JANUARY / FEBRUARY 2005

FORUM

Communicable concern: Health officials, scientists wait and watch for influenza outbreaks

The World Health Organization estimates that annual influenza epidemics affect 5-15 percent of the world’s population, resulting in between three and five million cases of severe illness, and between 250,000 and 500,000 deaths. Those numbers don’t get influenza listed among the world’s leading causes of death or disability. In fact, in developing regions, lower respiratory infections, tuberculosis, and measles all account for more deaths than influenza. But consider 1918, when an influenza pandemic known as the “Spanish flu” transcended continental divides on its way to resulting in between 20 and 50 million deaths worldwide (estimates vary). Pandemics in 1957 and 1968 were less severe, though their impact far exceeded normal figures for influenza. As recently as 1997 in Hong Kong, only the rapid response of health officials prevented another worldwide outbreak. Today, scientists study the virus that caused the 1918 pandemic, searching for the key to its bewildering virulence. Epidemiologists around the world are looking for clues that will help them solve the mystery of avian flu, as in parts of Asia the influenza virus shows a heightened ability to move from animal to human. All the while, health officials warn that the next pandemic could be just around the corner. Ordinary citizens wonder if the public health infrastructure is prepared for what may come.

A shape-shifting virus
For most people, influenza is an upper respiratory tract infection that lasts several days before the virus is eliminated by the body. Antibiotics, which are designed to kill bacteria, can do nothing to get rid of the virus, but there are treatments to ease the suffering from the familiar symptoms—the sudden onset of fever, coughing, chills, and aches and pains—and antivirals which can reduce the toll of the symptoms and, in the early stages of the disease, may help prevent infection. The virus can move easily from person to person through the air in droplets and small particles that are excreted when the infected cough or sneeze.

We can divide the influenza viruses that are currently in circulation and impact humans into two groups: A and B (a third group, C, rarely causes serious problems). Each of the three influenza strains that caused pandemics in the last century belonged to the type A group of viruses. Type A influenza viruses have been found to infect a wide variety of animals, including poultry, swine, horses, humans, and other mammals. Two subtypes of this group are important for humans: A(H3N2) and A(H1N1), of which the former is currently associated with more deaths.

The genetic makeup of influenza A virus enables it to evolve and exchange genes easily. The virus’s genetic material is made up of eight RNA segments that are encased in a lipid membrane containing proteins. The virus reproduces itself by entering a living cell, where it forces the cell to manufacture new viral proteins and additional copies of viral RNA. These pieces assemble and become new viruses that leave the host cell and move to infect other cells. New mutations are common, and if two different influenza strains infect the same cell, there is the potential for a reassortment of viral genes that produces a wholly new strain of the virus.

Influenza A viruses are defined by two different protein components, known as antigens, on the surface of the virus. They are spike-like features called haemagglutin (H), which has at least 15 known variants, or subtypes, and neuraminidase (N), which has nine subtypes. These subtypes are the keys to making it possible for the virus to reproduce.

Pandemic influenza: Potent but unpredictable
Three times in the last century—in 1918, 1957, and 1968—the influenza A viruses have undergone major genetic changes mainly in their H-component, resulting in global pandemics and large tolls in terms of both disease and deaths. The first exposure to H1N1 was in 1918 (Spanish influenza). H1N1 made another appearance in 976 with the swine flu, but there was no pandemic. In 1997 a pandemic was narrowly averted by fast-acting health officials who ordered all of the chickens in Hong Kong destroyed.

We know that each year brings with it a “flu season” that accounts for a fairly predictable number of cases. What we cannot predict, however, is the emergence of a pandemic influenza virus that has an unusual ability to spread and cause disease.

Anthony Fauci: “You cannot predict when [a pandemic] will happen. We hope that our public health infrastructure and our stockpiling of antivirals and vaccine production capability is able to move on a dime and respond.”

Anthony Fauci, MD, directs the National Institute of Allergy and Infectious Disease (NIAID), a division of the National Institutes of Health, which is involved in attacking influenza from various angles. The NIAID’s researchers are working to understand the mechanisms of pathogenicity of pandemic influenza viruses, and identify markers that signal the emergence of influenza strains with increased virulence. They are also studying how new flu viruses emerge from animal reservoirs to cause a pandemic. The purpose of this research is not only to feed into the arena of vaccine development, but also to minimize one of the influenza virus’s greatest assets: its unpredictability.

Fauci’s team is one of a number of research groups that have looked to the 1918 pandemic H1N1 virus—the virus that caused the Spanish flu—for clues to help define and predict pandemic viruses. The 1918 virus “was a very special virus with a virulence beyond what anyone had seen,” says Fauci.

