Deadly 1918 Spanish flue virus has been reconstructed and characterized

For the first time, this deadly 1918 Spanish flue virus has been reconstructed and characterized. This research, reported in this week's issue of Science, is part of a larger research initiative being led by Adolfo Garcia-Sastre, PhD, Professor of Microbiology and Peter Palese, PhD, Professor and Chairman of Microbiology at Mount Sinai School of Medicine.

Their goal is to gain a greater understanding of this virus in order to use this knowledge to predict future pandemics and develop novel vaccines and treatments.

Drs. Garcia-Sastre and Palese and Christopher Basler, PhD, Assistant Professor of Microbiology worked with colleagues at the Centers for Disease Control, the Armed Forces Institute of Pathology in Maryland and The United States Department of Agriculture to characterize the 1918 virus. The reconstructed virus is contained at the CDC, following stringent safety conditions designated for flu viruses and other "select agents."

The virus was reconstructed using reverse genetics, a technique Drs. Garcia-Sastre and Palese developed. (See below for a description of the reverse genetics technique, which is being widely used in research to develop vaccines for a potential pandemic.)

The emergence of another pandemic is considered highly likely by many experts, but it is currently not possible to predict which viruses will become pandemics or how virulent a pandemic virus will be. Understanding the Spanish flu, the most virulent and deadly pandemic in recent history, may provide the information needed to anticipate which flu viruses have the potential to cause pandemics, determine in advance how virulent the virus is, and develop vaccines and treatments to prevent the potential devastation of a pandemic.

Three major discoveries about the virulence of the 1918 virus are included in the Science report:

1. It is extremely virulent in mice, leading to rapid death.
2. It is pathogenic in embryonated chicken eggs
3. It grows very rapidly in human lung cells.

All three of these are in contrast to most flu viruses that infect humans. These generally are not pathogenic in other species and grow significantly slower in human lung cells.

Mounts Sinai School of Medicine researchers received US patent number 6,544,785 for a technique they developed to create viruses from DNA. The technique, known as reverse genetics or Plasmid Rescue Technology, is specifically designed to work with viruses that use RNA for storing their genetic material. Influenza is one such virus.

The genetic makeup of influenza viruses allows frequent minor genetic changes, known as antigenic drift, and these changes require annual reformulation of influenza vaccines. Each year the World Health Organization (WHO) works with health agencies in many countries to identify the strain(s) of influenza spreading in human populations. Once the strain(s) is isolated development of a vaccine begins. The slowness of the process is problematic even under the best of conditions, but should a particularly virulent strain such as the one that caused the pandemic of 1918 arise, delays in vaccine production could be catastrophic.

Based on historical patterns the WHO estimates that influenza pandemics can be expected to occur 3-4 times/century. A new pandemic is considered inevitable. "The speed of vaccine development will be particularly crucial when the next pandemic arrives," said Peter Palese, PhD, Chairman and Professor of Microbiology at Mount Sinai School of Medicine and one of the researchers listed on the patent.

While vaccines have been available for over 60 years, the length of time required for current methods of production is too long for effective response to a strain as virulent as the ones that have caused pandemics. Without reverse genetics, vaccine development is somewhat of a hit or miss procedure. Two strains are combining and nature takes its course until by chance a virus with the desired characteristics is obtained. A master strain is used to provide the desired growth qualities. This is combined with the form of the virus in circulation to obtain the proper antigenic qualities. After several generations of viruses have been produced, the resulting daughter strains are sorted through to identify which have the proper combination of characteristics.

Reverse genetics circumvents this usual procedure. Researchers can custom build a virus to meet their needs. The method is faster and also provides a means for researchers to alter the virus to have markers that allow safer handling and to eliminate pathogenic markers to enhance the safety of the vaccine. Custom building viruses for vaccines also facilitates greater quality control by reducing genetic variation in production.

The technique also makes practical the idea of developing a library of vaccines against a broad spectrum of avian viruses that have the potential to jump into humans. With such a stockpile, each year production of vaccines could begin as soon as circulating strains are identified.