A Cautionary Tale

New diseases, social factors challenge the victories of vaccines

Editor’s Note:  This story, first published in 2004, has been updated.

Lisa A. DuBois
Published: April, 2004

Consider the myriad of diseases that once were, but are no longer, scourges in the Western Hemisphere: polio, smallpox, rabies, measles, mumps, rubella, whooping cough, Haemophilus. Within a few generations, these diseases, which used to account for thousands of American deaths each year, have been virtually eradicated from the population.

Attribute that to one of the greatest triumphs in the history of medicine—the use of vaccines to prevent the spread of dangerous disease. Ever since the 18th Century, physicians have known that inoculating patients with extracted, weakened doses of a virus enabled them to develop immunity to deadly outbreaks. From the mid-20th and continuing into the 21st Century, public health officials have initiated a national campaign to ensure that children receive a series of immunizations against specific microbes. The result, in terms of population health, has been phenomenal.

Ironically, vaccines have now become victims of their own success. “The most effective public health strategy of the century is under great duress,” says Kathryn Edwards, M.D., who joined the division of Pediatric Infectious Diseases at Vanderbilt University Medical Center in 1980, and has subsequently worked on the evaluation and application of the Haemophilus influenza, pertussis, pneumococcus, meningococcus, smallpox, and trivalent influenza vaccines. “When we see disease, we understand how important it is to prevent it. But the more successful we are with our vaccines, the more we (eliminate) diseases and people never see them. So they never fear them.”

Because of some reports of bad side effects, a growing number of parents oppose having their children receive standard immunizations, such as the one against whooping cough. Yet without protection, pertussis can kill. Last year, four children died of whooping cough at Vanderbilt Children’s Hospital.

Edwards says, “I really feel like the Maytag Repairman. The better we are at preventing diseases, the more people are going to say these vaccines are bad. You can design an incredible vaccine, you can test it and know that it works beautifully and it’s safe, but unless you get it into the arms of kids, it’s a failure. So in this field you really have to think more programmatically, more practically and more about public health.”

Pitfalls in the system of vaccine delivery have never been more apparent than during the recent influenza epidemic of 2003-04, when physicians and patients alike were caught off-guard by an early, startlingly virulent and widespread outbreak of the Fujian-A strain of influenza. Deaths from the virus and from secondary infections rose well above the “epidemic threshold” defined by the U.S. Centers for Disease Control and Prevention (CDC). An alarming number of these deaths occurred in previously healthy children. This was a scenario infectious disease experts have predicted and dreaded for some time.

Illustration of an influenza virus partially cut away to reveal internal structures. The green core contains the genetic information of the virus wrapped up in protein. This combination of genetic material and protein is called the nucleocapsid.  Overlying the nucleocapsid is a layer of matrix protein, shown in purple. Over that is the viral envelope (blue-green and edged in yellow) derived from the host cell membrane.  The nucleocapsid and the matrix proteins become wrapped in cell membrane as they bud from the infected cell. The characteristic “spikes” of the influenza virus are surface membrane glycoproteins, called haemagglutinin, that are involved in attachment and fusion to the target cell. They radiate all over the surface and are interspersed (in some types) by clusters of neuraminidase, another membrane glycoprotein that enables newly formed virions to bud from infected cells.
These rapidly evolving glycoproteins are part of the reason flu vaccines must be adjusted to the prevailing influenza strains every  winter.
 
 
Editor's Note:  This illustration and for the cover illustration of the Spring 2004 issue were not credited correctly in the print version of the magazine. They are both by Russell Kightley.
 
Illustration by Russell Kightley. Copyright Russell Kightley Media

While the global press has latched on to potential bioterrorism agents like smallpox and anthrax, experts in virology have warned that the next great pandemic, or worldwide outbreak, most likely will be an influenza. “In many ways flu is the scariest disease there is,” says Edwards. “In contrast to AIDS, where you have to exchange blood or some sort of secretions, flu you get by what you breathe. It’s respiratorally spread, and in a moment a virus that’s in a pig lot in China can suddenly be in Los Angeles—and then all over the country.”

One of the most devastating pandemics of all time was the 1918-19 flu, which killed 500,000 people in the United States and over 20 million worldwide. The greatest death toll was among healthy young adults. An accepted theory is that the pandemic was caused by the movement of troops during World War I, but Peter Wright, M.D., former head of Vanderbilt’s Pediatric Infectious Diseases division, believes the answer may not be that simple. “The pandemic occurred equally in women,” he explains. “And I had occasion to look at the public health records in Iceland, and the same pattern of deaths occurred in Iceland, which was pretty isolated from the effects of World War I.”