The virulence of an influenza virus once it infects a host is determined by a complex set of factors, including how readily the virus enters different tissues, how quickly it replicates, and the violence of the host’s immune response to the intruder. For a virus to be considered a pandemic influenza A virus, it must be isolated from humans and have a novel hemogluttin or neurominidas—in other words, it’s something that hasn’t been seen before. Another defining characteristic is a susceptibility, or lack of antibody, to this novel virus in a large proportion of the population. Finally, the virus must demonstrate an ability to cause disease and spread from person to person. What this definition makes clear is the urgency felt by health officials and epidemiologists whenever unusual cases of the flu—or what might be the flu—are reported. By the time they have been able to determine that a pandemic virus is on the move, the death toll is already mounting.

Complications in the air
Going into this flu season, health officials worried that H5N1 had the potential to cause a pandemic, but the strain has not been very inefficient in its spread. That is good news, says Fauci, but he is quick to point out that the mortality rate in documented cases of avian influenza is about 70 percent. In fact, in the past year, more than 40 people in Thailand and Vietnam have contracted the avian virus, and more than 30 of them have died. The bird flu phenomenon presents a puzzle for health officials around the world, particularly in Asia, since scientists have yet to completely understand how a nonhuman flu virus adapts and becomes a human flu, and why more do not.

Robert Webster: The outbreak of avian influenza is “a wake-up call for the world to provide the resources needed to prevent future outbreaks of H5N1 among poultry or to prepare for a human pandemic of a very dangerous virus.”

Robert G. Webster, PhD, of St. Jude Children’s Research Hospital, is among a group of researchers that have argued (in the July 2004 issue of Nature) that the H5N1 virus could evolve into a worldwide threat to humans. Webster and his colleagues have linked avian influenza to three major outbreaks among poultry that have killed several people in East Asia over the past seven years. They say that the virus that caused these outbreaks can be attributed to a series of genetic reassortment events involving other viruses. The report in Nature details genetic studies of the evolving H5N1 virus that caused the initial human outbreak in Hong Kong in 1997—when a pandemic was put down by the destruction of Hong Kong’s chickens—and traces the origins of the highly pathogenic H5N1 disease that affected Asian poultry in 2003 and 2004. Unprecedented in its geographical range, the outbreaks of the last two years showed the enormous potential of this virus. “The transmission of H5N1 to even just a relatively few people was an ominous sign that it has the potential to adapt to humans,” says Webster.

By cleaning up open-air markets and regularly slaughtering infected birds, Hong Kong remained free of H5N1 outbreaks in poultry during the 2004 influenza crisis. According to Webster and his fellow researchers, this is the key right now to preventing a human pandemic of H5N1. “In order to reduce the ability of H5N1 to trigger another poultry epidemic, officials in East Asia must follow Hong Kong’s lead,” says Webster. “Otherwise, H5N1 will likely continue to infect birds and other animals and eventually could evolve into a dangerous human pathogen as well.”

Certainly, Hong Kong’s decisive action reduced the threat of the transmission of bird flu to humans, and possibly even prevented the outbreak of a human pandemic. That is a public health victory in the larger context of global infection control. But averting a potential public health catastrophe had a significant economic impact to poultry farmers in East Asia. The question remaining is whether such farmers and their governments should bear this financial burden by themselves.

“If we consider H5N1 to be a global problem that could get much worse, perhaps the costs should be borne instead by the World Health Organization’s global influenza program,” says Webster, who adds that the situation in Hong Kong is “a wake-up call for the world to provide the resources needed to prevent future outbreaks of H5N1 among poultry or to prepare for a human pandemic of a very dangerous virus.”

Responding to what we know, and to what we don’t
In November the World Health Organization (WHO) convened a meeting of regulatory authorities, health ministries in several countries, representatives of four laboratories in the WHO influenza network, and executives from 11 companies representing all of the major influenza vaccine manufacturers. The meeting’s participants agreed that should a pandemic virus emerge now, no manufacturer would be able to move immediately into commercial production before the summer of 2005.

In fact, though various types of influenza vaccines have been available for more than 60 years, during the two pandemics that occurred during that time, supplies have not come close to matching demand. Today the outbreak of the H5N1 virus has some health officials worried that conditions favor the emergence of a pandemic virus.

Should a pandemic occur, the nature of the vaccine development process will be partly to blame for the projected shortfall in the vaccine supply. Because the genetic makeup of influenza viruses allows a virus to frequently change—to undergo what is called an antigenic shift—the vaccines must be adjusted annually according to what viruses emerge during flu season. The WHO’s Global Influenza Surveillance Network , a partnership of 112 national influenza centers in 83 countries, is responsible for monitoring the influenza viruses circulating in humans, identifying new strains, determining the three most virulent strains, and concocting the recipe for the annual vaccine.

