ARRA IMPACT REPORT:
ARRA Funding Boosts NIH Response to H1N1 Pandemic


Public Health Burden
In the spring of 2009, a novel A (H1N1) influenza strain—2009 H1N1 influenza A—emerged to cause the first influenza pandemic in 41 years. According to the World Health Organization, the 2009 H1N1 pandemic led to more than 10,000 confirmed deaths worldwide. The U.S. Centers for Disease Control and Prevention (CDC) estimated that between 43 million and 89 million cases of 2009 H1N1 influenza and between about 8,870 and 18,300 2009 H1N1-related deaths occurred in the United States between April 2009 and April 10, 2010.1 Younger people between the ages of 10 and 24 seemed to be at higher risk for significant complications from this flu. Although the H1N1 pandemic ended later in 2010, H1N1 and seasonal influenza viruses are now circulating together in many parts of the world. It is likely that the 2009 H1N1 virus will continue to spread for years to come, like a regular seasonal influenza virus.

NIH supports a major research program related to seasonal influenza. After the outbreak of 2009 H1N1 influenza, NIH intensified the implementation of a vigorous research agenda that includes the basic scientific research and clinical trials needed to develop and test pandemic influenza vaccines and therapies. ARRA funds contributed to NIH’s much larger 2009 H1N1 influenza research agenda through the support of some very specific studies such as those described here.

Virus Evolution and Transmission
NIH allocated ARRA funding to support basic research to understand better how influenza viruses are transmitted, replicate, interact with their hosts, stimulate and evade immune responses, and evolve into new strains. Because virus evolution interferes with long-lasting natural or vaccine-induced immunity, new vaccines must be reformulated yearly or as each new strain emerges.

  • Potential Link Between H1N1 Virus Transmission and Viral Form and Structure: In studies in ferrets, researchers found that two viral genes, NA and M (both originating from a Eurasian swine virus that recombined with another virus to form pandemic H1N1), contributed to efficient transmission of the pandemic H1N1 virus (pH1N1) via respiratory droplets by modulating the release of virus particles into the air. NA codes for the neuraminidase protein and M for the M1 and M2 proteins of the virus. Airborne virus correlated with increased viral NA activity and the production of filament-shaped viral particles, suggesting a link between transmission and viral form and structure. This information could be useful in assessing the pandemic potential of future novel influenza viruses.2
  • Insights into Age-Related Differences in Illness and Death During 1918 and 2009 Influenza Pandemics: ARRA funding supported research to understand the age-related differences in illness and death during both the 1918 and 2009 H1N1 influenza pandemics. Scientists compared H1N1 influenza viruses from several decades and found that changes in the viral surface protein hemagglutinin A (HA) occurred between 1947 and 1950 such that people born later lack the cross-protective antibodies observed in people over 60 years of age during the 2009 pandemic. This likely explains the greater degree of illness and death caused by 2009 pH1N1 in children and young adults.3
  • Pathogenicity and Transmissibility of Swine H2N3 Virus: Researchers investigated the pathogenicity and transmissibility of swine H2N3 virus (isolated from diseased pigs in the United States in 2006) for non-human primates. The results indicated that this virus has potential to cause an outbreak in a non-immune or partially immune human population.4
  • Insights into Influenza Virus Adaptation to New Mammalian Host: Scientists adapted the extensively studied mouse influenza A PR8 strain to the guinea pig to study the viral gene changes that allowed the virus to propagate and transmit in the guinea pig. This work furthered understanding of how influenza viruses adapt to a new mammalian host and may inform future vaccination strategies.5

Disease Severity and Comparative Pathogenesis
Effective response to the emergence of highly lethal influenza viruses requires better understanding of the underlying features of highly pathogenic (disease-causing) influenza strains and the development of cross-protective vaccines. Scientists do not yet know which genetic changes would convert conventional avian or mammalian influenza viruses into more lethal viruses that could result in a future outbreak with pandemic potential. ARRA funds were used to explore the underlying features of highly pathogenic influenza strains.

  • Identification of Gene Mutations Associated with Pathogenicity: Researchers found that specific mutations in a gene associated with the enhanced pathogenicity of previous pandemic viruses decreased the pathogenicity of pH1N1 and associated tissue damage.6
  • Insights into Weaker Immune Response to Pandemic H1N1 Virus: Scientists showed that the HA protein from pH1N1 contributes to enhanced virus replication in cells deep in the lungs via escape from neutralization by surfactant protein D, which is part of the body’s first line of defense against viruses. The findings help explain the weaker immune response to pandemic flu and suggest avenues for developing new types of antiviral drugs.7
  • Impact of Secondary Bacterial Infection on Mortality of Influenza Pandemics: Researchers demonstrated in mice that secondary bacterial infection during 2009 pH1N1 infection resulted in more severe disease and loss of lung repair responses than did seasonal influenza viral and bacterial coinfection. This finding may help explain some differences in mortality during influenza pandemics.8
  • Obesity and Risk for Severe Infection of Pandemic H1N1 Virus: Scientists evaluated obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 virus. Obese mice have increased morbidity and mortality compared with non-obese mice following infection with the 2009 pH1N1 virus, supporting reports that obesity may be a risk factor for severe 2009 pH1N1 influenza infection in humans.9
  • Insights into Varying Disease Severity in Pandemic H1N1 Infections: Researchers observed varying disease severity and lung pathology in cynomolgus macaques infected with three distinct 2009 pH1N1 viruses, indicating that swine-origin flu strains with different pathogenic potential co-circulate. This finding may explain the varying disease severity observed in pH1N1-infected humans.10

