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Smallpox

The Fight to Eradicate a Global Scourge

David Koplow (Author)

Available worldwide

Paperback, 274 pages
ISBN: 9780520242203
March 2004
$34.95, £24.95
Though smallpox was eradicated from the planet two decades ago, recent terrorist acts have raised the horrific possibility that rogue states, laboratories, or terrorist groups are in possession of secret stockpiles of the virus that causes the disease, and may be preparing to unleash it on target populations.

Because it is a far deadlier killer than other biological warfare agents such as anthrax, and because the universal vaccination against smallpox was halted decades ago, a smallpox attack today would be nothing short of catastrophic. This clear, authoritative study looks at the long and fascinating history of the virus, with an informative overview of the political, biological, environmental, medical, and legal issues surrounding the question of whether or not the virus should be exterminated.

The only two known samples of the virus are currently stored in Atlanta and Russia. The World Health Organization has repeatedly scheduled their destruction—an action that would rid the planet of all publicly acknowledged smallpox strains forever. Opponents of this plan argue that by destroying these last samples we are denying the possibility that this unique virus could be turned to beneficial purposes in basic scientific research. Others see the stockpile as part of a deterrent against future germ attacks. Proponents of prompt eradication argue that scientists have already learned all they can from this particular virus, and that by destroying the stockpile we are preventing it from ever falling into the wrong hands. As a thirty-year veteran of arms control issues, David Koplow is uniquely suited to provide readers with an informed and well-considered understanding of the complexities involved in the handling of this deadly virus.
Acknowledgments
Introduction

1. The Rise and Fall of Smallpox
2. The Biology of Viruses
3. Smallpox as a Biological Weapon
4. Environmental Law and Policy
5. The World Health Organization
6. The Morality of Extinction
7. The Case for Extermination
8. The Case against Extermination
9. Conclusions and Recommendations

Notes
Select Bibliography
Index
David Koplow is Professor of Law at Georgetown University. From 1997 to 1999 he served as Deputy General Counsel for International Affairs at the U.S. Department of Defense, where he was the Pentagon's senior legal advisor on biological warfare issues, including smallpox. He has published extensively on arms control and national security matters, and is the author of By Fire and Ice: Dismantling Chemical Weapons While Preserving the Environment (1997) and Testing a Nuclear Test Ban (1996).
"David Koplow gathers, organizes, and lucidly presents the large body of material from a wide range of disciplines, which bears on the important public policy question whether or not to destroy existing stocks of variola. Engagingly written and accessible to a wide audience, this book will provide both policy makers and citizens with the basic information they need to reach informed and thoughtful judgments on this urgent issue."—John S. Applegate, author of The Regulation of Toxic Substances and Hazardous Wastes

"David Koplow's book is an important work on a crucial subject. The author brings together an extraordinary amount of information on a vital policy issue. There is nothing available that treats the issue of smallpox with any comparable degree of completeness. Koplow marshals sources from myriad disciplines in a coherent, well-rounded discussion providing a service to the casual as well as the sophisticated reader. This book is a one-stop reference, containing virtually all the information an analyst needs to know."—Barry Kellman, Director of the International Weapons Control Center, DePaul University College of Law.

Introduction

The virus responsible for smallpox—a tiny creature known as variola—has been a despised enemy of civilizations around the world. Over a period of at least three millennia it was second to none in inflicting human pain, suffering, and death. By some estimates, smallpox killed as many as 500 million people during the twentieth century alone, and as recently as thirty years ago, it was still at large in over thirty countries, attacking some fifteen million people annually and killing two million of them. Through history, we have battled this foe with incantations, poultices, quarantines, and vaccinations. After struggling to contain it, we have at last conquered the disease globally and placed the last acknowledged vestiges of the virus in high-security confinement. Now, under the auspices of the United Nations, humans may be about to take a final, irreversible, step: to exterminate the last remaining captive samples of the smallpox virus. Thus, a quarter century after smallpox as a disease was wiped off the face of the earth, after additional years of painstaking struggle and research, the last two stockpiles of the causative virus (at least the last two that we know about)—stored in 1/2-inch high plastic vials in 70° Celsius liquid nitrogen baths inside secure isolation chambers at the Centers for Disease Control and Prevention in Atlanta, Georgia, and at the Russian State Research Center of Virology and Biotechnology near Novosibirsk—are targeted for destruction.

If activists in the World Health Organization and in many governmental and private institutions around the world have their way, then within the next few years all the known variola samples, all the various strains, and all the residual infective materials will be inserted into an autoclave—a small, airtight laboratory sterilization furnace. The jets will be ignited, raising the temperature to 120° Celsius for forty-five minutes, and the process will be repeated. Then the vials that have housed the virus for so long will themselves be incinerated. In the end, there will be no tangible legacy at all of one of the most pernicious killers in earth's history.

We are thus on the precipice of a momentous decision: human beings are about to conduct the world's first deliberate extinction.

Extinction carries a certain irresistible cachet. The finality of —eradicating not just a particular individual but an entire species arouses human curiosity and wonderment. The notion of permanently and deliberately divesting the planet of a discrete life form, whether a terrifying dinosaur or an elusive aquatic plant, is—as it should be—both humbling and awe inspiring.

Of course, extinctions occur all the time: the earth loses dozens, if not hundreds, of species every year, usually without public fanfare, often without even human cognizance. We lose flora and fauna we have rarely seen, hardly studied, and never catalogued. Many of these collective deaths, perhaps most, are at least partly attributable to human activity. We overhunt some species; we irrevocably destroy the critical habitats of others; pollution drives still more into the abyss. In some instances—dodo birds, carrier pigeons—the extinction has become a notorious case study for subsequent generations to abhor. In a few instances—bald eagles, snail darter—a monumental social enterprise has been launched to preserve the endangered species, occasionally becoming at least partially successful. In most instances, however, humans little note nor long remember the passage of a dying breed.

With the eradication of smallpox, however, human accountability for the destruction of another kind of creature may become not only self-conscious but deliberate. This book is an analysis of that imminent, irrevocable action, investigating the facts underlying it, exploring the public values supporting it, and critiquing the decision-making apparatus leading up to it. The inquiry is necessarily both interdisciplinary and international in focus, examining the different categories of thought and activity that have led us to the brink of this decision. To understand our collective posture toward variola, and to think rationally about what to do next, we need to synthesize lessons from medicine, biology, military science, environmentalism, international organizations, and ethics. To decide whether to exercise the awesome power that technology and conscientious labor have now afforded us—and to decide what precedent to establish for the next time we are confronted with a comparable dilemma—we should pause now to deliberate a very delicate social choice.

In deciding whether to eradicate smallpox, the world community must address diverse and fundamental questions. Each of the next six chapters analyzes one key dimension of the story of smallpox. Chapter 1 scrutinizes the medical issues, beginning with a sketch of the history of smallpox and humankind's battle against it. It traces the devastating effects of smallpox across continents and through centuries. It also outlines the convoluted course of antismallpox activity, from ancient deity worship to Lady Montague's sixteenth-century invocation of variolation, Edward Jenner's eighteenth-century discovery of vaccination, and Dr. Donald ("D.A.") Henderson's twentieth-century leadership of the dramatic and successful eradication campaign.

Chapter 2 then turns to the biological dimension, posing fundamental questions such as: What is a virus? Is it alive, as a distinct species? What might we learn from continued research on this creature—a pathogen that afflicts only human beings, with no known animal or plant reservoir? And what more could we do to protect ourselves against a future outbreak of it? The chapter also presents, in layperson's terms, an analysis of modern research into genetic engineering, surveying whether futuristic DNA-splicing techniques and cloning technology might have implications for variola preservation.

Next, chapter 3 turns to the military dimension. It profiles how biological weapons agents, including the smallpox virus, have been conceptualized, and occasionally used, as weapons. Certainly disease has played a huge, albeit largely unintentional, role in hostilities: in virtually every international or internal conflict, more people (civilians and soldiers alike) have been felled by illness than by bullets or bombs. Pestilence has shifted battles, won wars, conquered empires, and changed history. However, most military authorities in the United States and elsewhere eventually came to dislike and distrust biological means of warfare, concluding that germs are simply too unpredictable and too uncontrollable for battlefield applications, and they were removed from most countries' active arsenals, unilaterally and voluntarily, more than two decades ago. Yet within the last few years, the revolution in genetic engineering has threatened to reverse that self-restraining judgment once again, and new incarnations of biological weaponry might prove to be far more effective and attractive—for terrorists no less than for regular armies. The upheavals on and after September 11, 2001, provide another fresh impetus for reexamination of the specter of unconventional warfare, such as smallpox bioterrorism.

