a Sugar Topping.

 

Here is the NIAID press release (slightly reformatted for readability)

 

 
NIH-Funded Scientists Find 2009 H1N1 Pandemic Influenza Vaccine Protects Mice from 1918 Influenza Virus

WHAT:  
Mice injected with a 2009 H1N1 pandemic influenza vaccine and then exposed to high levels of the virus responsible for the 1918 influenza pandemic do not get sick or die, report scientists funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

 

The new vaccine works against the old virus because the 1918 and the 2009 strains of H1N1 influenza share features that allow vaccine-generated antibodies to recognize both viruses.

 

To learn more, similar challenge studies need to be conducted in other animals, including monkeys, but the investigators say their results suggest people who are vaccinated against 2009 H1N1 influenza or were exposed to the virus could have similarly cross-protective antibodies against the 1918 strain of H1N1.

 

This finding, they add, should help allay concerns about the potential consequences of an accidental release of the 1918 influenza virus from high-containment laboratories or its possible use as a bioterror weapon.

 

Adolfo Garcia-Sastre, Ph.D., of Mount Sinai School of Medicine, New York, led the research. Groups of mice were exposed to lethal amounts of the 1918 influenza virus 14 or 28 days after receiving a 2009 H1N1 influenza vaccine; a seasonal H3N2 influenza vaccine (not designed to protect against H1N1 virus); or no vaccine.

 

All of the 2009-H1N1-vaccinated mice survived. Unvaccinated mice and mice that received the H3N2 vaccine all died. (A group of mice vaccinated with a seasonal flu vaccine designed to protect against a 2007 strain of H1N1 were mostly protected from lethal challenge; 80 percent of the mice in that group survived.)

 

The researchers also injected mice with blood serum taken from people who had received 2009 H1N1 influenza vaccine. The serum, which contained antibodies against 2009 H1N1 influenza virus, protected the mice from death when they were later exposed to the 1918 H1N1 influenza virus. All the experiments involving the 1918 virus were conducted under biosafety-level-3 conditions.

(Continue . . . )

 

NIH: Rapid Development Of Antiviral Resistance In Two Cases

 

 

# 4464

 

 

Victories over continually evolving pathogens are often fleeting at best.   No sooner do researchers release a new generation of antibiotics or antivirals, than these organisms begin to find ways to work around them.

 

Maryn McKenna’s terrific book Superbug: The Fatal Menace of MRSA goes into great detail about the road to antibiotic resistance, but we are seeing a similar path being followed by antivirals as well.

 

Amantadine managed to remain an effective treatment and/or prophylaxis against influenza A for four decades, although it was used only sparingly for the first 30 years or so.   

 

Overuse of Amantadine, particularly its inclusion into chicken feed during the 1990s to combat bird flu in Asia – has been credited with a dramatic rise in influenza’s resistance to the drug by 2005. 

 

Tamiflu (oseltamivir), released in 1999 proved extremely effective against influenza until 2008, when a resistant version of seasonal H1N1 appeared and quickly spread around the world.   Seasonal H3N2 remained susceptible to the drug. 

 

These two seasonal viruses have been (at least temporarily) replaced by novel H1N1, which fortunately remains sensitive to the drug.   Scientists do worry that over time, novel H1N1 could pick up resistance to Tamiflu as well.

 

Which brings us to a report issued yesterday by the NIH about two patients that developed resistance to Tamiflu, and in one case, to the newly approved peramivir.   

 

FOR IMMEDIATE RELEASE
Friday, March 26, 2010

Media Contact: Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov

Rapid Development of Drug-Resistant 2009 H1N1 Influenza Reported in Two Cases

Reevaluation of Treatment Strategies for Prolonged Infection Urged

Two people with compromised immune systems who became ill with 2009 H1N1 influenza developed drug-resistant strains of virus after less than two weeks on therapy, report doctors from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Doctors who treat prolonged influenza infection should be aware that even a short course of antiviral treatment may lead to drug-resistant virus, say the authors, and clinicians should consider this possibility as they develop initial treatment strategies for their patients who have impaired immune function.

