The emergence of the avian influenza virus H5N1 that is currently devastating chicken flocks in many countries and threatening to unleash a worldwide epidemic among humans has triggered a renewed interest among scientists in studying influenza A viruses, according to investigators at St. Jude Children’s Research Hospital. This renewed interest could lead to new discoveries of immune system response to viruses that could lead to better drugs and vaccines, the researchers write in a review article that appears in the May issue of Nature Immunology.

“Until recently, many immunologists were relatively uninterested in studying influenza immunity because there were already effective vaccines,” said Peter Doherty, Ph.D., member of the St. Jude Department of Immunology and co-recipient of the 1996 Nobel Prize for Medicine. “The current resurgence of interest in influenza immunology reflects the threat that H5N1 could evolve into a virus that spreads easily among humans. Over the years, influenza A viruses have been one of the most important models for studying how the immune system responds to viral infections. Further study of this virus and the immune response to it will no doubt help us prepare for this latest threat.”

Influenza A viruses infect a wide range of animals and cause influenza outbreaks among humans. Scientists categorize influenza A viruses according to the identity of two specific proteins on their surface, HA and NA. There are 16 known subtypes of HA (H) proteins and 9 subtypes of NA (N) proteins, which are used to name the viruses, such as H5N1. The virus uses the HA protein to attach itself to a cell it is about to infect. Newly made viruses inside infected cells use NA to escape from the cell and spread.

“Studies of influenza A led to the design of Relenza® and Tamiflu®, two currently available anti-flu drugs,” said Paul Thomas, Ph.D., a postdoctoral fellow in the St. Jude Department of Immunology and an author of the article. “But the history of influenza shows us that there is still a great deal more to learn about them.”
Influenza has occurred throughout history, but the world became aware of its deadly potential in 1918-19 when a pandemic - a worldwide epidemic - seemed to strike out of nowhere. It killed some 40 million people - many more than the number killed in World War I. This pandemic arose from a bird flu virus that adapted to humans, an event that scientists fear could happen with H5N1.
Although widespread influenza pandemics did not erupt again until 1957 and 1968, there is evidence that a virus resembling the 1957 strain was circulating among humans as far back as 1888.

After the 1918-1919 pandemic, immunologists learned that the immune system responds to influenza A viruses in two basic ways. The first is to stimulate the B lymphocytes that develop into antibody-forming plasma cells. If a person has the “right” antibodies in his or her blood as a consequence of being vaccinated, that person is completely protected. On the other hand, the CD8+ “killer” T lymphocytes, which attack and kill cells infected by the virus, take longer to respond, and the virus still replicates extensively before the lymphocytes can do their job. Even before people realize they have been infected, the flu viruses multiply rapidly in the respiratory system and leap to nearby people in the fine droplets of coughs or sneezes. This explains why yearly human flu epidemics can seem to explode out of nowhere and spread rapidly through a household and community before fading away.

Moreover, the HA and NA proteins of these viruses continually mutate, keeping a step ahead of the posse of antibodies that seek to bring them down. This molecular strategy, which forces scientists to redesign the flu vaccine each year, is called antigenic drift. An antigen is a molecule that triggers an immune system attack.

In contrast, an antigenic shift occurs when different viruses infect the same animal and exchange genes. In 1957, a human H1N1 and avian H2N2 infected the same animal and swapped some genes - a process called reassortment. The resulting viral offspring caused that year’s severe epidemic. According to the paper’s authors, even in the absence of a quick reassortment, the right antigenic drift could give influenza A viruses the ability to spread to new species, including humans.
The prospect of a human pandemic of H5N1 is alarming considering what can happen to people infected by this virus, according to the St. Jude investigators. The immune system response to H5N1 can run amok, with immune cells spewing out inflammatory chemicals called cytokines in a “cytokine storm” that causes airways to become inflamed and the alveoli to fill with fluid. The result can be rapid death. According to the investigators, this finding at least partially explains why so many young, otherwise healthy people succumbed to the 1918-1919 pandemic, as do many victims of H5N1 today; their young, healthy immune systems generate a strong cytokine storm.

However, breakthroughs in understanding the details of the battle between the immune system and influenza A viruses hold the promise of better therapies and vaccines.

“A key challenge to immunologists is learning how to exploit the exquisite sensitivity of CD8+ cells to different targets on H5N1 and other flu viruses,” said Richard Webby, Ph.D., an assistant member of the St. Jude Department of Infectious Diseases and co-author of the paper. “We could use that knowledge to design better vaccines.”

Vaccines made of live viruses like Flumist® have the advantage of stimulating the memories of previously alerted CD8+ T cells, according to the authors. And, because these weakened viruses can still replicate themselves in the body, lower doses are effective. However, regardless of whether virus used as a vaccine is alive or dead, the virus targeted by the vaccine can mutate an immune system primed by that vaccine.

Therefore, the “Holy Grail” of influenza vaccine is one that would target universal antigens that appear on all flu viruses and that do not readily mutate, according to the authors.

Even without a “Holy Grail” vaccine, however, a vaccine that targets an antigen or antigens that mutate could offer some protection, says Webby. “H5N1 isn’t a permanent infection, like HIV is,” he said. “So even partial control that limits the severity of lung damage should allow the immune system to clear out the virus and offer life-saving protection.”

Another advantage would be that even such partial protection would lessen the possibility that the virus would jump to another person and spread the infection.
“This clearly suggests that it would be prudent to stockpile a vaccine that is specific for one variant of the virus even if it loses some effectiveness when a somewhat different variant arises due to mutation,” Thomas added.

The other author of the paper is Stephen Turner (University of Melbourne, Australia).

This work was supported in part by the National Institutes of Health, the Australian National Health and Medical Research Council, Science Technology, Innovation funds from the State of Victoria, Australia, and ALSAC.