The environmental dimension is the topic of chapter 4, which considers the extent to which the new, but increasingly entrenched, planetary regard for protection of biological diversity may inform the eradication decision. As we have come to appreciate the importance of husbanding our planet's scarce resources, we recognize the magnificent kaleidoscope of species—and their dazzling array of genetic variation—as carrying irreplaceable human value. Already legions of treaties, principles of customary international law, and domestic statutes constrain our heretofore clumsy disregard of other species. Even if these enactments turn out not to be legally binding on the novel question of preservation or destruction of a miniature creature such as a virus, they still exemplify important principles, values, and intellectual constructs that should inform our choices.

Chapter 5 discusses another, very different type of international institutional or organizational process issue: the role of the United Nations, specifically the World Health Organization (WHO), in deciding the fate of the smallpox virus. Who, in this world of independent, sovereign states and an increasingly dense thicket of amorphous multilateral nongovernmental organizations, has the legal authority to make the final decision for all humankind in this type of life-and-death matter? How has, and how should, the WHO bureaucracy and governing institutions engage this challenging issue, and what procedures should it employ in order to act wisely for us all?

Chapter 6 then confronts some of the profound ethical aspects of the smallpox eradication campaign. What social lesson will we teach future generations by our dealings with variola? What is the precedent we are establishing for the next time this type of deliberate extinction opportunity arises (which may not be far off)? What moral doctrines should we employ to evaluate whether the virus should be sustained? What substantive criteria are relevant to this type of determination, as humans, in a new way, opt to play God—or perhaps to play Dr. Frankenstein? These questions admit of no easy answers, but they must be asked and some irrevocable lines must be drawn.

To separate these distinct "dimensions" in this way is, admittedly, somewhat artificial. In this complex and unprecedented question, everything is connected to everything else, and the boundaries we have constructed between various intellectual disciplines are ill-defined and porous. Still, it may be useful to deconstruct the gnarled mass of issues that bear on this decision and tease out the identifiable strands for separate consideration.

The next two chapters shift gears a bit. Chapter 7 presents the case for extermination, marshaling the arguments in favor of exterminating variola. It adduces five leading genres of arguments that can be asserted in support of the WHO's eradication decision, drawing freely upon the policy and technical considerations advanced in recent years by a variety of proponents. Chapter 8 presents the brief in opposition, assembling the best possible case against extermination. It weaves together five contrary arguments, again concentrating a variety of policies and preferences adduced by participants and observers. Together, these two presentations represent a scholarly and pragmatic debate drawing on all the preceding chapters, one that should help shape public policy dialogue.

Chapter 9 presents recommendations and concluding thoughts. My own "bottom line" is that I would not destroy these final exemplars of the smallpox virus. I would preserve them not out of a false sentimentality for a most undeserving scourge, nor simply out of an ethical concern that it is wrong for humans to play God in this way—although I take that to be a serious matter. Rather, I reject the hubris implicit in the conclusion that we no longer need the variola virus because our studies have already taught us everything we will ever need to know about it. I would retain these small reservoirs of DNA, just in case, as a relatively inexpensive form of biodiversity insurance, against the day when we may need this reprehensible scrap of genetic material to serve a noble end. Accompanying that conclusion are recommendations for the WHO, the United States, and other key actors on related policy matters ranging from counterterrorism initiatives to public health investments.

As far back as 1986, the WHO (or a cadre of experts within the institution) decreed that the variola residues should be promptly destroyed. Their target date was December 31, 1993—the first of a series of deadlines that have slipped unremarkably past while the virus samples linger on. The most recently established date (once described as the "final" extension for variola) was December 31, 2002—a day that has now been rendered moot, as have all the others, and will pass without dispositive action. The Bush administration has declared its opposition to any such destruction in the foreseeable future; its Russian counterparts have eagerly concurred; and the WHO bureaucracy, and its constituent member states, are still struggling to decide how to respond to the two dominant players' desertion from an erstwhile global consensus. No new target date for eradication has yet been established, but the WHO member countries still earnestly seek a prompt final resolution.

It is also important to note that the WHO may fail in any case to achieve its objective. Even if a strong global consensus is manifest, even if all countries declare their willingness to exterminate the last remaining variola samples, and even if the American and Russian repositories are, in fact, incinerated on schedule, all we can deal with in this way are the known stockpiles. All partisans acknowledge that other variola stashes may exist—hidden away by incompetence or malevolence—with the possibility of reemerging in some horrible scenario. Our policymaking, and our appreciation for the grand symbolism of our choices, must therefore be informed by that reality, and the rhetoric of our articulated goals modulated to that extent.

Stepping back just a bit, the variola question provides an opportunity to reflect anew that humankind has always struggled with, and against, nature, seeking to shield ourselves and our progeny from environmental threats. We have tamed rivers, felled forests, and established our dominion over the animals of the land and the fishes of the sea. We have waged ceaseless (but often fruitless) war against an array of biological pests: rodents, insects, and, now, viruses. But the step we contemplate taking with smallpox extends beyond merely resisting nature's forces, beyond domesticating a rival species or confining it to a circumscribed ecological niche. Here, we seek not only to control or defeat it; we intend to destroy it completely.

There is also a lesson here about risk. People have a difficult time thinking clearly and coherently about dangers that have a very low probability of occurrence but a very high cost if they do come about. Here, we are compelled to identify, assess, and trade off risks of very different types: bioterrorism, genetic engineering, laboratory accidents. How can we evaluate those risks in a manner that is rational, fair, and sensitive to all constituencies? In the main, the modern struggle against smallpox has been one of the finest achievements of the human race: we have demonstrated generosity, tenacity, inventiveness, and aplomb that have known no borders. In addressing the final step, the extinction of the last remaining viruses, how can that noble tradition best be sustained?

Over thousands of years the variola virus has tested our stamina, our intelligence, and our collective sensitivity. In struggling for a way to think coherently about this controversy, we have tended to fall back on familiar analogies, such as capital punishment: variola is depicted as an unrepentant convicted murder, now lingering on death row, with WHO considering whether to grant yet another stay of execution. That metaphor certainly has its appeal, but its explanatory power has limits, too. Now, we must face the reality that nothing in our collective experience is a valid model for organizing ourselves on this issue: it truly is a case of first impression. But just as surely, it will not be the last occasion for humans to confront these weighty issues.

Chapter 1
The Rise and Fall of Smallpox

 

The medical history of smallpox is a saga of untold human suffering, unforeseen human inventiveness, and—ultimately—unprecedented human triumph. Smallpox was a loathsome disease, spreading around the world from antiquity to modern times. It was transmitted by an invisible virus; it infected an individual person and an entire community with remarkable speed; and it proved fatal to nearly one-third of its victims. Those who somehow survived a painful two-week period of fever, skin eruptions, and internal organ damage were usually left with severe scarring and sometimes blinded. There was no cure.1

 

Origins of the Disease

No one knows for certain when, where, or how the smallpox virus first appeared on earth; we do know that it has circumnavigated the planet multiple times over many centuries, invading every place of human habitation. We also know more generally that the incidence of different forms of microbiological infection is probably almost as old as life itself: the first fossil traces of higher organisms, from half a billion years ago, reveal ample traces of insidious fungi and other parasitic attachments.

Even within written human history, it has proven impossible to trace the patterns of smallpox origins and evolution thoroughly, in part because of the lack, until the modern era, of a standardized medical lexicon. All sorts of plagues, rashes, pox diseases, and other pestilence were referred to interchangeably, and the ancient scribes' unscientific reports of the symptomatology do not always adequately distinguish the different types of ailments. Even in the modern era, accurate differential diagnosis has remained a challenge, as smallpox can sometimes masquerade as several distinct types of maladies, including the familiar chicken pox and more exotic novelties, until laboratory findings confirm the initial clinical impressions.

