Research for Flu

In addition to seasonal influenza, NIAID is also working to prepare for a potential pandemic flu threat. Pandemic flu occurs when a new flu virus strain emerges for which humans have little to no immunity, which enables the virus to spread easily from person-to-person. Flu viruses of this type can sicken millions around the globe.

How is NIAID addressing this critical topic?

NIAID is conducting and supporting research to find new and improved ways to diagnose, treat and prevent influenza infection. This includes working toward a universal flu vaccine that could provide long-lasting protection against multiple strains of influenza, such as those that cause seasonal flu as well as emerging forms capable of causing a global pandemic.

Source: NIAID (NIH)1

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Basic Research

NIAID supports and conducts basic research to learn more about the structure of influenza viruses and how they cause disease (pathogenesis)—an understanding that is critical to the development of new vaccines, therapeutics, and diagnostics.

Source: NIAID (NIH)2

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How Influenza Pandemics Occur

NIAID explains the emergence and potential spread of new influenza viruses.

Source: NIAID (NIH)3

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Influenza Basic Research

The NIAID influenza research program supports basic research to learn more about the structure and pathogenesis of influenza viruses—an understanding that is critical to the development of new vaccines, therapeutics, and diagnostics.

Some basic research focuses on specific questions regarding the biology of the virus, such as how it enters cells, replicates, mutates, evolves into new strains, and induces an immune response. Other projects are more broadly applicable. For example, the NIAID Influenza Genome Sequencing Project is a collaborative effort to obtain the complete genetic sequences of thousands of human and avian influenza strains. NIAID is rapidly making the sequence information publicly available, giving researchers genomic knowledge that may lead to the development of new and improved public health countermeasures. As of November 2011, more than 7,600 human and avian isolates have been completely sequenced and made publicly available.

NIAID also supports the research community by developing new animal models for the preclinical evaluation of vaccine and therapeutic candidates, and provides researchers with important biological resources, such as microarrays, clones, peptides, and reagents.

In NIAID in-house laboratories, researchers are studying the pathogenesis, immunogenicity, transmissibility, and genetic variability of influenza viruses. They are also investigating host immune responses to flu viruses in animal models and in humans and developing vaccines to prevent influenza, especially strains with pandemic potential. For more information on these studies, see Influenza Research in NIAID Labs.

Source: NIAID (NIH)4

Treatment Research for Flu

Treatment

NIAID supports research on influenza therapeutics to develop new drugs, determine effective drug combinations, and examine the mechanisms behind emerging drug resistance. This includes the support of innovative technologies used to design drugs that target specific viral proteins and cellular processes.

Source: NIAID (NIH)5

Research for Flu

Amantadine: A New View of the Flu

by Kirstie Saltsman, NIGMS

If you've ever gotten the flu, you know that we don't have many drugs to treat it. New information from scientists studying one antiflu medicine, amantadine, may pave the way for designing more such drugs.

Biophysicists Mei Hong at Iowa State University and William DeGrado at the University of Pennsylvania discovered how amantadine interacts with a flu protein called M2. This protein launches infection by creating a channel between the flu virus and a healthy cell.

When the researchers determined the detailed, 3-D structure of amantadine bound to M2, they revealed that the drug plugs this channel, preventing infection. They also noticed that amantadine fits loosely inside M2, possibly leaving room for altered versions of the protein to wiggle free and go on to infect a cell. If virus particles containing this version of M2 multiplied, they could lead to a drug-resistant strain.

Already, many strains of the flu resist treatment by amantadine. The biophysicists think that designing drugs that fit into M2 more tightly than amantadine does could provide an effective treatment for the flu that is more difficult for the virus to resist.

Source: MedLinePlus Magazine (NIH)6

Prevention Research for Flu

Antibodies Protect Against Range of Flu Viruses

Scientists isolated antibodies that protect mice against several deadly flu viruses. The accomplishment is a step toward a flu vaccine that can protect against multiple viral strains for several years.

Flu is caused by influenza viruses, which infect the nose, throat and lungs. These viruses constantly change, or mutate. Researchers need to reformulate the flu vaccine each year to match new strains. If a vaccine could prompt the body to make antibodies that latch onto unchanging parts of the virus, it might provide long-lasting protection.

