Having available the complete genetic map of the 1918 flu virus that killed 50 million people worldwide offers new insights into flu virus biology and will help prevent and control future epidemics, according to a paper published online in the journal mBio on Tuesday.

While the resurrection of such a deadly virus raises the prospect of it falling into the wrong hands, the biosecurity issues have been tightened up, and the knowledge gained from studying the complete structure of an "extinct" agent has been invaluable and will help us protect ourselves against future pandemics, say the authors, who are from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health in the US, and several other institutions, in the US and Australia.

In their paper, lead author and Chief of the Viral Pathogenesis and Evolution Section in the Laboratory of Infectious Diseases at NIAID, Jeffery K. Taubenberger, and colleagues, summarize the contribution that scientists have made in piecing together the various genetic structures of the 1918 flu virus over the years.

They recount how the "Spanish flu" pandemic of 1918, the "deadliest single event in recorded human history", frustrated early 20th century doctors and scientists trying to identify the cause, and how it spurred advances in discovery methods and health practices.

Eventually, some 15 years later, scientists began to isolate flu viruses, but biological methods for studying how they emerge, cause disease and then recede, did not become available until decades later.

It wasn't until 1996 that it became possible to recover fragments, albeit highly degraded, of viral genetic material from preserved tissue of flu victims of the 1918 epidemic. From these, using techniques like "reverse genetics", and studying the genetic material fragment by fragment, a clear and useful picture of the virus has gradually emerged.

1918 Virus Descendants Caused Later Pandemics

The authors explain how sufficient genetic fragments of viral RNA have now been recovered to allow sequencing and reconstruction of the complete 1918 virus, revealing that the viruses that caused the flu pandemics of 1957, 1968 and 2009 all descended from the 1918 virus.

They recap, for instance, on how studies have shown that the 2009 pandemic strain has similar structures to the 1918 virus, explaining why younger people, whose bodies had not been exposed to the this strain or its early descendants, were the most vulnerable to the 2009 flu virus.

"Thus, early in the 2009 pandemic, limited vaccine that might otherwise have been misdirected to the traditional risk group, the elderly (who were paradoxically at much lower risk in 2009), was instead administered to younger persons, who benefitted most," they write.

Universal Vaccine

Another big advance that came from discovering some of the physical structures of the 1918 virus, and in particular those common to other flu viruses, is the so-called "universal" flu vaccine that can be given less frequently, but offers broad protection against several flu viruses.

One such physical structure whose revelation is helping develop universal vaccines is the HA protein:

"Characterized protein motifs on the 1918 virus HA structure, conserved across many divergent HA proteins of different subtypes, are serving as a functional basis for next-generation vaccine approaches aimed at providing broad, cross-reactive immunity to [influenza A viruses] of different subtypes, including H5N1 viruses," write the authors.

It would be an obvious "major advance", they suggest, if such developments meant we could move away from having annual vaccinations, which currently is the only way we have of responding to the "continual antigenic drift of viral epitopes under the pressure of immune selection".

Keeping a Closer Watch on Animal Strains

In another area of research, comparisons of the 1918 virus to strains found in animals, have helped to pinpoint the changes they would have to undergo to adapt to human hosts. This work helps focus the close watch on animal strains in the right places.

Overall, the reconstruction of the 1918 flu virus has helped science take a big step forward in understanding how new viruses appear and evolve, say Taubenberger and colleagues.

They also say it has helped explain how our bodies and immune systems react to viruses, and the bacterial infections that often follow.

Initial Concerns About "Dual Use"

At first, there were some serious concerns about resurrecting an "extinct" pandemic virus, especially one of the deadliest infectious agents in human history, and the ensuing debate about whether the benefits outweighed the risk of the virus falling into the wrong hands raised some important issues around national security that led to changes in guidelines and protocols for biocontainment and biosafety.

This crystallized a number of questions about "dual use" research, which is defined as "work with clear benefits for society for which there also exists a theoretical potential for misuse (eg bioterrorism)", say the authors.

But overall, they suggest their review highlights "some of the important insights into influenza virus biology and public health that have already resulted from the sequencing and reconstruction of the 1918 virus".

"We argue that learning the most closely guarded secrets of our deadliest biological enemies is an essential means of protecting ourselves from future events of a similar nature," they note.

Written by Catharine Paddock PhD