The image of smallpox as ubiquitous and ominous was well captured for the entire world by the British historian T.B. Macaulay in 1848: "Smallpox was always present, filling the churchyard with corpses, tormenting with constant fear all whom it had not yet stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of the betrothed maiden objects of horror to the lover."2

The smallpox virus may have originated from a random mutation of some other, less venomous, and even older, strain of unknown virus, maybe around 10,000 b.c., perhaps somewhere in the fertile Ganges River plain in India. Some authors suggest—but it can be no more than speculation—that some relatively mild disease agents spontaneously adapted themselves from early domesticated animals or from lower primates to human hosts: the viruses that cause cowpox and monkey pox, for example, are still identifiable as close variola cousins today.

The term variola was derived in a.d. 570 by Bishop Marius of Avenches (near Lausanne, Switzerland) from the Latin varius, meaning spotted, or perhaps from another Latin term equally descriptive of the disease, varus, meaning pimple. In turn, the English word smallpox was coined in the sixteenth century, to distinguish between this disease and syphilis, which then became generally known as "the great pox," for the slight differences in the skin rashes the two maladies could produce. Other cultures likewise applied their own vocabulary in recognition of the power and destructiveness of smallpox: in some parts of West Africa, for example, it was known as naba, meaning "the chief of all diseases."

 

The first traces of what we now recognize as smallpox epidemics can be discerned among the records of ancient Egypt, India, China, and Greece, when agricultural settlements achieved population densities sufficient to sustain unbroken communication of the virus. Three mummies from the eighteenth and twentieth Egyptian dynasties (1570 to 1085 b.c.), for example, have exhibited the characteristic scarring interpreted by modern experts as evidence of smallpox. The first individually identified smallpox victim whose remains we can inspect, Pharaoh Ramses V, died in 1157 b.c., presumably from this disease: sophisticated modern analysis of his mummy has revealed the distinguishing pustular eruptions.3 He thereby inaugurated a miserable tradition of fatal or near-fatal smallpox infection among royalty and prominent leaders, as well as legions of their followers, in a great many countries. By some estimates, 10 percent of all human deaths worldwide each year were attributable to this one illness.4

Some of the best evidence about ancient epidemics comes to us from war records: about 1350 b.c. the Hittite armies, for example, were devastated by a fatal contagious disease that apparently originated among the Egyptian prisoners of war they had seized in Syria. The illness killed their king, Suppiluliumas I, as well as his son and successor, Arnuwandas II, and led to a period of degenerative instability within the Hittite empire. Some experts familiar with the records now contend that this, too, was variola at work. Similarly, smallpox is credited with killing one-quarter of Athens's soldiers and countless civilians around 430 b.c., undermining that city-state in its competition with Sparta. Carthaginian troops also became infected with a contagious disease while besieging Syracuse in 395 b.c., depriving them of the potential for capturing Sicily and thereby threatening Rome; Alexander the Great's foot soldiers, while invading India in 327 b.c., suffered from a virulent, often fatal, rash illness that may have been smallpox.

Half a world away, smallpox entered northern China in about 250 b.c. The Great Wall had been erected to repulse the invading Huns, but it proved little impediment to the virus they carried, and Chinese texts reported a terrible "epidemic throughout the empire" in 243 b.c. Japan, too, sparsely populated at that time to support endemic smallpox, was victimized nonetheless by recurrent epidemics, as visitors from China or elsewhere introduced the virus repeatedly, as early as the sixth century a.d.

On the average, smallpox killed at least 25 percent to 30 percent of the people it infected. The disease would spread with devastating speed, especially in the increasingly densely populated urban areas of Europe. Perhaps three to seven million people lost their lives to smallpox during the early days of the Roman Empire, and countless others were blinded or suffered other crippling impairments. Thereafter, increasing human mobility brought the disease to wider and wider areas of the planet, and sub-Saharan Africa, too, fell victim.

Through succeeding centuries, smallpox outbreaks occurred in an irregular geographic pattern. The only constant was the disease's ability to kill both the high-born and the commoner—not distinguishing between "princes and peasants," as the title of Donald Hopkins's 1983 book puts it. Queen Elizabeth I of England was infected in 1562; she survived, but two Japanese emperors, kings of Burma and Siam, and perhaps the Roman emperor Marcus Aurelius were less fortunate. Smallpox killed "a queen of England [Mary II], an Austrian emperor, a king of Spain, a tsar of Russia, a queen of Sweden, and a king of France in the eighty years before 1775."5 Abraham Lincoln was stricken with a mild case of smallpox upon his return from delivering the Gettysburg Address in 1863; perhaps he acquired the virus from his youngest son, Tad, who also survived; the president probably passed the infection on to his valet, William H. Johnson, who died.

Four characteristics of smallpox shaped its transmission patterns. First, the disease was spread through relatively close contact: the virus can be propelled through the air for short distances or passed along by immediate physical contact with a diseased person or with his or her clothing or linens. Proximity was thus a requirement for dispersion. Second, smallpox appeared in an acute, manifest form; it could not be carried asymptomatically or secretly. Third, it virtually never struck the same person twice: anyone who contracted the disease and managed to survive it thereby incurred lifelong immunity. (Consequently, adolescents whose faces bore its characteristic pockmarks were much in demand as nannies and servants; anyone else could be a conduit for variola) Fourth, the disease affected humans exclusively; there is no reservoir for variola in flora, fauna, soil, or air, as there is with so many other insidious disease agents.

The combination of those factors meant that smallpox would commonly appear in waves, several years apart. It might, for example, flare up in a particular city, where the closely spaced houses facilitated the virus's access to new bodies. A great many people could be quickly exposed to the disease. After the infection had run its course within the defined population, however, another outbreak was unlikely for several years, as most people would be either dead or immune. Only after a new generation had been born would there once again be a sufficiently large unprotected population for the virus to attack; when it was reintroduced, say, by a traveler, it would again work its way through the new victims. The grisly reality was that smallpox became, perforce, an episodic disease of children—in eighteenth-century Britain, for example, a full 90 percent of the victims were under ten years of age.6

A vivid illustration of the contagion was offered by the experience of the Spanish conquistadors in the New World in the early sixteenth century. Latin America, isolated from viral or other contact with Europe, was virgin territory for variola: no one there was already immune. When the virus was first imported into Caribbean islands by incoming slaves, whole tribes were instantly wiped out; half the native population of Puerto Rico was felled by smallpox within a few months in 1519. Later that year, when explorers Hernán Cortés and Panfilo de Narváez encountered the Aztec civilization of Mexico, variola accompanied them. As the disease spread quickly, the natives "died in heaps, like bedbugs."7 The Spaniards, many of whom had survived smallpox epidemics as children seemed impervious to the illness, a fact that heightened the impression that they had mystical powers. The Aztecs soon lost their emperor to smallpox, as well as numerous other local leaders who might have effectively resisted Cortés. Estimates of variola's death toll among the Aztecs range from two to fifteen million (out of a total population of less than thirty million), within only a few months.8

The macabre story was next repeated in Central America, as variola accompanied the Spanish southern advance upon the Mayan civilization. Epidemics struck Yucatan in 1520 or 1521, killing off half the population and a comparable percentage of its leadership. Likewise, the Incas in Peru were devastated a few years later, facilitating the ability of the small armies of Cortés and Francisco Pizarro to subdue opponents who greatly outnumbered them.

In North America, too, smallpox proved an essential, if unwitting, ally of the European colonizers. As late as 1600, there was probably no experience with smallpox north of Mexico, and, accordingly, no individual or social immunity. Following the earliest explorers, however, a decimating illness that may have been smallpox reportedly killed 90 percent of the Indians along the Massachusetts coast from 1617 to 1619. Another smallpox epidemic arose in the populations near Plymouth Colony in 1633, killing twenty immigrants from the Mayflower and whole tribes of Indians. Enormous epidemics soon swept westward, inflicting terror and mass death among tribes along the Great Lakes: the Hurons and the Iroquois were especially hard hit.

A century later, smallpox asserted itself again, during the French and Indian War of 1754 to 1763. In any particular battle, one side or the other (or both) suffered enormously from the illness, and neither could count on the ability to mount sustained military campaigns in the midst of disease. In 1755, the so-called Year of the Great Smallpox Epidemic, Native American tribes were profoundly struck, and thereafter outbreaks—at roughly one-decade intervals—plagued the cities of whites and villages of Indians alike.

