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Reconstruction of the 1918 Influenza Pandemic Virus
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Background on the Research

Biosafety Precautions CDC researchers and their colleagues have successfully Biosecurity Issues reconstructed the influenza virus that caused the 1918-19 flu pandemic, which killed as many as 50 million people worldwide. A report of their work, "Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus," was published in the October 7 issue of Science. The work is a collaboration among scientists from CDC, Mount Sinai School of Medicine, the Armed Forces Institute of Pathology, and Southeast Poultry Research Laboratory. The following questions and answers describe this important research and related issues.

Background on the Research
What research does the Science article describe? Why is it important? This report describes the successful reconstruction of the influenza A (H1N1) virus responsible for the 1918 "Spanish flu" pandemic and provides novel information about the properties that contributed to its exceptional virulence. This information is critical to evaluating the effectiveness of current and future public health interventions, which could be used in the event that a 1918-like strain reemerges, either naturally or through deliberate release. The knowledge from this work may also shed light on the pathogenesis of contemporary human influenza viruses with pandemic potential. The natural emergence of another pandemic virus is considered highly likely by many experts, and therefore novel insights into pathogenic mechanisms could contribute to the development of prophylactic and therapeutic interventions needed to control pandemic viruses. What are the reasons for doing these experiments? The influenza pandemic of 1918-19 killed an estimated 20 to 50 million people worldwide, many more than the subsequent pandemics of the 20th century. The biological properties that confer virulence to pandemic influenza viruses were poorly understood. Research to better understand how the individual genes of the1918 pandemic influenza virus contribute to the disease process could provide important insights into the basis of virulence. This kind of information will enable us to devise appropriate strategies for early diagnosis, treatment, and prevention, should a similar pandemic virus emerge. Additionally, such research will provide us with general principles with which we can better design antiviral drugs and other interventions against all influenza viruses with enhanced virulence. Who funded the work described in this article? Work with the reconstructed 1918 virus was conducted at and supported by CDC. The U.S. Department of Agriculture (USDA), the National Institutes of Health (NIH), and the Armed Forces Institute of Pathology (AFIP) all provided support for many other aspects of this research. When did CDC begin research on the 1918 virus? CDC studies of the 1918 influenza virus were begun in 2004 with the initiation of testing of viruses containing subsets of the eight genes of the 1918 virus. Previous articles describing the properties of such viruses were published before 2005. Reconstruction of the entire 1918 virus was begun in August 2005. What are the next steps for research on the 1918 pandemic influenza strain at CDC? CDC will evaluate the biological properties of the other individual genes that make up this virus (CDC has examined four of the virus' eight genes so far). Scientists will continue to study the hemagglutinin (HA) gene for potential treatments and other interventions for use against this

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virus. Researchers also want to gain a better understanding of the role of HA in causing inflammation of the lung, a factor that may contribute to the overall increased levels of illness and death associated with this virus. Could a 1918-like H1N1 virus re-emerge and cause a pandemic again? It is impossible to predict with certainly, but the probability of the 1918 virus re-emerging from a natural source appears to be remote. Influenza experts believe that a pandemic is most likely to be caused by an influenza subtype to which there is little, or no, preexisting immunity in the human population. There is evidence that some residual immunity to the 1918 virus, or a similar virus, is present in at least a portion of the human population. Since contemporary H1N1 viruses circulate widely and the current annual influenza vaccines contain an H1N1 component, a 1918-like H1N1 virus would not fit the current criteria for a new pandemic strain. Are current antivirals and vaccines effective against the 1918 virus? Yes. Two types of antiviral drugs, rimantadine (Flumadine) and oseltamivir (Tamiflu), have been shown to be effective against influenza viruses similar to the 1918 virus. Vaccines containing the 1918 HA or other subtype H1 HA proteins were effective in protecting mice against the 1918 virus. In fact, the current influenza vaccine provided some level of protection against the 1918 virus in mice. Are new prophylactics and therapeutics against the 1918 virus under way? The reconstruction of the 1918 virus will enable CDC to pursue development of a vaccine candidate reference virus that would provide optimal protection against this or similar viruses. Have these findings validated the current preparedness strategies? Will there be changes to the pandemic preparedness plan in light of these findings? Many experts believe that the next pandemic strain will be related to emergence of an avian influenza strain. The research reported in Science further validates that theory and suggests that we are headed in the right direction in our preparedness plans. The 1918 virus gene sequences are related more closely to avian H1N1 viruses than are any of the other known mammalian influenza H1N1 strains. The results of this research will be taken into account as part of the ongoing pandemic preparedness planning process. Will the 1918 virus strain used during these experiments at CDC be made available to other research institutions? CDC currently has no plans to distribute this virus. If other individual scientists desire to work with the agent, consideration will be given to hosting them at CDC.