 

Both patients in the new report developed resistance to the key influenza drug oseltamivir (Tamiflu), and one also demonstrated clinical resistance to another antiviral agent, now in experimental testing, intravenous peramivir, note senior authors Matthew J. Memoli, M.D., and Jeffery K. Taubenberger, M.D., Ph.D. This is the first reported case of clinically significant peramivir-resistant 2009 H1N1 illness, say the scientists. The report is scheduled to appear in print on May 1 in Clinical Infectious Diseases and is now online.

 

The people in the current case report had immune limitations due to blood stem cell transplants that occurred several years previously. Both recovered from their influenza infections.

 

“While the emergence of drug-resistant influenza virus is not in itself surprising, these cases demonstrate that resistant strains can emerge after only a brief period of drug therapy,” says NIAID Director Anthony S. Fauci, M.D. “We have a limited number of drugs available for treating influenza and these findings provide additional urgency to efforts to develop antivirals that attack influenza virus in novel ways.”

 

The 2009 H1N1 influenza virus is susceptible to just one of the two available classes of anti-influenza drugs, the neuraminidase inhibitors. Besides oseltamivir, other neuraminidase inhibitors are zanamivir (Relenza), which is inhaled, and the intravenously administered investigational drug peramivir. As the H1N1 influenza pandemic unfolded, laboratory tests of virus strains isolated from patients showed that some strains contained a genetic mutation (the H275Y mutation) that makes the virus less susceptible to some neuraminidase inhibitors.

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Lisa Schnirring at CIDRAP News has more details on this story.

 

 

Researchers report peramivir-resistant H1N1 case

Lisa Schnirring Staff Writer

Mar 26, 2010 (CIDRAP News) – Researchers today sounded two warnings for clinicians who manage pandemic H1N1 patients: that even a short course of oseltamivir (Tamiflu) can lead to antiviral resistance and that patients can develop resistance to peramivir, an alternative to oseltamivir in emergency situations.

 

The warnings come from a case report of two patients published today in an early online edition of Clinical Infectious Diseases (CID). The authors are from the National Institute of Allergy and Infectious Diseases (NIAID) and the US Food and Drug Administration (FDA). The study is scheduled to appear in the May 1 issue of CID.

 

The research team, headed by senior authors Matthew J. Memoli, MD, and Jeffery K. Taubenberger, MD, PhD, said the report details the first clinically significant peramivir-resistant pandemic H1N1 case.

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These are, admittedly, isolated incidents.  

 

And it should be noted that these two cases involved spontaneous resistance forming in immune compromised patients receiving Tamiflu, and are not due to some new Tamiflu/peramivir  resistant strain circulating in the wild.

 

The takeaway message from this report isn’t that these drugs are losing effectiveness, but that resistance can develop quickly in rare instances in some people receiving these medications.  

 

Which is another good reason why getting a flu shot every year is an exceedingly good idea.

 

While not 100% protective, getting the flu shot can significantly reduce your chances of catching the flu.

 

After all, it is better to try to prevent an illness, than to have to treat one.   

PBS: Anatomy Of A Pandemic

 

 

# 4140

 

Two of the finest communicators on influenza that I know of are Dr. Anne Schuchat, the Director of the CDC’s (NCIRD), and Dr. Michael Osterholm, Director of CIDRAP.

 

So I’m extraordinarily pleased that they, along with stellar list of public health officials, historians, writers and advocates are part of a PBS Newshour Documentary on the 2009 H1N1 pandemic.

 

 

 

Next week;  Monday (December 14th)  PBS Newshour will premier a documentary on the 2009 H1N1 pandemic.  

