H5N1 influenza strain raises concern about a pandemic

October 2005

WASHINGTON — The human avian H5N1 influenza cases occurring in Asia bring the threat of an influenza pandemic ever closer to our shores, said Benjamin Schwartz, MD, at a press conference sponsored here by the National Foundation for Infectious Diseases.

A possible pandemic

So far, there has been no confirmed person-to-person transmission, but if the strain mutates and develops that transmission capability, it could cause a deadly pandemic.

The Trust for America’s Health (TFAH) released state-by-state projections that found more than 500,000 Americans could die and more than 2.3 million could be hospitalized if a moderately severe strain of a pandemic influenza virus hit this country. Sixty-seven million Americans are at risk of contracting the pandemic influenza strain. A pandemic with the H5N1 strain could be worse though, according to Schwartz. The mortality rate so far is higher than 50%.

One would be hard pressed to find a public health official or infectious disease specialist who does not believe a pandemic is possible and probable, and that this H5N1 strain increases the likelihood of it being sooner rather than later. “I think [H5N1] has all of us not only fascinated, but anxious. I did not think that it would spread that quickly via migratory birds,” William Schaffner, MD, told Infectious Diseases in Children.

“Influenza pandemics occur when a new influenza strain to which most or all of the population is susceptible spreads among people. This new strain can develop by the sharing of genetic material between avian and human influenza virus strains, either in a coinfected animal such as a pig or in humans, or possibly by mutation of an avian influenza strain,” explained Schwartz, who is senior service advisor, National Vaccine Program Office at the Department of Health and Human Services (HHS), and who is working on the national pandemic plan.

Recombination

The chance of a recombination depends on the viral strain and how widespread it is among humans and animals. This is why the current H5N1 strain in Asia represents a major pandemic threat. Its scope is unprecedented, Schwartz said. H5N1, which can be asymptomatic, infects domestic poultry and wild waterfowl. Infected migrating birds can carry the virus long distances as well.

People with H5N1 infection generally have severe disease, Schwartz said. “Unlike the flu that occurs in the United States each year, which most often causes mild disease, reported H5N1 cases usually progress to pneumonia, frequently progress to respiratory failure and accompanying multiorgan system failure and, in more than half of all cases, death occurs.”

A normal flu season tends to kill the most vulnerable populations: the elderly, infants and those with chronic conditions. Most of the H5N1 deaths have occurred in young and previously healthy individuals, Schwartz added.

The ongoing disease in domestic and wild poultry and the evolution of the H5N1 virus, which appears to be adapting to spread among mammals, point to a growing threat. “However, it is unclear whether this strain of H5N1 will ever acquire the ability for efficient and sustained transmission among people,” he said.

So, public health officials prepare for a pandemic with an eye on H5N1, but a realization that the threat could be lurking somewhere else. The influenza pandemic of 1918 probably started in the middle of the United States, although it is difficult to pinpoint exactly where.

Many steps must be taken to prepare for a pandemic. Surveillance must be enhanced. The production capacity of influenza vaccines and antiviral drugs must be increased, and the capabilities of the health care systems to respond must be improved to reduce death and severe illness among those who contract the disease.

“Early detection of influenza among animals and people is critical,” Schwartz said, but many countries affected by avian influenza lack good surveillance systems, as well as the necessary laboratory, epidemiologic and veterinarian staff.

The NIH and WHO have provided money and manpower to improve the surveillance infrastructure of Asian countries, to strengthen detection and response capabilities, and to improve data management and information sharing.

From detection to protection

Vaccination will be the primary prevention strategy in a pandemic. “However, we face substantial challenges in developing and producing pandemic vaccine. Developing a vaccine to a new influenza strain may take up to six months,” Schwartz said, which makes early detection even more critical.

Even if there is a vaccine, the need will exceed production capacity. “Unlike annual influenza, where we focus our efforts on only part of the population, in a pandemic, everyone will be susceptible and vaccination most likely will be recommended universally,” he said. “And because every country, not just the United States, will be experiencing the pandemic, we assume that only vaccine manufactured within the United States will be available for our population, despite preexisting contractual agreements.”

There are only two companies with U.S. influenza vaccine manufacturing plants, Sanofi and MedImmune. Each season, Sanofi makes about 60 million doses of the inactivated trivalent vaccine, Fluzone. During a pandemic, the company said it might be able to deliver 4 million doses per week. MedImmune also said it would ramp up production of its intranasal vaccine if a pandemic occurred, but this vaccine is not indicated as broadly as the inactivated vaccine.

“Our current [inactivated] flu vaccine is grown in embryonated eggs and to guard against disruption of this critical raw material, we have entered into a contract that assures the year-round ability to produce influenza vaccine and to guard against shortages,” Schwartz said.

The NIH is exploring ways to make vaccine using cell culture instead, which would double the ability to manufacture U.S. influenza vaccine, and it is trying to develop dose-stretching strategies that enhance the immune response but use less antigen in each dose. This would increase the supply by several fold, he said.