As Anthony Fauci points out, there is a lack of flexibility in this process that makes it “very difficult to backtrack and start from square one.” Most importantly, it takes time. “One of the weaknesses or fragility of vaccine-making is that it is time-sensitive. It isn’t like making a big stockpile of Lipitor and selling it as you want to sell it.”

The dangerous strains of the virus are identified around January, several months before the next flu season begins, and production of the vaccine starts. By the time the vaccine has been tested and licensed by regulators, and packaged and shipped to health care providers, the flu season is just around the corner. The process offers little room for error or delay.

Another obvious barrier to vaccine production is the reluctance of pharmaceutical companies to take on a new production line that offers very thin profit margins. For this reason Fauci and others have called for incentives to entice drug-makers to get in the game, such as regulatory relief, tax incentives, research resources, and liability protection.

Marc Lipsitch: “Given the certainty that each year a fairly predictable number of people will die from influenza, it seems that increasing the investment in the process of vaccine production would have inarguable benefits.”

Marc Lipsitch, an epidemiologist at the Harvard School of Public Health, says that “given the certainty that each year a fairly predictable number of people will die from influenza, it seems that increasing the investment in the process of vaccine production would have inarguable benefits. Every year there is an outbreak—tens of thousands of deaths in the United States alone—and yet the funds dedicated to research in this area are disproportionately small, compared to what is spent on, for example, biosensors to defend against a bioterrorist attack, an event which statistically is far less likely to occur.”

Lipsitch adds that there is room for advancement on both the technological and logistical sides of vaccine production. The bulk of today’s influenza vaccine is created through a system that hasn’t changed much in a half century, depending on chicken eggs—a limited resource—and educated guesses about which strains of the virus will circulate each winter. FluMist, the nasal spray vaccine, is an improvement, but it uses a live, although weakened, virus and is only approved for healthy people between the ages of five and 49—which leaves out the most vulnerable members of the population at both ends of the spectrum. Some experts say the best hope is a genetically engineered vaccine that could be quickly altered to match whatever flu strains are in circulation. Others are working to design a set of dummy or precursor strains for each of the subtypes, so that some of the engineering that must be done at the beginning of the vaccine production process can be done, thus giving the vaccine manufacturers a head start on the flu season.

As scientists continue to look for alternatives or improvements to the current vaccine system, a basic fact remains: the vaccines work for a significant number of people. Among healthy adults the vaccine is very effective (70-90 percent) in terms of reducing morbidity. There is some disagreement about the vaccine’s effectiveness among the elderly; the World Health Organization estimates that vaccination reduces influenza-related morbidity by as much 60 percent, but other experts argue that the percentage is actually much lower. Whatever the exact figures on effectiveness, what is not in doubt is that the supply of the vaccine rarely matches demand. Given the annual shortages, Lipsitch believes that antiviral drugs for influenza are an important adjunct to—though not a substitute for—the influenza vaccine for both treatment and prevention. “Although there is not enough production capacity to make antivirals available to prevent a pandemic, we can make millions of doses per year,” said Lipsitch. “And we can stockpile antivirals in Asia, so that they can speed up their response when outbreaks occur. Of course, if we wait until the pandemic happens to do this, those countries that have stores of antivirals are likely to hold onto them.”

Click the diagram above to view how a genetic change in a virus, called an antigenic shift, can enable the virus to jump from one animal species to another, including humans. (Diagram courtesy of the National Institute of Allergy and Infectious Disease website)

If not today, when? And what then?
Is an influenza pandemic imminent? Does the phenomenon of avian influenza change the flu dynamic completely? Lipsitch is more focused on what we can do to prepare ourselves, whether by revolutionizing the vaccine production process or by refining our response mechanisms, with an eye towards identifying the measures that are effective in stopping the virus from spreading. Fauci at NIAID is involved in both the basic science research that deconstructs the virus, as well as the fine points of preparation and response. Neither can predict the next pandemic, but both are cautiously optimistic about the ability to deal with a pandemic, should one occur. Addressing the issue in November, Fauci said, “If you look at history, it’s unlikely that all of a sudden we will have a totally massive pandemic, easily spread from person to person, happen in December. Will it happen next year? I don’t know. Possibly. Is it going to happen sometime in the reasonable future? The answer is yes. We’re due for it. We have a lot of chickens getting infected, and more and more jumping from chicken to human. But you cannot predict when it will happen. We hope that our public health infrastructure and our stockpiling of antivirals and vaccine production capability is able to move on a dime and respond.”

Copyright 2006 Harvard Medical International