Vaccines and Other Preventive Measures
Two types of vaccines are licensed for prevention of influenza in the United States: 1) inactivated (chemically killed) vaccines and 2) live attenuated (weakened) vaccines engineered to produce the two viral surface proteins. ARRA funds supported preclinical and clinical vaccine studies focusing on the 2009 H1N1 virus.

  • Impact of Prior Exposure to Swine Origin H1N1 Viruses and Immunity against 2009 Pandemic H1N1 Virus: Research studies in mice and ferrets showed that prior exposure to related swine-origin H1N1 viruses provided some protective immunity against the 2009 pH1N1 virus. However, only the 2009 pH1N1 vaccine conferred complete protection against the 2009 pH1N1 virus in both animal models. Prior infection with a seasonal influenza virus or seasonal live attenuated influenza vaccine (LAIV) primed mice for a robust response to a single dose of pLAIV that was associated with protection equivalent to two doses of the matched pandemic vaccine.11
  • Nasal Spray Vaccine of Pandemic H1N1 Virus Effective in Rhesus Macaques: Scientists compared the replication of 2009 pH1N1 virus in African green monkeys and rhesus macaques. They found that both species support the replication of pH1N1 virus to different degrees, and that a live attenuated pH1N1 vaccine developed for nasal spray administration elicited protective immunity against pH1N1 virus infection in rhesus macaques.12
  • Effect of Vaccinations Against Recent Pandemic Influenza Viruses May Provide Some Protection against Virus from Much Earlier Pandemic: Researchers determined that vaccination with the 1976 swH1N1 (swine flu) or 2009 pH1N1 vaccines protected mice from a lethal challenge with the 1918 H1N1 virus, which caused the worst influenza pandemic in recorded history. These findings suggest that the general population may be protected from a future 1918-like pandemic because of prior infection or immunization with the 1976 or 2009 H1N1 viruses. Researchers also showed that a pH1N1 neuraminidase vaccine protected mice from a lethal H5N1 influenza virus challenge. This finding may help in developing vaccines that protect humans against seasonal and pandemic viruses.13
  • Insights Toward the Development of a Universal Influenza Vaccine: Studies in mice supported the idea that individuals who have been previously exposed to, and have antibodies against, 1918-like H1N1 viruses or classical swine H1N1 are likely to be protected against the novel swine-origin 2009 H1N1 virus. These studies have been important in shaping research to develop universal influenza vaccines.14
  • Computer Algorithm Used to Design Universal Influenza Vaccine Candidate: Scientists used a novel computer algorithm to design a universal influenza vaccine candidate. This vaccine was shown to protect against lethal H5N1 challenge in non-human primates.15
  • Insights to Improve Development of Influenza Vaccines and Treatments: Researchers examined the interactions between a broadly neutralizing human antibody and the HA proteins from the 1918 H1N1 virus and from a recent lethal case of H5N1 bird flu. These studies, which revealed how the antibody neutralizes the virus, should accelerate the design and development of improved vaccines and antibody-based treatments for influenza.16
  • Protecting Against Secondary Bacterial Infections: Researchers showed how seasonal FluMist vaccination protects mice from infection with the 2009 H1N1 pandemic influenza virus strain and also from secondary pneumococcal (bacterial) infection—a complication also common in humans.17
  • Analog of Double-Stranded RNA May Prevent Influenza Infection: Another study evaluated PIKA, a stabilized chemical analog of double-stranded RNA, as a method of preventing infection with 2009 pH1N1 virus and four other flu viruses. Results of this study support further evaluation of PIKA for influenza prevention.18

Clinical Research
ARRA funds were used to quickly establish and support clinical trials in adult and pediatric patients with the 2009 H1N1 influenza virus research. Findings will inform both future treatment of influenza patients and public health preparedness.

  • Pandemic Influenza and Seasonal Influenza in Patients with Compromised Immune Systems: Researchers evaluated the natural history of pH1N1 infection versus seasonal influenza in patients with compromised (weakened) immune systems and in healthy patients. These studies highlighted the difficulties in treating influenza, especially in patients who are susceptible to prolonged infection due to underlying illness.19
  • Study of H1N1 Vaccine for Older People: Scientists completed a clinical study examining the immunogenicity and efficacy of the 2009 H1N1 live attenuated influenza vaccine (LAIV), made from weakened live virus, in people aged 60 to 70 years old. Little is known of LAIV's effects on this population.20
  • Insights into Immune Response to H1N1 Virus in Healthy Adults: Researchers conducted a study to find the smallest dose of influenza A H1N1 virus that may cause a mild to moderate flu infection in healthy adult volunteers. The study examined some of the basic, unanswered questions regarding the development of influenza in humans and the immune response to the virus in healthy adults. Analysis of the study results is in progress.21
  • Insights into Mortalities Following 2009 pH1N1 Infections: Investigators described the pulmonary pathology findings in 34 people who died following 2009 pH1N1 viral infections. Secondary bacterial infections in the respiratory tract, preexisting obesity, cardiopulmonary diseases, and other underlying illnesses were prominent findings.22
  • Examination of Population Immunity by Age: Researchers evaluated population immunity by age to understand the likely course of the pH1N1 pandemic.23