During the Revolutionary War, smallpox altered military strategy and shifted the course of battles. George Washington (who himself had survived a bout with smallpox, caught during a visit to Barbados in 1751) was loath to send his troops into Boston in pursuit of a fleeing British General William Howe in 1776, because of a smallpox epidemic then raging in the city. Later, smallpox among the colonials (rather than the military prowess of British reinforcements) compelled them to break off their threatening siege of Quebec, which could have been a decisive rebel triumph. Smallpox continued to harass both sides for the duration of the war, and fear of the contagion even played a role in the logistical maneuvers leading up to the Yorktown campaign in 1781.

 

By the eighteenth century—when smallpox was killing an average of 400,000 people per year in Europe alone9—leading medical authorities in many countries had begun to differentiate smallpox from other, similar impairments and had developed a sophisticated understanding of variola's disease progression. With the increasing reliance on the scientific method, they had routinely and painstakingly recorded the progression of the illness in an individual and in an entire population. The inquiry was confounded, however, by the fact that the disease could assume markedly different characteristics in otherwise similar individuals, giving rise to nomenclature differentiating half a dozen different smallpox types, including "fulminating," "malignant," "benign," and "modified."

In a "standard" case, variola virus was thought to enter the human body through the lungs or, less frequently, the skin. Smallpox typically started with a ten- to fourteen-day incubation or latency period following the initial exposure (the "pre-eruptive stage"), during which the infected person exhibited no signs or symptoms of pathology. For the next three days (the "prodromal stage"), various flulike effects would emerge: some victims suffered headache, backache, nausea, fever, chills, convulsions, and delusions, and a scarlet rash might appear on the face or body. Then, oddly, for a day or two, the fever would subside and the victim would feel better, as if recovering from some other, less deadly, ailment.

At that point (the "eruptive stage"), however, the smallpox infection worsened. A rash would erupt and spread over the body, more densely on the face and extremities than on the torso. Gradually, the flat parts of the rash would rise into pimples, blisters, and, finally, pustules. Those would eventually dry into crusts or scabs. The skin would turn pink, then red, as if it had been burned or scalded; it felt hot to the touch and would sometimes peel off in limp sheets. Internally, the virus would invade the lungs, heart, liver, intestines, and other organs. Eyes were a particular target: ulceration of the cornea left about 1 percent of smallpox survivors blind in one or both eyes. For survivors, permanent scars on the skin, of widely varying number and intensity, were a characteristic legacy of the disease.

A victim might die within a few days after the onset of the intense symptoms or linger for two weeks or more. The immediate cause of death was usually either toxemia or a hemorrhaging into the skin, throat, lungs, intestines, or uterus. Potentially lethal secondary infections could also arise from opportunistic bacteria invading the lesions caused by the virus.

Communication of the illness to surrounding people was readily accomplished, particularly during the winter and spring. The skin rashes and the open sores on the throat were opportune conduits for the initial victim to expel millions of viruses into the immediate vicinity, where they could be inhaled by the next target. The period of infectivity could last three weeks, from just before the rash appeared until the last scab dropped off. (Fortunately, large outbreaks centered on schools or marketplaces were somewhat unusual: by the time a person was fully infective, he or she was usually bedridden. Families, and later, hospitals, became the virus's preferred venue for communication.) Corpses, too, could spread the virus, and a victim's clothing, sheets, towels, and shroud could retain dangerous pus or scabs, further accelerating variola's transmission. About half the people exposed to the virus—an event that could require only a few minutes' contact—would be infected by it, and a quarter to a third of those infected would soon perish.10

An important subsidiary mystery about smallpox concerns the birth of two new strains of the virus, closely related to the original smallpox agent but with noticeably different characteristics. Sometime during the late nineteenth century, a milder form of the disease, sometimes referred to as amaas or alastrim, was identified in Southern Africa and the West Indies: it generally caused less severe pockmarking, and was fatal in only about 1 percent of cases. Subsequent laboratory analysis confirmed that this new agent, eventually designated Variola minor, was genetically distinct from, although quite similar to, the original breed, which then became known as Variola major. Infection with either strain resulted in cross-immunity: anyone who survived a bout with one could not be infected by the other.

As Variola minor spread through Brazil, England, and especially North America, it tended to displace its more vicious cousin, and local fatality rates declined precipitously. To compound the oddity, a third, intermediate strain was uncovered in East and West Africa in 1963: Variola intermedius killed about 12 percent of its victims.11 To this day, no one knows where, when, or how these less noxious smallpox relatives crept into existence.

 

Treatment Regimens

The horrors of smallpox inspired a wide variety of creative treatment regimens, derived in each age from the prevailing social misunderstandings of the nature and origins of diseases. Many early civilizations, in India, China, Africa, and Latin America, designated a god or goddess of smallpox and offered sacrifices to honor or appease the deity. Others routinely practiced therapeutic bleeding, to leach the body of "excessive humors" and restore the internal balance that could ward off contagion. "Heat therapy" was the leading treatment in sixteenth-century Europe, although it is now considered inapposite to deal with a fever by packing the victim in blankets and huddling next to a fire. Some cultures, overresponding to the color of the smallpox rash, adopted "red therapy": surround the diseased individual with red-colored blankets, curtains, and other items, have him or her drink red liquids, and use only red implements in treatments. As silly (or even dangerous) as some of those approaches now seem, modern medical science has been able to do little better. Even today, there is no specific treatment for smallpox, and there is no effective antiviral medication; a case of smallpox generally still must run its course.

As the transmission mechanisms of smallpox and other diseases became more obvious, efforts at isolation and quarantine became common. Ships arriving from distant ports were sometimes carefully inspected before crew and cargo could disembark, and sick passengers were segregated from the community at large. Townspeople tried to avoid, or even to expel, smallpox-infected individuals from their midst, hoping to cut short the disease cycle. But inconsistent enforcement of these rules often rendered futile the primitive public health measures.

The first efficacious medical process for combating smallpox was "variolation" (or "inoculation"), which amounted to deliberately inducing a mild form of the disease, in the hope that the victim would recover and thereby gain lifelong immunity. Ancient Chinese, Indian, and African cultures had performed this process for centuries, following a variety of treatment regimens. In China, a dried powder composed of smallpox skin crusts harvested from a current disease victim was inhaled by others, like taking snuff. In the Middle East, a small amount of pus from a smallpox lesion was inserted into a cut on the arm of the person to be protected.

An individual who acquired smallpox artificially in this fashion would ordinarily suffer a moderate case of the disease—less rash, shorter illness, and only about a 1 or 2 percent chance of dying.12 (But he or she was still fully infectious and could spread full-strength smallpox to other people.)

A few European authorities had become generally familiar with the concept and practice of variolation, but the medical establishment there proved too conservative to consider seriously the potential of the process. Variolation failed to gain widespread attention and acceptance in the West until it was aggressively promoted by Lady Mary Wortley Montagu, whose husband was the British ambassador to the Ottoman Empire from 1717 to 1718.After observing the technique's effectiveness among the Turks and having her own two children successfully variolated, she sponsored the concept at home. During the smallpox epidemic of 1721, two daughters of the Prince of Wales (the future King George II) were variolated, too, thereby ensuring the procedure's notoriety, if not its immediate acceptance, throughout the country.

At about the same time, variolation arose in the American colonies, as the Reverend Cotton Mather in Boston learned of the practice from his African slave, Onesimus. Mather, too, promoted it within the local medical community during a 1721 smallpox outbreak. He and his associates, however, encountered considerable resistance, both from other physicians and the citizenry, who feared that variolation could become a vehicle for inadvertently spreading the disease even more widely. There was also a popular sentiment against any activity that would interfere with the "natural" course of smallpox. Mather and his "progressive" associates were condemned for ungodly hubris and became a target of verbal and physical brickbats.

Many of the American colonies passed laws to prohibit or tightly regulate variolation; because of this legislation, the practice was much less common in America than it became in England. One ramification of that difference was that early in the Revolutionary War, British soldiers were noticeably less susceptible to the threat of smallpox. George Washington, whose face was deeply pitted as a result of his own bout with smallpox at age nineteen, was initially an outspoken opponent of variolation, believing it would spread the disease. Upon learning of a supposed British plot to use smallpox as a weapon against the Continental Army, however, he assembled a special unit of one thousand pockmarked fighters to counteract the danger that the Redcoats might pose. Shortly thereafter, Washington became a zealous convert to variolation, and in 1777 he ordered compulsory variolation of all new recruits.