NIH-funded researchers previously isolated antibodies that target a wide range of influenza “type A” viruses. Type A viruses are responsible for avian flu, the 1918 pandemic flu and seasonal flu.

In the new study, scientists took a similar approach to find antibodies that neutralize influenza “type B” viruses. Influenza B viruses have received less attention. They’re less likely to cause worldwide outbreaks. But they can cause seasonal flu.

Researchers collected and tested antibodies from people recently vaccinated for seasonal flu. The scientists identified 3 antibodies that latched onto a specific region on different influenza B viruses. One of these 3 also bound type A viruses.

All 3 antibodies protected mice from deadly influenza B viruses. The broader-binding one also guarded against lethal doses of 2 types of influenza A viruses.

“To develop a truly universal flu vaccine or therapy, one needs to be able to provide protection against influenza A and influenza B viruses,” says one of the head authors, Dr. Ian A. Wilson of the Scripps Research Institute. “With this report, we now have broadly neutralizing antibodies against both.”

Source: NIH News in Health (NIH)7

Vaccine Research for Flu

To make effective flu vaccines, researchers pay close attention to how and when the flu virus changes. Dr. Derek J. Smith, an NIH-funded researcher from the University of Cambridge in England, recently developed a new technique, called antigenic cartography, that will help guide vaccine development. It involves testing how strongly thousands of flu strains attach to various human antibodies. This information is then compared to a world map to trace how flu viruses evolve and spread throughout the year.

Smith’s team has learned that the most common type of flu starts a predictable, yearly journey in East and Southeast Asia, then travels around the world and ends up in South America. In addition to improving the effectiveness of the flu vaccine, Smith says his method may help scientists develop vaccines against some of the world’s craftiest and deadliest viruses. “Antigenic cartography should be applicable to other infectious diseases caused by pathogens that change over time, such as hepatitis C, HIV and malaria,” he says.

Source: NIH News in Health (NIH)8

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Vaccines

Developing new and improved influenza vaccines as well as a universal flu vaccine are high priorities for NIAID. Specifically, NIAID conducts and supports research to find innovative technologies to improve vaccine production flexibility; new more broadly protective flu vaccines; create vaccines that are effective against newly emerging influenza viruses; develop adjuvants to boost vaccine results; and create a universal flu vaccine effective against multiple influenza strains.

Source: NIAID (NIH)9

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Influenza Vaccines

Developing new and improved vaccines is a high priority for NIAID. The NIAID influenza vaccine research program supports activities on

  • Innovative technologies to improve production flexibility
  • New, more broadly protective vaccines
  • Vaccines effective against newly emerging influenza viruses
  • Adjuvant development, from early discovery to clinical evaluation
  • Safety and efficacy in special populations

Source: NIAID (NIH)10

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Clinical Studies: Critical Tools to Evaluate Vaccines and Treatments

The Vaccine and Treatment Evaluation Units (VTEUs), supported by the NIAID Division of Microbiology and Infectious Diseases since the 1960s, comprise a consortium of academic centers and organizations that provide a ready resource for conducting clinical trials to evaluate promising vaccines and treatments for infectious diseases.

The VTEUs conduct a broad range of studies including Phase I, Phase II, Phase III, and Phase IV clinical trials of bacterial, viral, and parasitic vaccines, therapeutics, and other biologics and drugs as preventive and therapeutic measures against infectious diseases in people of all ages and risk categories. The VTEUs can also undertake a variety of studies that support product development such as evaluations of novel investigational product delivery systems and reevaluation of current vaccine formulations and schedules of delivery.

Source: NIAID (NIH)11

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In the United States, NIAID laboratories are developing novel vaccine candidates for seasonal influenza viruses and for avian strains with pandemic potential. In late 2006, the NIAID Vaccine Research Center initiated the first human trial of an investigational DNA vaccine against the H5N1 avian influenza virus, a strain that has infected and continues to threaten humans. In addition, researchers in the NIAID Laboratory of Infectious Diseases are working with MedImmune to generate candidate live-attenuated vaccines for a broad range of influenza subtypes with pandemic potential. To date, five of these vaccine candidates have advanced to Phase I clinical trials.