Biosafety Precautions
Is the public at risk from the experiments being done on this virus? The work described in this report was done using stringent biosafety and biosecurity precautions that are designed to protect workers and the public from possible exposure to this virus (for example, from accidental release of the virus into the environment). What biosafety and biosecurity precautions for protecting laboratory workers and the public were in place while this work was being done? Before the experiments were begun, two tiers of internal CDC approval were conducted: an Institutional Biosafety Committee review and an Animal Care and Use Committee review. All viruses containing one or more gene segments from the 1918 influenza virus were generated and handled in accordance with biosafety guidelines of the Interim CDC-NIH Recommendation for Raising the Biosafety Level Laboratory Work Involving Noncontemporary Human Influenza Viruses. Although the 1918 virus was not designated as a select agent at the time this work was performed, all procedures were carried out using the heightened biosecurity elements mandated by CDC's Select Agent program. The Intra-governmental Select Agents and Toxins Technical Advisory Committee recommended that the reconstructed 1918 influenza virus be added to the list of HHS select agents on September 30, 2005. Following this recommendation, CDC amended its regulations and designated all reconstructed replication competent forms of the 1918 pandemic influenza virus containing any portion of the coding regions of all eight gene segments (reconstructed 1918 Influenza virus) as a select agent. What are the appropriate biosafety practices and containment conditions for work with the 1918 strain of influenza? Biosafety Level 3 or Animal Biosafety Level 3 practices, procedures and facilities, plus enhancements that include special procedures (discussed in the next question below), are recommended for work with the 1918 strain. There are four biosafety levels that correspond to the degree of risk posed by the research and involve graded levels of protection for personnel, the environment, and the community. Biosafety Level 4 provides the most stringent containment conditions, Biosafety Level 1 the least stringent. These biosafety levels consist of a combination of laboratory practices and techniques, safety equipment, and laboratory facilities that are appropriate for the operations being performed. The specific criteria for each biosafety level are

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detailed in the CDC/NIH publication Biosafety in Microbiological and Biomedical Laboratories. What is Biosafety Level 3 "enhanced"? What are the specific enhancements used for work with the 1918 strain of influenza? A Biosafety Level 3 facility with specific enhancements includes primary (safety cabinets, isolation chambers, gloves and gowns) and secondary (facility construction, HEPA filtration treatment of exhaust air) barriers to protect laboratory workers and the public from accidental exposure. The specific additional ("enhanced") procedures used for work with the 1918 strain include:
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Rigorous adherence to additional respiratory protection and clothing change protocols; Use of negative pressure, HEPA-filtered respirators or positive air-purifying respirators (PAPRs); Use of HEPA filtration for treatment of exhaust air; and Amendment of personnel practices to include personal showers prior to exiting the laboratory.

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Further details of the biosafety recommendations for work with various human and animal influenza viruses, including 1918 virus, can be found in the interim CDC/NIH guidance for such work at Interim CDC-NIH Recommendation for Raising the Biosafety Level Laboratory Work Involving Noncontemporary Human Influenza Viruses. Can these experiments be done safely using containment provided by BSL-3 with enhancements? Highly trained laboratorians can work with the 1918 influenza virus strain safely using BSL-3enhanced containment. Researchers at CDC have specialized training and go through a rigorous biosafety (and security) clearance process. For the work reported in the Science article, the lead CDC researcher provided routine weekly written reports to CDC management officials, including the agency's Chief Science Officer, and was instructed to notify agency officials immediately of any concerns related to biosafety or biosecurity. A BSL-3 facility with specific enhancements includes primary (safety cabinets, isolation cabinets, gloves, gowns) and secondary (facility construction) barriers to protect laboratory workers and the public from accidental exposure. Specific enhancements include change-of-clothing and shower-out requirements, and the use of a powered air purifying respirator (PAPR; half body suits). The primary and secondary barriers plus additional personal safety practices provide appropriate containment for conducting such influenza research. CDC evaluated the specific studies to be conducted as well as the highly experienced scientific team conducting the research and concluded that this work could proceed under BSL-3 containment with enhancements. Why was BSL-3-enhanced containment used for work on the 1918 H1N1 virus when most human influenza viruses of the H1N1 subtype are handled under much less stringent containment? The appropriate biosafety measures for working a given pathogen depend upon a number of factors, including previous experience with the pathogen or similar pathogens, the virulence and transmissibility of the pathogen, the type of experiment, and the availability of vaccines and/or antimicrobial drugs effective against the pathogen. Prior to reconstruction of the 1918 virus, CDC carefully evaluated the specific studies to be conducted and concluded that this research could safely and securely be done under BSL-3-enhanced containment. All viruses containing one or more gene segments from the 1918 influenza virus were generated and handled under highcontainment (BSL 3-enhanced) laboratory conditions in accordance with guidelines of NIH and CDC. The recommendations for biosafety levels are made by a panel of experts and are followed in a stringent manner. A higher level of containment (biosafety level 4) is utilized for work on novel or exotic pathogens for which there is no treatment or vaccine. This is not the case for the 1918 virus. Decedents of the 1918 influenza virus still circulate today, and the current influenza vaccine provides some protection against the 1918 virus. In addition, two types of antiviral drugs, rimantadine (Flumadine) and oseltamivir (Tamiflu), are effective against viruses bearing 1918 virus gene products targeted by the antiviral drugs. The physical and engineering design of BSL-3-enhanced containment is very similar to that used in BSL-4 laboratories. The BSL-3 laboratory also has state-of-the-art directional airflow control which filters outgoing air, and all waste is autoclaved or decontaminated before it leaves the work area, preventing escape of infectious agents. Recent media reports have described the disappearance of plague-infected mice from a U.S. laboratory. Could mice infected with the 1918 influenza virus escape or be removed from CDC laboratories? The rigorous biosafety and biosecurity precautions used at CDC for experiments done with the