The next achievement in the struggle against smallpox came from Dr. Edward Jenner, a rural English physician who had come to practice variolation routinely and who, himself, had almost died as a result of variolation when he was eight years old. He observed that dairymaids who had been infected with a mild pustular skin infection known as cowpox were thereafter confident that they could never be stricken with smallpox, and the local experience (or, at least, the folklore) seemed to corroborate the connection. After a decade of theorizing and empirical observation, Jenner undertook his famous experiment on May 14, 1796, injecting eight-year-old James Phipps of Berkeley with cowpox pus obtained from lesions on the hand of a milkmaid named Sarah Nelmes. When later Phipps turned out to have robust immunity against smallpox variolation attempts, Jenner published his thesis and recommendations.

Jenner's proposals, like Montagu's and Mather's, stimulated strong reactions: both profound celebrations for salvation from smallpox, and intense, sporadic opposition for promoting an allegedly unnatural and dangerous deviation from established medical practice. But the value of Jenner's innovation soon became obvious, and the practice rapidly spread throughout the world. The difficulties of transoceanic conveyance of the infective cowpox material to waiting doctors across the Atlantic and elsewhere were overcome by impregnating threads with dried vaccine, or by maintaining an unbroken chain of arm-to-arm serial infection among ship passengers throughout the weeks of the voyage.

Because the original infective material was derived from cowpox, Jenner labeled his process "vaccination" (after the Latin vacca, cow). To memorialize that innovation, Louis Pasteur in 1881 generalized the term vaccination to apply to all other sorts of immunizing injections, including those for other illnesses. Today, we recognize the cowpox virus as a separate species but a close familial relative of the smallpox virus , even though we do not fully understand the operational principles of cross-immunity.

But another mystery remains. The virus that has been used over a period of several decades to vaccinate against smallpox—all the various strains employed throughout the United States and the world —is no longer true cowpox. The modern prophylactic, known as vaccinia virus, is a novel, separate creature. It may be a hybrid, the result of a microscopic mutation that somehow combined some of the features of the germs causing smallpox with those of Jenner's cowpox, and perhaps with those of yet another related disease known as "horse pox." In the two hundred years since Jenner, at some unknown time and place, the original stocks of cowpox virus that were used for vaccination have all been replaced with vaccinia virus, which has proven to be more effective and robust in producing immunity. Remarkably, that transformation to the "new" protective strand of orthopox virus was somehow inadvertent, invisible to the practitioners, and global.

As great a boon to humankind as the smallpox vaccination was, however, it was not a panacea. First there were risks of side effects: about one person in fifty thousand would experience adverse reactions of various sorts, and about one in a million would die. Other unfortunate people would inadvertently acquire other viral or bacterial infections along with the intended vaccination, and still others presented special conditions that contraindicated use of the vaccine altogether.13 Moreover, the vaccination did not confer lifelong immunity, the way that variolation (or exposure to a full case of smallpox) did: after about ten years, a repeat was necessary. Also, many self-advertised vaccinators were dishonest, careless, or incompetent, or they dealt with impure or impotent vaccine strains, so in some areas, large numbers of the putative vaccinations were ineffective. In addition, many people, in many countries, continued to deride the whole concept of vaccination (especially compulsory vaccination) as immoral, an interference in the natural order of life, or an infringement upon personal autonomy. And, as with any medical procedure, financial and logistical barriers impeded the effort to vaccinate all those in need.

Consequently, smallpox persisted, and in some places thrived, around the world. Three major European pandemics, in 1824-1829, 1837-1840, and 1870-1875, spread the disease throughout the continent—not with the same virulence of earlier centuries, but deadly nonetheless. Russia suffered 100,000 smallpox deaths in 1856; France between 60,000 and 90,000 in 1870-1871; and Germany 162,000 in 1871-1872.14

Into the twentieth century, smallpox remained a global scourge—it was endemic in 124 countries in 1920—but it was no longer universal. Germany and the Scandinavian countries had reduced smallpox deaths to small numbers through compulsory vaccination, although European Russia still lost over 400,000 people to smallpox during the period 1900 to 1910, and Spain and Italy were hit hard too. In the United States (a country reluctant to adopt mandatory antismallpox measures), an outbreak of a mild form of smallpox infected 130,000 people from 1901 to 1902 and 200,000 in 1920 to 1921. Some 64,000 Filipinos perished from smallpox from 1918 to 1919; India regularly reported over 100,000 smallpox fatalities per year; and Nigeria suffered 22,000 cases, including 6,000 fatalities, in 1930.15

Even afterWorld War II, when endemic smallpox had been eradicated from most of the developed countries, it was more out of sight than out of mind. Thousands of cases were still being reported annually around the globe, and perhaps only 1 percent of the cases were accurately tabulated. Massive, sometimes deliberate, underreporting was the norm, concealing what were probably fifty million cases of smallpox per year in the 1950s.16 Accordingly, compulsory vaccination of the population continued in many countries, international travelers were watched closely, and episodic eruptions of the disease were endured with alarming frequency.

For example, in 1945, an American soldier returning from Japan ignited an outbreak of sixty-five cases (twenty of them fatal) in Seattle, Washington.17 The last eruption of the disease in the United States occurred in 1949, when eight people were infected (with one death) in the lower Rio Grande valley of Texas, but smallpox scares or rumors were persistent thereafter.18 Other countries, industrialized and nonindustrialized alike, continued to import smallpox episodically into the 1970s—there were forty-nine reintroductions of the disease into Europe between 1950 and 1971—often with widespread fatalities and panic.19

As late as 1967, cases of smallpox were still being reported in forty-four countries, and the disease was considered endemic in thirty-one countries, containing some 60 percent of the world's population. There may have been as many as ten to fifteen million cases that year, resulting in some two million deaths.20 The disease that had originally afflicted all of humankind had, by this point, evolved essentially into a problem of the poor: less developed countries south of the equator were continuously devastated, while the economically developed countries had managed, more or less, to barricade themselves against the worst effects of variola.

 

The Global Eradication Program

The idea of developing a worldwide campaign to eradicate smallpox flickered hopefully from the first moments of Jenner's discovery. Farsighted people immediately waxed rhetorical about wiping out the disease and freeing humankind from its burden. As Thomas Jefferson wrote to Jenner in 1806, "You have erased from the calendar of human afflictions one of its greatest. Yours is the comfortable reflection that mankind can never forget that you have lived. Future nations will know by history only that the loathsome smallpox has existed."21 However, more than a century and a half were to pass before concrete collective steps were taken.

With such virulent diseases, of course, any local solutions remain imperfect—no population could be secure from the threat of smallpox, as long as the disease retained its foothold anywhere—especially as human mobility dramatically increased. At the same time, many people disputed the notion that complete eradication (as opposed to containment and management of the disease) would ever be universally possible. Still, piecemeal progress was achieved, and smallpox was increasingly erased from the developed world during the twentieth century.

Public attention—driven by both humanitarianism and a cost-effective self-interest—turned increasingly to cooperative efforts at developing a worldwide solution. Eventually, global health authorities were able to demonstrate convincingly that the financial costs to the developed countries of sponsoring an effective universal smallpox eradication campaign would be more than offset by releasing themselves from the recurrent national costs of smallpox prevention and monitoring.

In 1950, the Pan American Sanitary Organization (a forerunner of the Western Hemisphere's arm of the World Health Organization [WHO], which was itself a "specialized agency" of the then new United Nations) approved a program to eradicate smallpox from the Americas. Within only eight years, and at a cost of less than $75,000 annually, that goal was accomplished for the Caribbean, Central America, and much of South America, although not for Brazil or Argentina.22 In 1958, at the annual World Health Assembly meeting in Minneapolis, Victor M. Zhdanov of the Soviet Union further proposed, and the WHO then adopted as its official policy, the principle of seeking global smallpox eradication. This was a bold, unprecedented bureaucratic move, and in the face of technological, financial, and logistical limitations, it soon foundered. Competition with other diseases was undoubtedly an inhibiting factor: many countries were more concerned with malaria or measles, for example, than with smallpox, and it was difficult to craft a single-minded organizational approach.23

In January 1967, the WHO mandate was renewed, under the aegis of the Intensified Smallpox Eradication Program (ISEP), this time with a modest pot of $2.4 million in seed money, and a ten-year time frame to concentrate the energies.24 Dr. Donald ("D.A.") Henderson, a medical epidemiologist on detail from the U.S. Public Health Service, assumed leadership of the WHO campaign and immediately set about creating the necessary infrastructure, including a multinational cadre of talented and dedicated individuals.