Source: NIAID (NIH)12

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The Southeast Asia Influenza Clinical Research Network (SEA ICRN), co-supported by NIAID and the Wellcome Trust, brings together hospitals and institutions in Indonesia, Singapore, Thailand, the United Kingdom, the United States, and Vietnam to advance scientific knowledge and clinical management of human influenza caused by avian or human viruses. SEA ICRN studies aim to improve patient care and to help inform public health policy on influenza treatment. The network also works with national ministries of health and other authorities to facilitate the sharing of samples of influenza viruses for research purposes.

More information on Vaccine and Treatment Evaluation Units (VTEUs) and Influenza Research in NIAID Labs.

Source: NIAID (NIH)13

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Vaccine Technologies

NIAID supports research on current and new vaccine technologies to facilitate the development of innovative influenza vaccine production platforms.

Source: NIAID (NIH)14

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A live, attenuated influenza vaccine, FluMist, was licensed by MedImmune, Inc., which was developed by LID with participation of extramural NIAID.

Vaccines against potential pandemic influenza strains have been developed in collaboration with Medimmune and have been tested in clinical trials.

Source: NIAID (NIH)15

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A live, attenuated human metapneumovirus vaccine is being tested in a clinical trial.

Source: NIAID (NIH)16

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A human volunteer influenza challenge model has been developed for testing vaccines, immunotherapeutics, and antivirals in clinical trials.

Source: NIAID (NIH)17

Vaccine Research for Flu

Universal Flu Vaccine: Closing In on a Universal Flu Vaccine

Scientists developed a way to generate antibodies that attack many strains of influenza viruses in animals. The success moves researchers a step closer to a universal flu vaccine—one that protects against multiple viral strains for several years.

Each year influenza, or flu, kills about 36,000 people nationwide. Researchers need to reformulate the vaccine each flu season because the viruses continuously change. A universal flu vaccine would block many viral strains for years and greatly control the spread of influenza.

NIH researchers were able to develop a vaccine that protects against multiple strains of the flu subtype called H1N1. The vaccine includes a piece of DNA that makes a specific viral protein. They vaccinated mice, ferrets and monkeys. Some of the animals later received a booster shot of a seasonal flu vaccine.

Animals given both the DNA and the boost vaccines produced antibodies that blocked several H1N1 strains. The antibodies also blocked other flu subtypes, including H5N1.

The scientists next tested to see if the vaccine could protect animals from infection. After getting the boost, 20 mice were exposed to the deadly 1934 flu virus, and 80% survived. Mice receiving DNA only or seasonal flu vaccine only all died. Ferrets who got the DNA-boost vaccine were also protected from infection.

“This significant advance lays the groundwork for the development of a vaccine to provide long-lasting protection against any strain of influenza,” says Dr. Anthony S. Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases.

Source: NIH News in Health (NIH)18

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Universal Flu Vaccine: Universal Flu Vaccine

Scientists at NIAID are working to develop a universal influenza vaccine, so-called because it could confer decades-long protection from any flu virus strain. In recent experiments with mice, ferrets and monkeys, researchers at the NIAID Vaccine Research Center used a two-step immunization approach to elicit antibodies that attacked a variety of influenza virus strains. For more information, see the NIAID news release.

Source: NIAID (NIH)19

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Universal Flu Vaccine: Scientists have been working for years on a universal flu vaccine, or a vaccine that confers protection against all influenza viruses, including unrelated subtypes that infect animals and can be transmitted to humans.

One possible approach is to create a vaccine that would elicit antibodies targeting a different part of the HA glycoprotein: the stem. Unlike the head, the HA stem is less likely to mutate and remains consistent across strains of flu within a particular hemagglutinin group. If this type of immunity can be elicited, then in theory, a vaccinated person could be protected against future seasonal strains of influenza virus and have at least partial protection against future pandemic strains.

Scientists from the Vaccine Research Center and the Laboratory of Infectious Diseases at NIAID, part of the National Institutes of Health, developed a nanoparticle vaccine with a stabilized HA stem from an H1N1 influenza virus. The vaccine lacks the HA head region to more effectively stimulate antibodies that hitch themselves to the stem.