The New York Times recently reported that studies using an experimental H5N1 vaccine were efficacious. There is a small stockpile of H5N1 vaccine, and the United States plans to stockpile 20 million doses of this vaccine. However, the Census Bureau says there are 294 million people in the United States, so only a small portion of the population would be vaccinated.

“The country remains vulnerable, especially in the beginning, and HHS will have to define priorities for vaccination in the first wave of a pandemic,” Schwartz said.

Regardless of ramped up production, it is clear that many people would not be vaccinated immediately. Priority groups will need to be defined. This is going to be difficult. The 1918 pandemic strain attacked young and previously healthy people, as the H5N1 strain seems to be doing, but the 1957 and 1968 pandemic strains went after the typical influenza victims: the elderly and infants.

Vaccine recommendations might target the same people who are at risk during a normal influenza season or they might target those who are critical to pandemic response and societal function, such as health care, police, fire and corrections workers, as well as those who maintain critical infrastructure like utility, sanitation and transportation workers.

It might be a good idea to use the first batch of H5N1 vaccine to prime the immune system of the targeted audience because two doses might be needed for complete protection against a new virus, explained Schaffner, professor in and chairman of the department of preventive medicine and professor of medicine in the division of infectious diseases at Vanderbilt University School of Medicine in Nashville, Tenn. However, there are no data to support that approach, and some experts think it could be an unnecessary exposure to a vaccine, he added.

“If it is necessary to give two doses, if you start from ground zero, you have a longer distance to run to get people protected,” he said, but you can get a “running start” if you give some doses to the priority groups. “A lot depends on how much can be manufactured, how much we are comfortable having in the stockpile and whether we can make some more and already start immunizing with the first dose if two are necessary,” Schaffner added.

There is also the problem of confusing the public, which may not be able to distinguish the H5N1 vaccine from the annual influenza vaccine, according to Schaffner.

Although the United States will try to prevent disease with vaccination, people will still develop influenza, so antiviral drugs will be a primary treatment strategy because they reduce flu severity and decrease complications and hospitalizations. “Because the global production capacity of effective drugs is limited, antivirals maintained in the strategic national stockpile will comprise our main supply,” Schwartz said, adding that the stockpile has 2.3 million treatment courses of oseltamivir (Tamiflu, Roche), but the government plans to purchase enough to increase it to 20 million courses.

More than 2 million Americans may need hospitalization during a moderately severe pandemic, but there are only about 965,000 staff hospital beds, according to the TFAH report.

Preparing for a pandemic

The CDC and U.S. Health and Resources and Services Administration have provided $1.35 billion toward helping states become prepared for national and bioterrorist health threats, Schwartz said. The money is being used to complete the states’ preparedness plans, to conduct preparedness exercises, to improve collaboration between public and private sectors and to increase the surge capacity by increasing the number of staff and hospital beds by 15% to 20%, according to Schwartz.

Schaffner said Schwartz’s comments about increasing capacity sound as though more staff and beds will be available. “I wonder if that is the case. At least in our neck of the woods, that money has gone to better prepare ourselves for trying with existing resources to take care of a larger percentage of patients,” he explained. Vanderbilt put those preparedness plans to the test two years ago when influenza hit the area hard and early. “We put phase 1 of our plan into effect, and what that means is that you review every patient in the hospital and decide whether they can be discharged a half a day or a day sooner than previously planned,” he said, so that the bed can be made available to the influenza patient.

Phase 2 would curtail elective admission, and phase 3 of the Vanderbilt plan would designate entire wards as influenza wards, changing certain step-down units into acute care units.

“Notice, we didn’t build any more beds; notice, we didn’t hire any more nurses. We would anticipate when this sort of outbreak hits that just about every hospital in town is full and all the agency nurses are working somewhere,” Schaffner said.

Schwartz said all states have drafted preparedness plans and submitted them to the CDC for review. In addition, 90% have conducted emergency response drills, 90% have surge capacity plans and 60% have reported they already have reached surge capacity objectives. At the hospital level, 97% participate in regional planning groups and 95% report having plans to extend their staffing in the event of an emergency. This leaves 10% to 40% of states in each category unprepared.

The need for these plans became even more apparent after Hurricane Katrina. “After Katrina, virtually every disaster preparedness unit is reevaluating their preparedness plans, including our own here at Vanderbilt. After Katrina, it is clear that there were a number of glitches, including communication problems,” Schaffner said. He added that “[these events] make us even more determined to move ahead with pandemic preparedness. ... As we have seen with Katrina, what you need is flexibility and the ability for collaborators to adjust to changing situations.”

If the pandemic hits in November, Schwartz explained, “we will respond with all of the capabilities and capacities we have available. If the pandemic hits the following influenza season, we will have more capacities and capabilities and will probably respond better.”