Immediate ISEP goals were improvement in the international mechanism for identifying and reporting smallpox cases (99 percent of which were estimated not to have made it into published national statistics) and in the development and mass production of unprecedented quantities of high-quality freeze-dried vaccine. (The Soviet Union alone donated nearly 1.4 billion doses of vaccine to the antismallpox campaigns.) Extraordinary inventiveness also came to the rescue, with both high technology (the jet injector, capable of vaccinating up to 1,000-1,500 people per hour) and low technology (the bifurcated needle, easily sterilized for repeated uses, not requiring any spare parts or maintenance, and simple to train nonexperts to use in the field).25

Political factors exerted influence as well. In the first instance, leadership by the planet's two superpowers, the United States and the Soviet Union, was essential in crafting and sustaining the global enterprise. Scores of countries temporarily set aside some of their usual insistence on rigid sovereign autonomy to collaborate in a remarkably open and accommodating fashion; seventy-nine nations tolerated a degree of foreign expert intervention that had not always been so graciously accepted in other contexts. At the same time, the WHO program had to surmount ten years of global political sensitivities, civil wars, apartheid, and strained relations, all during some of the darkest days of the cold war.

West and Central Africa were among the first targets of the Intensified Smallpox Eradication Program, selected to demonstrate that WHO efforts could succeed even in countries with systemic poverty and starkly limited domestic health infrastructures. An early strategic breakthrough was the adoption of the "surveillance-containment" concept: instead of seeking to vaccinate everyone (i.e., attempting to achieve a near 100 percent compliance record in each country), a less ambitious but equally successful tactic was to reliably identify and locate each new smallpox outbreak and for each of these locales immediately vaccinate everyone who may have already, or still might, come into contact with the virus. Quarantining an area and sealing off the outbreak before the virus could spread very far proved more manageable than the Herculean task of vaccinating truly everyone.

Twenty countries in West Africa (including six of those previously identified as among the most highly endemic smallpox locales in the world) were declared to be smallpox free within three and one-half years of the campaign's initiation. Other successes followed: Brazil encountered its last smallpox case in April 1971, Indonesia in January 1972. By the end of that year, variola's formerly global range had been restricted to six countries: India, Pakistan, Bangladesh, Nepal, Ethiopia, and Sudan.

This record of swift success should not suggest that the outcome was easy or foreordained. Indeed, civil wars and international armed conflicts disrupted the program; political interference was a constant worry; harsh temperatures, monsoons, and other local conditions impeded the efforts of the UN officials; resources were always scarce; and resistance from skeptical, disorganized, dishonest, or fearful natives was common. In some circumstances, WHO representatives had to walk miles, lugging their equipment to remote villages where pox illnesses had been fragmentarily reported and undertake often fruitless house-to-house searches for the elusive variola. The virus would occasionally skip "behind the lines," suddenly reappearing in West Germany in 1970, in Yugoslavia in 1972, or in other locations where it had seemingly been eradicated much earlier. Even massive tragedies were not yet a thing of the past: as late as 1974, a terrible smallpox epidemic in northeast India killed 25,000 people.26

But the WHO program persisted, eventually eliminating even the final variola bastions. The last known case of naturally occurring smallpox was found in Somalia (ironically, a country that had been smallpox free for over a decade but where importation from Ethiopia had reestablished the disease) in October 1977. Ali Maow Maalin, a twenty-three-year-old cook in a hospital in the coastal town of Merka, had occasionally volunteered as an aide to the WHO workers, although, oddly, he himself had never been vaccinated. He developed the characteristic rash shortly after accompanying a smallpox victim to a vaccination site. His case was quickly identified, additional vaccinations were given to all his associates, and he soon recovered fully. No one else—in Somalia, or elsewhere around the world—has since suffered from endemic smallpox.

The standards and practices of the WHO required two years of disease-free conditions before a country could be officially declared rid of smallpox. During those intervals, the vaccination campaigns continued, and efforts intensified to identify any remaining possible eruptions—including offering $1000 to anyone who could produce another case (none were found). Even suspect cases were treated as international emergencies, prompting painstaking investigation and analysis. Unless the WHO certification regime was, and was perceived as being, airtight, national authorities would not rely upon it, and they would still be reluctant to relax their vaccination efforts and other antismallpox activities. Finally, on October 26, 1979, the crowning moment came: the United Nations campaign ceremoniously certified that the world was free from the disease.

 

Even as smallpox was being eradicated in the world at large, however, samples of variola virus remained plentiful in laboratories. Some of these strains were held for research purposes, some were kept as exemplars to help forensic experts identify any newly emergent virus strains, and some were apparently maintained due to simple bureaucratic inertia. The quality of the labs that housed the stockpiles varied enormously, as did their safety procedures and research protocols. In 1975, at least seventy-five laboratories, dispersed all over the planet, held infective variola stocks. Upon prompting by the WHO, many of these institutions consented to destroy their repositories or ship them to central collections, so by 1977 only eighteen reported retention of the virus, and that number gradually declined to only two by 1983.27

One factor spurring the countries to destroy or consolidate their smallpox virus stocks was the hazard posed by variola—as vividly illustrated by two infamous British laboratory accidents. The first, in London in March 1973, occurred when Ann Algeo, a twenty-three-year-old unvaccinated technician at the Mycological Reference Laboratory at the London School of Hygiene and Tropical Medicine casually observed a (presumably vaccinated) coworker harvest (on an open workbench in the lab) some variola samples that had been grown in eggs for research purposes. The observer became ill and was hospitalized with what was later identified as a mild case of smallpox—but the diagnosis was not timely, and she stayed in a general hospital ward for a week. During that time, she passed the infection to two unsuspecting people who had come to visit a relative in an adjacent bed, and they became the first smallpox fatalities in Britain in over a decade. A nurse who cared for one of those two victims was also infected, but she managed to recover.

Five years later, an even more peculiar laboratory anomaly occurred in Birmingham, England. Janet Parker, a forty-year-old medical photographer, worked in a small office and darkroom located one floor above the Department of Medical Microbiology laboratory of the University of Birmingham, where smallpox research was conducted without what we would now insist on as fundamental safety standards. In August 1978—nearly a year after the last "natural" smallpox case in Somalia—she became fatally ill with the disease. Postmortem investigators speculated that the virus may worked its way upward, through a ventilation and service duct, to a small telephone booth that Parker had occasionally used; alternatively, she may have had face-to-face contact with laboratory personnel or visitors.

In any event, Parker (who had last been vaccinated twelve years earlier) died within a month of infection, but before being hospitalized, she came into contact with a great many unsuspecting people—three hundred of whom were identified, tracked down, vaccinated, quarantined, and monitored. Only one of these three hundred, her mother, acquired the illness—fortunately, a relatively minor case Two other deaths occurred as a result of the stresses of the outbreak. Parker's father, presumably strained by the chain of events, suffered a heart attack and died after visiting his daughter in the hospital. And Professor Henry Bedson, a world-famous scholar on smallpox, and the director of the Birmingham laboratory whose faulty procedures had initiated the outbreak, shortly thereafter committed suicide while quarantined at his home, ridden by guilt and distraught that he had misled British and WHO authorities about his laboratory's procedures, intentions, and safeguards.

These laboratory accidents sound a cautionary note, not simply about maintaining adequate safeguards and rigorous housekeeping procedures but also about the potential social consequences of a major mishap: if variola were somehow to escape today, the consequences for the world could be profound. Unlike in earlier generations, there is little natural immunity left in the world—the vast majority of the human population has not been recently vaccinated, and a small percentage are now veterans of the disease. Through most of human experience, most outbreaks of smallpox had some "natural" limit, when the virus had exhausted the younger generation, butting up against those who had acquired immunity during an earlier epidemic, it died out. Today, however, the situation for humans globally is more akin to that of the seventeenth-century Native American tribes, who were devastated by their initial exposure, because none of their members had immunity. Like them, the global population today once again approaches 100 percent vulnerability.