Kathryn Edwards, M.D., (seated, left) and Marie Griffin, M.D., (seated right) review findings from a vaccine surveillance study with research nurse Ann Clay, R.N., standing left) and Diane Kent, .N., (standing right), study coordinator.
Photo by Anne Rayner
Depending on a population’s level of immunity to a particular strain and to subtle changes that occur in a virus’ makeup, he says, influenza has a capacity to be more or less virulent and more or less deadly. Influenza virus types A, B, and C are classified based on the antigenic differences between two surface glycoproteins, H and N—hemagglutinin, which facilitates entry of the virus into host cells, and neuraminidase, which assists in the spread of infection. To illustrate just how insidious these antigenic changes can be, the 2003-04 vaccine contained protection against the H3N2 Panama-A strain, but not against its noxious H3N2 Fujian-A cousin that emerged too late to be included in doses manufactured for the season.

Most of the flu viruses that are emerging today originate in China and areas of the Far East where crowded, open air, poultry and meat markets create a prime breeding ground for viruses found in fowl and other animals including civets, small mammals that have been linked to SARS. These viruses constantly reassort and recombine their genes, creating new strains, some of which are pathogenic to humans. If influenza’s surface proteins were as stable as mumps or rubella’s, for example, one vaccine would offer lifetime protection. Instead, flu strains mutate quickly and unexpectedly, and antibodies against one strain don’t necessarily provide immunity to the next year’s outbreak. Public health officials, under the aegis of the World Health Organization and the National Institutes of Health, meet annually in Geneva to evaluate which pathogens are appearing on the scene, and to commit to developing vaccines for the upcoming crop of viruses. In other words, getting a good flu vaccine in any given season is like shooting a moving target.

Once the group identifies three dominant viral strains, pharmaceutical companies estimate the number of vaccines needed around the world and grow them up in chicken eggs, a time-consuming technique that has been used since the 1940s.

Reverse genetics

Speaking from Hong Kong, where he is part of the WHO surveillance team, Robert Webster, Ph.D., an infectious disease expert at St. Jude Children’s Research Hospital in Memphis, claims that they knew Fujian-A was in the human population as early as February 2003, but they couldn’t grow it up in time for a vaccine. Had they been able to use a technique known as “reverse genetics,” he insists, Fujian-A would not have wreaked such havoc.

The current technique for developing a vaccine requires six months, and tens of millions of eggs. Scientists produce a “viral seed strain” by reassorting two currently circulating viruses. With reverse genetics, scientists can rapidly engineer the seed strain in the laboratory by picking and choosing the H and N genes they want. In this way, they can custom design a vaccine that will be safe for humans, but which will also generate an immune response. The virus still must be grown up in eggs to produce a vaccine, but the process can be completed in weeks instead of months.

“We have the technique for reverse genetics,” Webster says, “and it could have been used this year, but it’s not an approved method yet. We have to get approval for using that technique to generate vaccines quickly.” The flu vaccine shortage that occurred this winter “is just the tip of the iceberg,” he says. For example, a strain of avian flu even more virulent than the one that spread through Asia this winter could appear in the United States and cause more illness and death than the Fujian-A strain did. He adds, “If we get one of the new strains we’re seeing in animals in Hong Kong, and if you think we’re going to have plenty of vaccine in the face of pandemic, think again.”

Part of the problem, says Marie Griffin, M.D., a pharmacoepidemiologist and professor of Preventive Medicine at Vanderbilt, is that the burden of disease from influenza has, historically, been under-appreciated. The past three or four flu seasons have been mild, so Americans didn’t rush out to get a flu vaccine, and manufacturers threw away millions of excess doses last year. Each year influenza causes around 40,000 excess deaths, mostly in people over the age of 65, many of whom have other chronic illnesses. However, annually around 20 percent to 40 percent of children, who may be immunologically “naïve” to a new flu strain, also come down with influenza.

“What tips the balance towards us recommending that children get vaccinated is that some of those kids have severe consequences from flu,” Griffin says. “What we’re learning, or maybe learning again, is that there are quite a few kids under the age of two who end up getting hospitalized for influenza, which is a bad outcome even if few of those kids die.”

Recent data indicate that in an average year, not a virulent year like the current one, one or two children per thousand, who are under age two, may be hospitalized with flu. “That adds up,” she says. “It’s common enough that from a public health perspective it’s large, yet rare enough that from an individual pediatrician’s perspective it’s not that much.” Even more surprising, according to a recent unpublished CDC-sponsored study by Griffin and Edwards, 74 percent of infants and toddlers hospitalized with flu were otherwise healthy and not considered “high risk” for complications.

The CDC estimates that the annual associated costs from influenza—including doctor visits, hospitalizations, medicines, days lost from work, child care, etc.—exceed $12 billion a year. Moreover, the burden of disease from children with the flu is actually greater than that in people over 65. Griffin says that new rapid viral diagnostic tests have also raised awareness about how much flu is in the population at any given time.

The obvious solution would be that all people of all ages, who can safely do so, should receive all vaccines all of the time. Unfortunately, obstacles to the production and delivery of vaccines make that impossible.

FluMist, the nasal mist vaccine that uses a live, attenuated virus, was actually developed 10 years ago, but only became available to the public in 2003. One reason for the delay is that any new vaccine must first be tested in 30,000 to 40,000 people before it is approved for general use, making clinical trials extremely expensive and cumbersome. Another issue is vaccine safety.

