Give Me Immunity or Give Me Death

By Jason Socrates Bardi

Having been among the early converts, in this part of the globe, to [smallpox vaccine's] efficiency, I took an early part in recommending it to my countrymen. I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family. Medicine has never before produced any single improvement of such utility.

———Thomas Jefferson, from a letter to Edward Jenner, 1806

When Meriwether Lewis and William Clark began planning their mission of exploring the American West, they received a special package from President Thomas Jefferson, who had commissioned Lewis to lead the expedition.

Jefferson instructed Lewis to carry with him Jenner's smallpox vaccine and distribute it to the Indian tribes throughout the West, many of which had already sustained outbreaks of smallpox. Variola, the virus that causes smallpox, had continued its expansion into the new world.

"Inform those of them with whom you may be, of it's efficacy as a preservative from the smallpox & instruct & encourage them in the use of it," said Jefferson.

Jefferson was hoping that the vaccine—which contained live cowpox virus—could possibly stave off smallpox epidemics among the immunologically naïve western tribes, whose landmass isolation had allowed them to escape the devastating disease.

Sadly, though, the vaccine did not survive the journey west. And within a few decades, smallpox outbreaks with mortality rates as high as 90 percent would devastate many of the western tribes.

"The history of these things is quite interesting," says Michael B. A. Oldstone, a professor in the Department of The Scripps Research Institute(TSRI), who is equally interested in viruses themselves.

Small, Significant

The smallpox virus belongs to a family of nature's most ruthless killers—the RNA viruses, which are among the oldest and most notorious adversaries the human species has ever had, and which Oldstone has spent a career studying.

They range from measles, mumps, and rubella virus to the viruses that cause foot and mouth disease, polio, hepatitis A and C, yellow fever, human immunodeficiency virus, and the "Spanish Flu" influenza virus, which killed more Americans in World War I than died in combat.

In this day and age of solving genomes and mapping the expression of thousands of genes to particular tissues, RNA viruses are somewhat of a paradox. On the one hand, they can bring societies to their knees. Smallpox killed more people in the 20th century than died in all the century's wars combined.

On the other hand, RNA viruses are rather unassuming. They are like the old VW bugs of the pathogen world—small, simple, and seemingly able to run forever. An RNA virus can have as few as four genes. Nearly all of them have under 10 genes. The largest RNA virus has only 12 genes.

Yet, RNA viruses are able to alter cell function and profoundly affect the complex, eukaryotic life forms that they infect. An RNA virus with only four genes can cripple or kill a mammal with 40,000 genes.

Take the choriomeningitis virus, for instance, one of the viruses that Oldstone has studied for several years. Its genome is segmented into two separate pieces of RNA that are packaged together. They are packaged inside a compact virion, an infectious virus particle. And together, the entire genome is only a few thousand bases—six orders of magnitude smaller than the cells it infects—and has only four genes. Yet it can easily persist for the lifetime of that organism.

"Everything the virus needs is in these four genes—it's amazing," says Oldstone, adding that, by comparison, herpes virus has 250 genes.

This leads one to ponder—as it led Oldstone to puzzle over years ago—how, with so few genes, these RNA viruses are able to do what they do. At the outset of his career, Oldstone decided to ask, specifically, what are the host factors that are involved in the infection? What proteins and other molecules in the infected organism are the viruses interacting with? And how can we use the tens of thousands of genes in our brains to stop those handful of viral genes? His work in this area since he began his career at TSRI has led to recognition and many awards, including the J. Allyn Taylor International Prize in Medicine for the study of host–virus interactions.

The Most Contagious of Them All

One of the viruses that Oldstone has studied for a number of years, measles, is the most contagious infectious agent known to humankind.

With an infection rate of 98 to 99 percent, measles is a highly infectious virus that causes a maculopapular rash, fevers, diarrhea, and, one to two times out of a thousand, death. Measles is also highly contagious, and until the advent of mandatory vaccination programs in the United States, there were an estimated three to four million cases annually. Some 90 percent of the U.S. population had had measles by the age of 15.

There has been a commercially available vaccine for measles in use since 1963, and, though effective, this vaccine must be kept refrigerated for the duration of its one-year shelf life. This is problematic in tropical climates like southern Asia and sub-Saharan Africa, which continue to support endemic measles infection. The World Health Organization (WHO) estimates that in 2001 there were 30 million cases of measles worldwide and over one million deaths.

The measles virus has eight genes and gets a lot of use out of them, infecting lymphocytes, dendritic cells, and cells of the nervous system. The viral receptors that facilitate the entry of measles into cells are known, and one of these receptors, called CD46, is of particular interest to Oldstone. The measles virus has a hemagglutinin glycoprotein that binds to a single, broad surface on one side of CD46, which is expressed on virtually all cells in the body, and as a result, measles virus can infect multiple organs, including the brain.

Cases of measles can be severe when the virus infects the brain, because the body's immune response can cause massive damage to the central nervous system, and about one out of every million cases results in a chronic, progressive, fatal neurological disease.

However, mortality from measles is usually much higher than this because the disease is immunosuppressive—it infects cells of the immune system—and if "opportunistic" infectious agents like Mycobacterium tuberculosis or Staphylococcus are present, the immunosuppression can lead to a secondary infection, which is often fatal. Measles mortality can be is as high as 33 percent.



Next Page | The Persistence of Viral Infections

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Michael Oldstone, professor at TSRI, is also the author of a historical narrative, Viruses, Plagues, & History.






































Measles, the most contagious infectious agent known to humankind, has afflicted many societies, as this drawing by a sixteenth-century Aztec shows. Drawing from the Códue Florentino.