 

And on Tuesday, December 15 at 4 p.m. ET: "PBS NewsHour" will hold an Online Forum with Dr. Anne Schuchat, the Director of the CDC National Center for Immunization and Respiratory Diseases (NCIRD), and Dr. Michael Osterholm, world-renown influenza expert and Director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota. 

 

The Moderator will be Betty Ann Bowser, health correspondent for “PBS NewsHour

 

Today, the documentary’s companion website went online, with video segments, previews, pandemic news, Q&As,  and even a place to ask public health officials questions.

 

PBS describes the documentary it this way:

 

“Anatomy of a Pandemic” will carefully examine the major issues surrounding the 2009 H1N1 influenza virus outbreak, commonly referred to as “swine flu”, using the current pandemic to explore best practices for the U.S. and other world governments when faced with any widespread health emergency.

 

Ray Suarez, senior correspondent for “PBS NewsHour”, will report from the front lines of the effort to combat this outbreak — from federal vaccination headquarters and state command and control centers to big city hospital emergency rooms where the first waves of serious cases will appear.  The program will contextualize the current outbreak with pandemics of the past, including the 1918 influenza pandemic that caused between 50 and 100 million deaths worldwide.

 

“Anatomy of a Pandemic” will focus as well on the science of influenza, including the development and implementation of the current H1N1 vaccine, next generation vaccine techniques, and the quest to create a potential universal vaccine.  Premieres Monday, December 14 at 9 p.m. ET on public broadcsting stations nationwide

 

 

Some of the videos available online (along with transcripts) include:

 

Interview: Anthony Fauci

Fauci, a director at the National Institutes of Health, relates his greatest disease fears, and what health officials are watching for in the future.

Video & Transcript

 

Interview: Barbara Ferrer

Ferrer, head of the Boston Public Health Commission, says minorities and the poor are seeing the worst of H1N1.

Video & Transcript

 

Interview: Anne Schuchat

Schuchat, director of CDC's National Center for Immunization and Respiratory Diseases, talks about the challenges of the H1N1 pandemic.

Video & Transcript

 

Interview: Michael Osterholm

Flu expert Dr. Michael Osterholm grades the U.S. response to the pandemic so far.

Video & Transcript

 

Interview: Barbara Loe Fisher

Fisher, of the National Vaccine Information Center, urges parents to take an active role in learning about vaccines.

Video & Transcript

 

According to the press release:

Experts involved with “Anatomy of a Pandemic” include leading U.S. influenza officials from the CDC and other health organizations, writers and historians. Among those specialists are the following individuals (subject to change):

• Dr. Michael Osterholm, world-renown influenza expert and Director of the Center for Infectious Disease Research and Policy at the University of Minnesota;

• John Barry, the prize-winning and New York Times best-selling author of The Great Influenza, a study of the 1918 pandemic;

• Dr. Jay C. Butler, the Director of the CDC H1N1 Vaccine Task Force;

• Dr. Nancy J. Cox, the Director of the CDC Influenza Division;

• Dr. Anthony S. Fauci, the Director of National Institute of Allergy and Infectious Diseases (NIAID) and the Chief of the Laboratory of Immunoregulation (LIR);

• Dr. Wayne Marasco, a universal vaccine specialist and associate professor with the Department of Medicine, Harvard Medical School and associate professor in Cancer Immunology and AIDS with the Dana-Farber Cancer Institute;

• Dr. Anne Schuchat, the Director of the CDC National Center for Immunization and Respiratory Diseases (NCIRD);

• and Dr. David Sencer, a former director of the CDC who forced to resign after the failure of the 1976 vaccine campaign.

 

Quite a line up.

 

I’ll, of course, remind my readers next week about this broadcast and the online forum the following day, but take the time now to visit the PBS Newshour website and explore.

Study: Protective Immune Memory In Healthy Adults

 

 

# 4022

 

One of the ongoing mysteries surrounding the H1N1 pandemic is why some older adults seem to have limited immunity to this virus, while many younger adults and children do not.

