Q&A: Insights from recreating the 1918 flu virus

Jeffery Taubenberger, MD, PhD
Jeffery K. Taubenberger

In a review published in Science Translational Medicine, researchers summarized key findings and unanswered questions from the 1918 influenza pandemic and discussed how reconstructing the pandemic strain has revealed insights into the potential origin of the virus and the features that made it uniquely fatal.

Jeffery K. Taubenberger, MD, PhD, chief of the viral pathogenesis and evolution section in the laboratory of infectious diseases at the NIH’s National Institute of Allergy and Infectious Diseases, and colleagues noted that learning more about the 1918 pandemic can help identify pre-pandemic influenza strains and design better vaccination and public health protocols during future pandemics.

Infectious Disease News asked Taubenberger about how the 1918 virus was reconstructed, what questions have been answered about the pandemic, and what questions remain. Taubenberger was one of the scientists who collaborated to reconstruct the virus over a decade ago. – by Joe Gramigna

Q: Is there a risk associated with recreating the 1918 virus, and is that risk worth the knowledge we get from it?

Photo of flu antigens 
Influenza virus antigens (reddish brown) among human respiratory epithelial cells in lung.
Source: J.K. Taubenberger et al., Science Translational Medicine (2019)

A: As we look back at the centennial of the influenza pandemic of 1918 to 1919, it is critical to recall that it is the deadliest single event in recorded human history, killing at least 50 million people worldwide. The unprecedented morbidity and mortality frustrated physicians and scientists at the time, who were not able to identify the etiologic agent. The cause of the 1918 pandemic and the basis of its severity was one of the most discussed medical mysteries for most of the 20th century. The milestone achievement of reconstructing an “extinct” pandemic virus raised many questions that had not been asked before, including whether it was necessary or wise to recreate a naturally extinct virus that represented one of the deadliest infectious agents in human history. The reconstruction was approved following consultation with senior United States government scientists and officials at the Department of Health and Human Services, wherein the conclusion was reached that this research would likely play a key role in ongoing pandemic influenza preparedness. The 1918 virus was quickly put under strict regulation under the Federal Select Agent Program at the CDC. Guidelines contained in the Biosafety in Microbiological and Biomedical Laboratories manual were quickly modified to support development of safe protocols for biocontainment and biosafety. Many important insights into influenza virus biology and public health have already resulted from the sequencing and reconstruction of the 1918 virus. Studying the 1918 virus is an important means of protecting ourselves from future events of a similar nature.

Q: How were you and your team able to reconstruct the 1918 virus?

 

A: Development of PCR technology in the 1980s made it possible in the late 1990s to recover and sequence highly degraded fragments of viral RNA retained in preserved tissues from persons who succumbed between 1918 and 1919. The initial 1918 virus sequences were recovered from formalin-fixed, paraffin-embedded lung tissues from autopsy cases of U.S. soldiers dying of influenza pneumonia in 1918 whose tissue samples were stored in the National Tissue Repository of the Armed Forces Institute of Pathology (AFIP). Additional positive cases were subsequently identified from other autopsy cases from the AFIP, the Royal London Hospital and from a frozen body interred in the permafrost in northern Alaska. In a multi-institutional collaboration, using the technique of viral “reverse genetics,” these viral RNA sequences permitted eventual reconstruction of the complete 1918 virus in 2005. It is remarkable that tiny fragments of viral RNA recovered from just a handful of the pandemic’s tens of millions of victims have allowed, now a century after their deaths, new insights into influenza virus biology and pathogenesis and have provided important information about how to prevent and control future pandemics.

 

Q: What questions were answered by reconstructing the virus, and what questions remain?

 

A: One of the important questions about influenza pandemics — past and future — is how influenza A viruses that originate in different animal species can switch hosts and adapt to humans so that they can efficiently infect and transmit between persons, allowing a pandemic to form. The 1918 influenza virus genome is very avian influenza virus-like in many features, suggesting that the ultimate origin of the pandemic virus was from a wild bird, but the timing, geographic origin and exact mechanisms of pandemic emergence remain unanswered. A second key question is why was the 1918 pandemic so severe, and why did it result in so many deaths? Much work has been done in the last 15 years to model 1918 influenza pathogenicity in cell culture and in animal models. Although the virus’ pathogenicity is complex, there are viral virulence factors, especially associated with the avian influenza-like H1 subtype hemagglutinin and the polymerase genes, but a significant component of lung damage is associated with the host proinflammatory response inducing an immunopathology. Finally, almost all people who died in 1918 developed a secondary bacterial pneumonia, and much work has been done to characterize how severe influenza infections lead to the development of secondary bacterial pneumonias. Another critical question still unanswered is explaining the unusual age-specific mortality of the 1918 pandemic, in which young adults (peaking in their late 20s) had far higher than expected case fatalities. This is perhaps the greatest outstanding question about the 1918 pandemic that still needs to be answered.