An important difference is the existence today of a known and reliable vaccine. The world resolved in 1980 to maintain a security stockpile of heat-stable, freeze-dried vaccinia, with 200 million doses to be held by the World Health Organization and another 100 million in various national stocks. The WHO inventory was to be preserved in appropriately cold storage (20° Celsius), in two sites, Geneva, Switzerland, and New Delhi, India, and was supplemented by a stash of about 3.7 million bifurcated needles, as well as by reliable seed lots capable of producing more serum, should the need arise.28

Relatively soon, however, those "safety net" plans were frustrated. Difficulties maintaining proper quality control and funding the contemplated standby stockpiles led to reductions in the inventory and its consolidation in Switzerland. Production of new vaccine virtually stopped, and the capacity to generate additional vaccinia atrophied. In 1986, the relevant WHO committee determined that continued maintenance of the global inventory was no longer necessary, and the current WHO stockpile amounts to no more than 500,000 doses.29 National holdings in various countries may now total about sixty to ninety million doses of uneven quality.30

Through 2001, the United States housed a ready stockpile of six to fifteen million doses of vaccinia, enough for no more than about 6 percent of the national population.31 Questions have arisen regarding the continuing viability of these aging stocks—U.S. manufacture stopped in 1975—and some deterioration due to time and moisture has undoubtedly occurred. Still, governmental authorities not only deem the vaccine sufficiently potent but have considered the possibility that if a need ever arose, the vaccine could be diluted perhaps five or tenfold, allowing treatment of millions more people.

In addition, the U.S. government has recently launched no fewer than three programs to produce additional smallpox vaccine.32 First, the Department of Defense, through its Joint Vaccine Acquisition Program, contracted in 1997 with a Maryland firm called BioReliance to deliver 300,000 doses of an improved vaccine for $22.4 million (approximately $70 per dose). This inventory, to be administered under the Smallpox Vaccine Biodefense Program to service members deployed to the locations of greatest threat, would consist of essentially the traditional vaccinia virus, but it would be manufactured with improved, cleaner and safer, techniques still to be developed and tested.33

Second, the Centers for Disease Control and Prevention (under the U.S. Department of Health and Human Services) in 2000 awarded a $343 million contract to OraVax, a Massachusetts biotechnology company, to manufacture forty million doses of vaccine beginning in 2004 and continuing through 2020 for a stockpile for the general civilian population at a cost of about $8 per dose.34 The quantity of forty million was based on the recommendations of the Working Group on Civilian Biodefense, but after the October 2001 anthrax scares, and amidst increasing concerns about bioterrorism generally, both the quantity and the delivery timetable were modified.35

For both these contracts, the process of obtaining (or somehow obviating) approval from the U.S. Food and Drug Administration—an institution that rigorously regulates the marketing of new pharmaceuticals—may prove to be daunting. Although the vaccinia virus itself remains essentially the same as it has been for decades, the process for generating and collecting it in quantity must now be modernized. The traditional technique had been to obtain pus from the pox lesions on the flank tissues of an infected calf, but that method, of course, also harvested a plethora of unwanted bacteria and other contaminants. Modern laboratory techniques to ensure sterile preparations, now mandatory for any new pharmaceutical substances, would require careful development and FDA certification, which can require expensive and time-consuming testing. The FDA has pledged to intensify its review of any new smallpox vaccine production and has proposed flexible new regulations to streamline the process in these extraordinary situations, but the agency cannot become merely a "rubber stamp" where drug safety and efficacy are concerned.

Third, following the September 11, 2001, terrorist attacks on the World Trade Center and the Pentagon, the Bush administration announced plans to seek.$500 million in emergency funds to procure 300 million doses of smallpox vaccine—enough to treat everyone in America—by the end of 2002. Disputes over the contracting process and feuds between small and large potential bidders threatened to disrupt the process, but at least fifty million new vaccine doses were scheduled for prompt delivery.

Two propitious developments then intervened. First, experiments confirmed that the existing vaccine stocks could be diluted at least five times and still retain their effectiveness—suddenly multiplying the available protections. Second, Aventis Pasteur, a French vaccine- making company, discovered a previously overlooked inventory of eighty-five million doses of similar vaccine, housed in its Pennsylvania warehouse, and donated it to the U.S. government. Suddenly, the prior shortage of smallpox vaccine was transformed into an oversupply, and other countries, too, were pursuing the manufacture of additional stocks.

No government currently intends to resume universal vaccination of civilian populations, and it is not clear whether the antismallpox treatment would be made available for individuals who sought it (as some already have).

Along with building up an immense vaccine inventory, there must be an understanding of the vaccine's limitations. Vaccinia is strongly contraindicated for many people: those with skin diseases such as eczema, those immunosuppressed by diseases (such as HIV/AIDS) or by organ transplants, pregnant women, and others. Statistically, the record has been that slightly more than one person in one million has died due to adverse vaccine reactions, and many more have been incapacitated for short or long periods. The frequency of serious complications from vaccinia was higher than that for any other vaccine now on the market to combat any other disease. Current projections have raised fears that a nationwide smallpox vaccination campaign today might result in as many as 600 to 1,000 deaths.36

Moreover, the most suitable medication to combat these often unforeseeable cases of encephalitis or other dangerous conditions, a substance known as vaccinia immune globulin (VIG), is exceedingly rare. The government's stockpile has grown so small—only 675 doses are now available—that virtually all smallpox vaccinations have long been suspended. Efforts to generate more VIG are also under way, but the process is laborious.37

As a result of the risk of severe adverse reactions, the World Health Organization has reaffirmed its conclusion that mass vaccination of civilians, in the absence of evidence of a smallpox outbreak, is not warranted. The traditional surveillance and containment strategy, developed and perfected during the global smallpox eradication campaign—of quickly identifying and isolating any cases, shipping vaccine stocks to the affected area immediately, and vaccinating all the potentially exposed people—would be used instead.38

Worldwide health security may therefore not be as perilous as it might seem, even should variola manage to "escape." Nevertheless, the adequacy of that safety net is now being questioned, and one of the ironies arising from humankind's successful battle against smallpox is that our guard has been let down, and our "herd immunity" has largely expired. As many as 120 million Americans have never been vaccinated against smallpox and are fully vulnerable. The protection that older Americans once enjoyed from previous vaccinations has surely waned, at an unknown rate—no one really knows how rapidly the vaccine protection declines (either in the sense of avoiding the disease altogether or in suffering only a relatively modest version of it). As a result, any smallpox incidents now could carry enormous adverse potential.

 

The world has been free from the smallpox disease for over twenty years. In 1971, the U.S. Public Health Service recommended termination of the long-standing program of routine vaccination of civilian populations in this country, and that alteration in state and local practice became the norm within a few years. In 1982, the WHO's international health regulations deleted smallpox from the list of vaccinations required for international travel, and most countries followed suit. In 1983, Wyeth Laboratories, the only licensed producer of smallpox vaccine in the United States, discontinued the general distribution of the vaccine. By 1986, routine vaccination had ceased in all countries. The termination of these ambitious vaccination programs, and of the associated quarantine procedures, was an enormous boon for the affected countries—they saved far more in foregone protection costs than they had contributed to the WHO smallpox eradication campaign. In financial terms, then, apart from mitigating human suffering, the eradication effort was a monumental success.39

By the early 1980s, only military personnel and pox virus researchers continued to receive automatic protection against variola. North Atlantic Treaty Organization countries, including the United States, as well as Israel, Australia, Sweden, and a few others, persisted in vaccinating all or most troops. The Soviet Union had halted smallpox vaccination even for its soldiers in 1979 but resumed the practice in 1984, apparently in part because the United States had continued the immunization program for its military. In 1990, the United States terminated the program of automatic smallpox vaccination of service members—a decision driven more by concerns about adverse side effects than by the ending of the cold war. Russia, Canada, and others stopped shortly thereafter (although some special forces elements may still receive this form of protection), and only Israel is known to continue routine military vaccination on a large scale today.