This has obviously sparked a good deal of investigation over the past 6 months, and in recent weeks we’ve seen a number of studies supporting the notion that some older people may have a degree of limited pre-existing immunity to this virus.

 

For some people that may mean they will be able to fight off infection completely, and for others it may mean they suffer lesser symptoms, or recover sooner, than they might otherwise.

None of this is a guarantee, of course.  But the relative risk of infection does seem to go down with age.  

 

 

Last week, in a blog entitled, NEJM: Boomers Have More Immunity I wrote about a short, and pretty straight forward letter to the NEJM, by David N. Fisman, M.D., M.P.H. at the University of Toronto  who wrote about the limited immunity that those over the age of 53 appear to have to the H1N1 pandemic virus.

 

His conclusion?

 

Those born between 1957 and 1975 appear to have less immunity than the boomer generation, but more than those born after 1975. 

 

Older Age and a Reduced Likelihood of 2009 H1N1 Virus Infection

Volume 361:2000-2001 November 12, 2009 Number 20

 

And a month ago, I blogged about Two H1N1 Immunity Studies from the EID Journal, that hypothesized that over time exposure to other circulating influenza strains – or perhaps repeated seasonal flu vaccinations – may have helped to provoke a limited immune response in some people to this novel pandemic strain.

 

Preexisting Immunity to Pandemic (H1N1) 2009
Z. Xing and C.J. Cardona  (186 KB, 5 pages)

 

Serologic Survey of Pandemic (H1N1) 2009 Virus, Guangxi Province, China H. Chen et al.  (155 KB, 4 pages)

 

Today, we get word of another study, this time from La Jolla Institute for Allergy and Immunology, Calif. and NIAID, that finds that older people who have been exposed to previous influenzas may have picked up some limited protective immune memory.

 

 

National Institute of Allergy and
Infectious Diseases (NIAID)
http://www.niaid.nih.gov

FOR IMMEDIATE RELEASE
Monday, Nov. 16, 2009

 
Immune System of Healthy Adults May Be Better Prepared Than Expected to Fight 2009 H1N1 Influenza Virus

WHAT:

A new study shows that molecular similarities exist between the 2009 H1N1 influenza virus and other strains of seasonal H1N1 virus that have been circulating in the population since 1988. These results suggest that healthy adults may have a level of protective immune memory that can blunt the severity of infection caused by the 2009 H1N1 influenza virus.

 

The study team was led by Bjoern Peters, Ph.D., and Alessandro Sette, Ph.D., of La Jolla Institute for Allergy and Immunology, Calif., grantees of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

 

 

The investigators looked at molecular structures known to be recognized by the immune system—called epitopes—on 2009 H1N1 influenza and seasonal H1N1 viruses. Viral epitopes are recognized by immune cells called B and T cells: B cells make antibodies that can bind to viruses, blocking infection, and T cells help to eliminate virus-infected cells.

 

Using data gathered and reviewed from the scientific literature and deposited into the NIAID-supported Immune Epitope Database and Analysis Resource (www.iedb.org), the investigators found that some viral epitopes are identical in both the 2009 and seasonal H1N1 viral strains. Those epitopes that could be recognized by two subsets of T cells, called CD4 and CD8 T cells, are 41 percent and 69 percent identical, respectively. Subsequent experiments using blood samples taken from healthy adults demonstrated that this level of T-cell epitope conservation may provide some protection and lessen flu severity in healthy adults infected with the 2009 H1N1 influenza virus.

 

Analysis of the database also found that among six viral surface epitopes that can bind antibody, thereby preventing infection, only one is conserved between 2009 and seasonal H1N1 viral strains.

 

These results suggest that healthy individuals may have immune memory that recognizes the 2009 H1N1 strain and therefore can mount some measure of an immune attack. The findings also may help explain why the 2009 H1N1 influenza pandemic affects young children more severely than it does healthy older adults and also why two H1N1 vaccinations are needed to protect children ages nine years and under.