 

Q: What are the primary lessons learned from the 1918 influenza pandemic that can help us prepare for future pandemics?

 

A: One key lesson of the 1918 influenza pandemic is that some currently circulating avian influenza A viruses share pathogenic features with the 1918 influenza virus, and therefore it is possible that a future pandemic may have the morbidity and mortality impact of the 1918 influenza virus. More is needed to understand basic mechanisms of host switch and pathogenicity. A second key lesson is the need to develop new generations of efficacious, broadly protective (so called “universal”) influenza vaccines to prevent or mitigate the impact of future pandemic viruses. A third key lesson is understanding the importance of secondary bacterial pneumonias and seeking to prevent their development through viral vaccine control, development of prognostic biomarkers of impending pneumonia and the further development of bacterial vaccines, such as for Streptococcus pyogenes and Staphylococcus aureus.

 

Q: Are there other viruses that should be reconstructed?

 

A: It will be important to obtain sequences of influenza viruses that circulated before 1918 to help us further understand the origin of the 1918 pandemic. On the other hand, obtaining sequences from post-pandemic seasonal H1N1 influenza A viruses from the 1920s and early 1930s will help answer questions about the virulence of the 1918 virus and its early adaptation and evolution in humans.

 

References:

Morens DM, Taubenberger JK. J Infect Dis. 2019;doi:10.1093/infdis/jiy728.

NIAID. Unmasking the 1918 influenza virus: An important step toward pandemic influenza preparedness. http://www.flu.org.cn/en/article-3800.html. Accessed July 26, 2019.

Sheng ZM, et al. PNAS. 2011;doi:10.1073/pnas.1111179108.

Taubenberger JK, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aau5485.

Taubenberger JK, et al. Microbiol. 2012;doi:10.1128/mBio.00201-12.

Taubenberger JK, et al. Antivir Ther. 2017;doi:12(4 Pt B):581-91.

Tumpey TM, et al. Science. 2005;doi:10.1126/science.1119392.

 

Disclosure: Taubenberger reports no relevant financial disclosures.

Jeffery Taubenberger, MD, PhD
Jeffery K. Taubenberger

In a review published in Science Translational Medicine, researchers summarized key findings and unanswered questions from the 1918 influenza pandemic and discussed how reconstructing the pandemic strain has revealed insights into the potential origin of the virus and the features that made it uniquely fatal.

Jeffery K. Taubenberger, MD, PhD, chief of the viral pathogenesis and evolution section in the laboratory of infectious diseases at the NIH’s National Institute of Allergy and Infectious Diseases, and colleagues noted that learning more about the 1918 pandemic can help identify pre-pandemic influenza strains and design better vaccination and public health protocols during future pandemics.

Infectious Disease News asked Taubenberger about how the 1918 virus was reconstructed, what questions have been answered about the pandemic, and what questions remain. Taubenberger was one of the scientists who collaborated to reconstruct the virus over a decade ago. – by Joe Gramigna

Q: Is there a risk associated with recreating the 1918 virus, and is that risk worth the knowledge we get from it?

Photo of flu antigens 
Influenza virus antigens (reddish brown) among human respiratory epithelial cells in lung.
Source: J.K. Taubenberger et al., Science Translational Medicine (2019)

A: As we look back at the centennial of the influenza pandemic of 1918 to 1919, it is critical to recall that it is the deadliest single event in recorded human history, killing at least 50 million people worldwide. The unprecedented morbidity and mortality frustrated physicians and scientists at the time, who were not able to identify the etiologic agent. The cause of the 1918 pandemic and the basis of its severity was one of the most discussed medical mysteries for most of the 20th century. The milestone achievement of reconstructing an “extinct” pandemic virus raised many questions that had not been asked before, including whether it was necessary or wise to recreate a naturally extinct virus that represented one of the deadliest infectious agents in human history. The reconstruction was approved following consultation with senior United States government scientists and officials at the Department of Health and Human Services, wherein the conclusion was reached that this research would likely play a key role in ongoing pandemic influenza preparedness. The 1918 virus was quickly put under strict regulation under the Federal Select Agent Program at the CDC. Guidelines contained in the Biosafety in Microbiological and Biomedical Laboratories manual were quickly modified to support development of safe protocols for biocontainment and biosafety. Many important insights into influenza virus biology and public health have already resulted from the sequencing and reconstruction of the 1918 virus. Studying the 1918 virus is an important means of protecting ourselves from future events of a similar nature.