The last remaining ampules containing the variola virus (at least the last specimens that the world knows about) have now been concentrated in two freezers. The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, houses about 450 samples; the Russian State Research Center of Virology and Biotechnology near Novosibirsk maintains an inventory of about 120 isolates. Each facility has instituted internationally approved safety standards, backed up by periodic inspections, until the date of final disposition arrives. The CDC inventory, for example, is tightly guarded and stored in the most secure portions of the Atlanta facility, and officials there are reluctant to describe the protections in detail.

With those final test tubes, the story of smallpox concludes—or at least the medical dimension of the story, after some 3,000 years of terror, death, and suffering, is at last drawing to a close.

 


Notes

Chapter 1

1 The authoritative histories of smallpox and humankind's struggles against it are Frank Fenner, D. A. Henderson, Isao Arita, Zdenek Jezek, and Ivan D. Ladnyi, Smallpox and Its Eradication (Geneva: World Health Organization, 1988), and Donald R. Hopkins, Princes and Peasants: Smallpox in History (Chicago: University of Chicago Press, 1983). See also James Cross Giblin, When Plague Strikes: The Black Death, Smallpox, AIDS (New York: Harper Collins, 1995); Abbas M. Behbehani, The Smallpox Story: In Words and Pictures (Kansas City: University of Kansas Medical Center, 1988); and Joel N. Shurkin, The Invisible Fire: The Story of Mankind's Victory over the Ancient Scourge of Smallpox (New York: Putnam, 1979).

2 T. B. Macaulay, The History of England from the Accession of James II (London: J.M. Dent and Sons, 1800).

3 Hopkins, Princes and Peasants, 14-15 (describing the author's personal inspection of the mummy in 1979); and Fenner et al., Smallpox and Its Eradication, 210-11.

4 Nicolau Barquet and Pere Domingo, "Smallpox: The Triumph over the Most Terrible of the Ministers of Death," Annals of Internal Medicine 127 (October 15, 1997), 635, http://38.232.17.254/journals/annals/15oct97/smallpox, p. 3, visited December 17, 1999 (citing inter alia, Mary II of England in 1694, Emperor Higashiyama of Japan in 1709, and Peter II of Russia in 1730); Ed Regis, Virus Ground Zero: Stalking the Killer Viruses with the Centers for Disease Control (New York: Pocket Books, 1996), 63.

5 Hopkins, Princes and Peasants, 41.

6 Abbas M. Behbehani, "Smallpox," in ed. Joshua Lederberg, Encyclopedia of Microbiology, vol. 4 (San Diego: Academic Press, 1992), 34; Hopkins, Princes and Peasants, 8, 52; Giblin, When Plague Strikes, 65-66; Fenner et al., Smallpox and Its Eradication, 215.

7 Hopkins, Princes and Peasants, 206 (quoting Spanish friar Fray Toribio Motolinia).

8 Hopkins, Princes and Peasants 207; Giblin, When Plague Strikes, 67-71; E. Wagner Stearn and Allen E. Stearn, The Effect of Smallpox on the Destiny of the Amerindian (Boston: B. Humphries, 1945) 127.

9 Michael Radetsky, "Smallpox: A History of Its Rise and Fall," Pediatric Infectious Disease Journal 18, no. 2 (February 1999), 85.

10 Fenner et al., Smallpox and Its Eradication, 199.

11 But see Fenner et al., Smallpox and Its Eradication, 4 (declining to recognize Variola intermedius as a distinct entity.)

12 Fenner et al., Smallpox and Its Eradication, 246.

13 Fenner et al., Smallpox and Its Eradication, 307-08 (summarizing general consensus on four conditions that constituted contraindications to vaccination: immune disorders, eczema, pregnancy, and disorders of the central nervous system.) See also D. A. Henderson, "Variola and Vaccinia," in ed. J. Claude Bennett and Fred Plum, Cecil Textbook of Medicine, 20th ed. (Philadelphia: W.B. Saunders, 1996), 1767-68; D. A. Henderson, "Smallpox as a Biological Weapon: Medical and Public Health Management, Consensus Statement of the Working Group on Civilian Biodefense," Journal of the American Medical Association 281, no. 22 (June 9, 1999), 2127, 2134-35; Advisory Committee on Immunization Practices, "Vaccinia (Smallpox) Vaccine Recommendations of the Advisory Committee on Immunization Practices," MMWR Reports and Recommendations 50 (June 22, 2001), 1-25.

14 Hopkins, Princes and Peasants, 87, 89-90; Fenner et al., Smallpox and Its Eradication,231-32, 272.

15 Hopkins, Princes and Peasants, 133, 154, 197-98; Fenner et al., Smallpox and Its Eradication, 315-63.

16 Fenner et al., Smallpox and Its Eradication, 175, 196.

17 Hopkins, Princes and Peasants, 293-94.

18 Hopkins, Princes and Peasants, 294.

19 Hopkins, Princes and Peasants, 98.

20 Fenner et al., Smallpox and Its Eradication, 175, 394-95, 516-17, 1345.

21 Quoted in Hopkins, Princes and Peasants, 310.

22 Fenner et al., Smallpox and Its Eradication, 172, 333-35, 389-91.

23 Fenner et al., Smallpox and Its Eradication, 370-87, 393-99, 1007-08.

24 Fenner et al., Smallpox and Its Eradication, 410-18, 422-25.

25 Fenner et al., Smallpox and Its Eradication, 421-592.

26 Hopkins, Princes and Peasants, 310; Fenner et al., Smallpox and Its Eradication, 532.

27 Fenner et al., Smallpox and Its Eradication, 1338-40.

28 Fenner et al., Smallpox and Its Eradication, 1268-70.

29 Fenner et al., Smallpox and Its Eradication, 1269-70; Henderson, et al., "Variola and Vaccinia," 2132.

30 James LeDuc and John Becher, "Current Status of Smallpox Vaccine: Letter to the editor," Emerging Infectious Diseases 5, no. 4 (July-August 1999), 593; Laurie Garrett, "The Nightmare of Bioterrorism," Foreign Affairs 80, no. 1 (January/February 2001), 76, 77.

31 See D. A. Henderson, "Smallpox: Clinical and Epidemiologic Features," Emerging Infectious Diseases, no. 4 (July-August 1999), http://www.cdc.gov/ncidod/EID/vol5no4/henderson.htm, p. 2 ("U.S. national vaccine stocks are sufficient to immunize only 6 to 7 million persons. This amount is only marginally sufficient for emergency needs. Plans are now being made to expand this reserve. However, at least 36 months are required before large quantities can be produced.")

32 Judith Miller and Sheryl Gay Stolberg, "Attacks Led to Push for More Smallpox Vaccine," New York Times, October 22, 2001, A1.

33 Dana Hedgpeth, "BioReliance vs. Bioterrorism," Washington Post, August 24, 2000, E1.

34 "Bioterrorism Concerns Spark First Smallpox Vaccine Production in 30 Years," CBW Chronicle 3, no. 2 (December 2000), 1; J. Donald Millar, "Paradox in Prevention: Managing the Threat of Smallpox Bioterrorism," PHPAB's Health Policy Focus (February 2000), p. 2.

35 Miller and Stolberg, Attacks Led to Push for More Smallpox Vaccine," A1.

36 Gina Kolata, "'Cure' for Bioterror May Be Worse Than the Disease," New York Times, October 22, 2001, B9; Susan Okie and Justin Gillis, "U.S. Mounts Smallpox Vaccine Push," Washington Post, October 28, 2001, A18.

37 D. A. Henderson et al., Smallpox as a Biological Weapon, 2127, 2132; LeDuc and Becher, "Current Status of Smallpox Vaccine," 593 (only 675 doses of VIG are available, and administration of them has been suspended due to discoloration of unknown cause and effect; the U.S. Department of Defense has recently contracted for the production of additional supplies); Advisory Committee on Immunization Practices, "Vaccinia (Smallpox) Vaccine Recommendations," 1-25 (noting that VIG does not negate all the adverse side effects of vaccinia exposure, and carries some contraindications of its own).

38 World Health Organization, "WHO Fact Sheet on Smallpox," www.who.int/emc/diseases/smallpox/factsheet, visited February 7, 2002; World Health Organization, "Statement WHO/16: World Health Organization Announces Updated Guidance on Smallpox Vaccination," October 2, 2001.

39 Shurkin, The Invisible Fire, 408-09.

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