Contributing NIH Institutes & Centers

  • National Institute of Allergy and Infectious Diseases (NIAID)

  1. CDC 2009 H1N1 Statistics
  2. 1ZIAAI001109-01, http://www.ncbi.nlm.nih.gov/pubmed/22241979 - SUBBARAO, KANTA - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  3. 1ZIAAI001109-02, http://www.ncbi.nlm.nih.gov/pubmed/22674976 - SUBBARAO, KANTA - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  4. 1ZIAAI001088-02, http://www.ncbi.nlm.nih.gov/pubmed/22808082 - FELDMANN, HEINRICH - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  5. 1ZIAAI001104-02 - YEWDELL, JONATHAN - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  6. 1ZIAAI001114-02, http://www.ncbi.nlm.nih.gov/pubmed/20689744 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  7. 1ZIAAI001114-02 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - -
    3P01AI083222-01A2S1 - SEATON, BARBARA A - BOSTON UNIVERSITY MEDICAL CAMPUS - BOSTON - MA
    1P01AI083222-01A2 - SEATON, BARBARA A - BOSTON UNIVERSITY MEDICAL CAMPUS - BOSTON - MA
    5P01AI083222-02 - SEATON, BARBARA A - BOSTON UNIVERSITY MEDICAL CAMPUS - BOSTON - MA
    http://www.ncbi.nlm.nih.gov/pubmed/21334038
  8. 1ZIAAI001114-02, http://www.ncbi.nlm.nih.gov/pubmed/21933918 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  9. 1ZIAAI001114-02, http://www.ncbi.nlm.nih.gov/pubmed/21668672 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  10. 1ZIAAI001088-02, http://www.ncbi.nlm.nih.gov/pubmed/21084481, http://www.ncbi.nlm.nih.gov/pubmed/21262125 - FELDMANN, HEINRICH - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  11. 1ZIAAI001109-02, http://www.ncbi.nlm.nih.gov/pubmed/20926110, http://www.ncbi.nlm.nih.gov/pubmed/21257740, http://www.ncbi.nlm.nih.gov/pubmed/21199945 - SUBBARAO, KANTA - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  12. 1ZIAAI001109-02, http://www.ncbi.nlm.nih.gov/pubmed/22789506 - SUBBARAO, KANTA - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  13. 2P01AI058113-06 - GARCIA-SASTRE, ADOLFO - MOUNT SINAI SCHOOL OF MEDICINE - NEW YORK - NY
    1ZIAAI001114-02 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
    http://www.ncbi.nlm.nih.gov/pubmed/21477139, http://www.ncbi.nlm.nih.gov/pubmed/20409208, http://www.ncbi.nlm.nih.gov/pubmed/22727831, http://www.ncbi.nlm.nih.gov/pubmed/20975689
  14. 2P01AI058113-06, http://www.ncbi.nlm.nih.gov/pubmed/20126449 - GARCIA-SASTRE, ADOLFO - MOUNT SINAI SCHOOL OF MEDICINE - NEW YORK - NY
  15. 3U01AI077771-02S1, http://www.ncbi.nlm.nih.gov/pubmed/22448011 - ROSS, TED M - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  16. 2P01AI058113-06, http://www.ncbi.nlm.nih.gov/pubmed/19251591 - GARCIA-SASTRE, ADOLFO - MOUNT SINAI SCHOOL OF MEDICINE - NEW YORK - NY
  17. 3R01AI041715-12S1, http://www.ncbi.nlm.nih.gov/pubmed/21160043 - METZGER, DENNIS W. - ALBANY MEDICAL COLLEGE - ALBANY - NY
  18. 1ZIAAI001109-02, http://www.ncbi.nlm.nih.gov/pubmed/20667572 - SUBBARAO, KANTA - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  19. http://www.ncbi.nlm.nih.gov/pubmed/20345239, http://www.ncbi.nlm.nih.gov/pubmed/22575875, http://www.ncbi.nlm.nih.gov/pubmed/19553589, http://www.ncbi.nlm.nih.gov/pubmed/19933640
  20. NCT01055184
  21. NCT01646138
    1ZIAAI001113-02 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  22. 1ZIAAI001113-02, http://www.ncbi.nlm.nih.gov/pubmed/20121613 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A
  23. 1ZIAAI001113-02, http://www.ncbi.nlm.nih.gov/pubmed/20877580 - TAUBENBERGER, JEFFERY - NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES - N/A - N/A