ARTICLE:

J Greenbaum et al. Pre-existing immunity against swine-origin H1N1 influenza viruses in the general human populace. Proceedings of National Academy of Sciences. DOI: 10.1073/PNAS.0911580106.

HHS Science Briefing

 

 

# 3935

 

The HHS has just concluded a science briefing held with Dr. Anne Schuchat, Director of of the CDC's National Center for Immunization and Respiratory Diseases and by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and Dr. Bruce Gellin, the director of the National Vaccine Program Office.

 

The purpose of the meeting was to bring us up to date on recent NIAID clinical trials conducted on the H1N1 vaccine involving healthy pregnant women, and healthy children under the age of 10, and to answer reporter’s questions about vaccine safety.

 

With pregnant women, the good news is a single 15 µg vaccine dose provoked a robust immune response in 92% of the subjects tested.  A 30 µg dose was only slightly more effective (96%).

 

Among children under the age of 10, two doses of H1N1 vaccine, given roughly 4 weeks apart, provoked a robust immune response.

 

Children between the ages of 6 and 35 months only saw a robust response after 1 dose 25% of the time, and children aged 3 to 9 years, only 55% of the time.

 

Therefore, the recommendation remains that children under the age of 10 receive two doses of the vaccine. 

 

More details are available from these two press releases, available from the NIAID website.

 

 

Monday, Nov. 2, 2009

Media Contact: NIAID Office of Communications
(301) 402-1663
niaidnews@niaid.nih.gov

Initial Results Show Pregnant Women Mount Strong Immune Response To One Dose of 2009 H1N1 Flu Vaccine

Healthy pregnant women mount a robust immune response following just one dose of 2009 H1N1 influenza vaccine, according to initial results from an ongoing clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health.

 

“For pregnant women, who are among the most vulnerable to serious health problems from 2009 H1N1 infection, these initial results are very reassuring,” says NIAID Director Anthony S. Fauci, M.D.  “The immune responses seen in these healthy pregnant women are comparable to those seen in healthy adults at the same time point after a single vaccination, and the vaccine has been well tolerated.”

 

According to the Centers for Disease Control and Prevention, since the outbreak began last spring, at least 100 pregnant women have been hospitalized in intensive care units in the United States and at the last official count, 28 pregnant women have died.

 

A preliminary analysis of blood samples taken 21 days post-vaccination from a subgroup of 50 pregnant women participating in the trial shows the following:

• In 25 women who received a single 15-microgram dose of the vaccine, the H1N1 flu vaccine elicited an immune response likely to be protective in 92 percent, or 23 of 25, of these women. 
• In 25 women who received a single 30-microgram dose of the vaccine, the H1N1 flu vaccine elicited an immune response likely to be protective in 96 percent, or 24 of 25, of these women.

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November 2, 2009
BULLETIN

 

Updated Results: In Youngest Children, a Second Dose of 2009 H1N1 Influenza Vaccine Elicits Robust Immune Response

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, today announced interim results that show that children nine years of age and younger have a significantly improved immune response when given a second 15-microgram dose of 2009 H1N1 influenza vaccine.

The clinical trial evaluated the immune response of children six months to 17 years of age who received two doses of either 15 or 30 micrograms of 2009 H1N1 influenza vaccine. One of the most important findings from this study is that among children nine years old and younger, the second dose elicited a robust immune response after eight to 10 days, a significant improvement over the immune responses in this age group following only a single dose.

 
These findings support the current recommendation of the Advisory Committee on Immunization Practices (ACIP), which sets U.S. recommendations for all immunizations: To achieve an immune response likely to protect from illness, children nine years of age and younger should receive two 15-microgram doses of 2009 H1N1 vaccine. The trial data also continue to support the recommendation that children ten years of age and older should receive only one 15-microgram dose of vaccine.

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