Results

Investigators immunized mice and ferrets with the experimental vaccine based on sequences from H1 and subsequently challenged the animals with a lethal dose of H5N1 influenza. The vaccine elicited cross-reactive antibodies that completely protected mice and partially protected ferrets against significant disease. It is important to note that the vaccine was created from an H1 HA stem but elicited protection against a different HA subtype (H5) (heterosubtypic protection). While the vaccine did not elicit broadly neutralizing antibodies, protection was shown to be antibody-mediated. Investigators injected antibodies from the immunized mice into non-immunized mice, and protected mice against a lethal challenge with H5N1 influenza. This confirms that the antibodies served to protect the mice. Together, the results provide proof-of-concept that a vaccine that elicits antibodies that target the HA stem can offer broad protection against diverse influenza strains.

Next Steps

Moving forward, investigators may make additional refinements to the vaccine to improve its ability to elicit cross-reactive neutralizing antibodies and binding antibodies. In addition, they will work on a similar approach to protect against viruses with group 2 hemagglutinins. Investigators will also work toward a Phase 1 clinical trial to test the vaccine for safety and immunogenicity in humans. If both are demonstrated, this vaccine concept could move into larger-scale efficacy studies.

Source: NIAID (NIH)20

Diagnostic Research for Flu

Diagnosis

As the risk of a flu pandemic increases, healthcare professionals must be able to quickly distinguish one flu strain from another. Therefore, NIAID supports research to design diagnostics that are faster, more accurate, more cost-effective, and more portable.

Source: NIAID (NIH)21

Causal Research for Flu

Influenza: Get the (Antigenic) Drift

Have you ever wondered why you need a flu vaccination each year? NIAID explains the ever-changing nature of influenza viruses.

Source: NIAID (NIH)22

Genetics Research for Flu

IFIH1 gene mutation: Rare Gene Mutation May Have Link to Common Cold

COLDS SEEM HARDER to escape as the temperature drops and people spend more time indoors. They are also not well understood by doctors and scientists. Recently though, NIH-supported research found a new piece of information about this common infection.

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) identified a rare genetic mutation earlier this year. It can result in a person being more prone to infection by human rhinoviruses (HRVs), the main cause of the common cold. The study looked at the case of a young child who had respiratory infections, including colds, influenza, and bacterial pneumonia, within only a few weeks of birth. The genetic analysis of the child found a mutation in the IFIH1 gene. The gene mutation created problems with proteins in her respiratory tract.

“The human immune response to common cold viruses is poorly understood,” said NIAID Director Anthony S. Fauci, M.D. “By investigating this unique case, our researchers not only helped this child but also helped answer some important scientific questions about these widespread infections that affect nearly everyone.”

Researchers then analyzed a database of more than 60,000 volunteers’ genomes. While the genetic mutation was rare, they found multiple variations in the IFIH1 gene that could lead to these dysfunctional proteins in the respiratory tract.

Insights from the study may lead to new strategies for treating patients with severe complications from colds.

SOURCE: NIH Research Matters

Source: MedLinePlus Magazine (NIH)23

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References

  1. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza
  2. ibid.
  3. ibid.
  4. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza-basic-research
  5. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza
  6. Source: MedLinePlus Magazine (NIH): medlineplus.gov/ magazine/ issues/ summer12/ articles/ summer12pg14-15.html
  7. Source: NIH News in Health (NIH): newsinhealth.nih.gov/ issue/ oct2012/ capsule1
  8. Source: NIH News in Health (NIH): newsinhealth.nih.gov/ 2008/ August/ feature1.htm
  9. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza
  10. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza-vaccines
  11. ibid.
  12. ibid.
  13. ibid.
  14. ibid.
  15. Source: NIAID (NIH): niaid.nih.gov/ research/ lab-infectious-diseases
  16. ibid.
  17. ibid.
  18. Source: NIH News in Health (NIH): newsinhealth.nih.gov/ issue/ sep2010/ capsule2
  19. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza-vaccines
  20. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ niaid-researchers-advance-development-universal-flu-vaccine
  21. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ influenza
  22. ibid.
  23. Source: MedLinePlus Magazine (NIH): medlineplus.gov/ magazine/ issues/ fall17/ articles/ fall17pg29.html

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