“No one is willing to tolerate any kind of adverse event anymore,” Edwards says. “The reason the nasal flu vaccine is not licensed for kids under five is because some kids who’d gotten the nasal flu vaccine had some wheezing—although it’s probably the best way to vaccinate little kids. We’re in a real bind because we need to be innovative, but we have more controls and more obstacles to licensing products.”

“One of the things going on in vaccine development today is that we are taking on harder targets to immunize against,” says James Crowe, M.D., professor of Pediatrics at Vanderbilt and an expert on respiratory syncytial virus (RSV), the leading cause of lower respiratory tract disease, such as wheezing and pneumonia, in infants under two months of age. Rather than target viruses that spread through the blood, such as measles, investigators are now trying to attack viruses like RSV that cause disease at the mucosal surface but never enter the blood—a much more difficult proposition, Crowe says.

Targeting children

An experimental inactivated RSV vaccine candidate developed in the 1960s enhanced rather than prevented disease, and was not further studied in humans. Newer, safer live, attenuated vaccine candidates can generate a good immune response in children older than six months, but not in younger infants—those at greatest risk for complications from RSV infection.

Crowe explains, “We believe that at the time of birth babies are in transition from an environment in which they are not exposed to foreign antigens to one where they immediately need to start making antibody responses. It may be that the answer to how to induce better immune responses in children is to give vaccines more frequently very early in life, so that we catch children at a time point when their immunologic development is moving along. The whole public health infrastructure would have to be reoriented for vaccines that have to be given more than once during the first month of life. We’re currently not set up to do that.”

As researchers work to create a vaccine against HIV/AIDS, infrastructure issues become even more problematic. Comprehensive studies show that in developing countries such a vaccine would have to be targeted towards 12- to 15-year-old children, who are not yet sexually active. To date, there is no effective AIDS vaccine, and the pressure is mounting to find one. Says Wright, “Perhaps the new antiretroviral drugs can slow an epidemic, but I don’t think anyone will make a projection that HIV will go away without a vaccine component. The cost of AIDS in the countries of Africa where 10 to 15 percent of the young adults have HIV is of great interest to the U.S. government.” He cites the potential for social disruption and political instability if such a large number of the most productive members of a country’s work force becomes sick. “It is appropriate to take those costs into account as we introduce new vaccines,” he says.

In fact, cost and liability, rather than scientific know-how, have become the greatest barriers to vaccine production. Even minor side effects and reactions from new vaccines are likely to result in lawsuits, a liability that vaccine manufacturers are unwilling to bear. The government will have to pick up the tab. Says Webster, “There used to be five manufacturers of flu vaccine in the United States. Now there is only one company manufacturing the standard injectable, and one making the nasal mist vaccine. I would like to send a message to our nation’s legislators: If you want to have a vaccine in the face of a pandemic, then you’d better consider the liability issues now.”

Vaccines, Edwards explains, are not like other drugs. A drug to prevent ulcer disease, for example, will be taken by millions of people over the course of years, whereas people may take a particular vaccine only once in a lifetime. “So the market share for vaccine is totally different than the market share for a pharmaceutical,” she says. “The incentive to make new, sexy vaccines that could use incredible technology is not what it is for pharmaceuticals. Coupled to that, a lot of vaccines are given to children—and children don’t vote.”

In addition, Americans are used to purchasing their vaccines at bargain basement prices, since the government purchases half the vaccines available in this country. Edwards says, “If you work for a pharmaceutical company, you have to ask why you should be investing resources in a vaccine you give once a year to part of the population, and sell it to half those people for cost.”

The public health response to SARS proved that scientists are becoming more adept at mounting dramatic research responses to the sudden emergence of traumatic diseases. They are less skilled at maintaining public support while they prepare for the next viral pandemic, which typically surfaces every 50 years or so. Should such an incident take place, a well-oiled system for manufacturing and delivering vaccines will be crucial to saving millions of lives. Such a system does not yet exist.

If there is a plus side to the cloud of bioterrorism that hangs over the Western world, it is that governments are infusing money into public health to address potential threats of epidemics and pandemics. “The flu provides a good model for testing how well we respond to major outbreaks of disease,” Griffin says. “We now know much more about what we need to do and where the gaps in the system are.”

One of those gaps, she says, is the under-use of effective antiviral medications, which have tended to be under-prescribed by physicians and under-tested in various populations.

Webster echoes that sentiment, insisting, “We need to begin stockpiling antiviral flu medicine. Because flu strains mutate so quickly, it won’t help to stockpile flu vaccines, but the flu drug is effective against every single strain of flu we’ve tested it against. Legislators have to put that on their radar screens. The precursors, the viruses, for a pandemic like the one in 1918 are out there.”

Still, Edwards believes there is reason to hope. “The more we continue to prepare for a disease, and particularly for a bioterrorism event,” she says, “the less likely it is it will happen.”

Mary Beth Gardiner contributed to this story.

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