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1918 virus make it extremely unlikely that an animal infected with the 1918 virus could escape or be removed from CDC laboratories. For the experiments described in this report, all animals used were properly contained and accounted for. Earlier this year, samples of a "non-contemporary" influenza virus strain (H2N2) were shipped to laboratories worldwide as part of proficiency testing panels. Could the 1918 pandemic influenza virus be inadvertently distributed in a similar manner? No. The "non-contemporary" H2N2 virus was available from many sources and inadvertently shipped by private suppliers as part of the proficiency panel. CDC currently has no plans to distribute this virus.

Biosecurity Issues
Does the generation of the 1918 Spanish influenza pandemic virus containing the complete coding sequence of the eight viral gene segments violate the Biological Weapons Convention? No. Article I of the Biological Weapons Convention (BWC) specifically allows for microbiological research for "prophylactic, protective, or other peaceful purposes. Article X of the BWC encourages the "fullest possible exchange of… scientific and technological information" for the use of biological agents for the prevention of disease and other peaceful purposes. Further, Article X of the BWC provides that the BWC should not hamper technological development in the field of peaceful bacteriological activities. Because the emergence of another pandemic virus is considered likely, if not inevitable, characterization of the 1918 virus may enable us to recognize the potential threat posed by new influenza virus strains, and it will shed light on the prophylactic and therapeutic countermeasures that will be needed to control pandemic viruses. Does the report provide a "blueprint" for bioterrorists to develop and unleash a devastating pandemic on the world? No. This report does not provide the blueprint for bioterrorist to develop a pandemic influenza strain. The reverse genetics system that was used to generate the 1918 virus is a widely used laboratory technique. While there are concerns that this approach could potentially be misused for purposes of bioterrorism, there are also clear and significant potential benefits of sharing this information with the scientific community: namely, facilitating the development of effective interventions, thereby strengthening public health and national security. Is the 1918 influenza virus a select agent? The Intra-governmental Select Agents and Toxins Technical Advisory Committee convened on September 30, 2005, and recommended that the reconstructed 1918 influenza virus be added to the list of HHS select agents. Following this recommendation, CDC amended its regulations and designated all reconstructed replication competent forms of the 1918 pandemic influenza virus containing any portion of the coding regions of all eight gene segments (reconstructed 1918 Influenza virus) as a select agent. What is the Select Agent Program? The Centers for Disease Control and Prevention (CDC) regulates the possession, use and transfer of select agents and toxins that have the potential to pose a severe threat to public health and safety. The CDC Select Agent Program oversees these activities and registers all laboratories and other entities in the United States of America that possess, use or transfer a select agent or toxin. The U.S. Departments of Health and Human Services (HHS) and Agriculture (USDA) published final rules for the possession, use, and transfer of select agents and toxins (42 C.F.R. Part 73, 7 C.F.R. Part 331, and 9 C.F.R. Part 121) in the Federal Register on March 18, 2005. All provisions of these final rules supersede those contained in the interim final rules and became effective on April 18, 2005.

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