PAGE BREAK

Q: How were you and your team able to reconstruct the 1918 virus?

 

A: Development of PCR technology in the 1980s made it possible in the late 1990s to recover and sequence highly degraded fragments of viral RNA retained in preserved tissues from persons who succumbed between 1918 and 1919. The initial 1918 virus sequences were recovered from formalin-fixed, paraffin-embedded lung tissues from autopsy cases of U.S. soldiers dying of influenza pneumonia in 1918 whose tissue samples were stored in the National Tissue Repository of the Armed Forces Institute of Pathology (AFIP). Additional positive cases were subsequently identified from other autopsy cases from the AFIP, the Royal London Hospital and from a frozen body interred in the permafrost in northern Alaska. In a multi-institutional collaboration, using the technique of viral “reverse genetics,” these viral RNA sequences permitted eventual reconstruction of the complete 1918 virus in 2005. It is remarkable that tiny fragments of viral RNA recovered from just a handful of the pandemic’s tens of millions of victims have allowed, now a century after their deaths, new insights into influenza virus biology and pathogenesis and have provided important information about how to prevent and control future pandemics.

 

Q: What questions were answered by reconstructing the virus, and what questions remain?

 

A: One of the important questions about influenza pandemics — past and future — is how influenza A viruses that originate in different animal species can switch hosts and adapt to humans so that they can efficiently infect and transmit between persons, allowing a pandemic to form. The 1918 influenza virus genome is very avian influenza virus-like in many features, suggesting that the ultimate origin of the pandemic virus was from a wild bird, but the timing, geographic origin and exact mechanisms of pandemic emergence remain unanswered. A second key question is why was the 1918 pandemic so severe, and why did it result in so many deaths? Much work has been done in the last 15 years to model 1918 influenza pathogenicity in cell culture and in animal models. Although the virus’ pathogenicity is complex, there are viral virulence factors, especially associated with the avian influenza-like H1 subtype hemagglutinin and the polymerase genes, but a significant component of lung damage is associated with the host proinflammatory response inducing an immunopathology. Finally, almost all people who died in 1918 developed a secondary bacterial pneumonia, and much work has been done to characterize how severe influenza infections lead to the development of secondary bacterial pneumonias. Another critical question still unanswered is explaining the unusual age-specific mortality of the 1918 pandemic, in which young adults (peaking in their late 20s) had far higher than expected case fatalities. This is perhaps the greatest outstanding question about the 1918 pandemic that still needs to be answered.

 

Q: What are the primary lessons learned from the 1918 influenza pandemic that can help us prepare for future pandemics?

 

A: One key lesson of the 1918 influenza pandemic is that some currently circulating avian influenza A viruses share pathogenic features with the 1918 influenza virus, and therefore it is possible that a future pandemic may have the morbidity and mortality impact of the 1918 influenza virus. More is needed to understand basic mechanisms of host switch and pathogenicity. A second key lesson is the need to develop new generations of efficacious, broadly protective (so called “universal”) influenza vaccines to prevent or mitigate the impact of future pandemic viruses. A third key lesson is understanding the importance of secondary bacterial pneumonias and seeking to prevent their development through viral vaccine control, development of prognostic biomarkers of impending pneumonia and the further development of bacterial vaccines, such as for Streptococcus pyogenes and Staphylococcus aureus.

 

Q: Are there other viruses that should be reconstructed?

 

A: It will be important to obtain sequences of influenza viruses that circulated before 1918 to help us further understand the origin of the 1918 pandemic. On the other hand, obtaining sequences from post-pandemic seasonal H1N1 influenza A viruses from the 1920s and early 1930s will help answer questions about the virulence of the 1918 virus and its early adaptation and evolution in humans.

 

References:

Morens DM, Taubenberger JK. J Infect Dis. 2019;doi:10.1093/infdis/jiy728.

NIAID. Unmasking the 1918 influenza virus: An important step toward pandemic influenza preparedness. http://www.flu.org.cn/en/article-3800.html. Accessed July 26, 2019.

Sheng ZM, et al. PNAS. 2011;doi:10.1073/pnas.1111179108.

Taubenberger JK, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aau5485.

Taubenberger JK, et al. Microbiol. 2012;doi:10.1128/mBio.00201-12.

Taubenberger JK, et al. Antivir Ther. 2017;doi:12(4 Pt B):581-91.

Tumpey TM, et al. Science. 2005;doi:10.1126/science.1119392.

 

Disclosure: Taubenberger reports no relevant financial disclosures.