I soon learned the vaccination would not be a simple procedure. It would most likely lead to a fever, flu-like symptoms, and an oozing sore on my arm that could take four weeks to heal. More importantly, because it involved being infected with a small dose of a living organism—the procedure for so-called “live-virus” vaccines—I would become infectious. If I wasn’t careful, I could transmit cowpox to any pregnant women or immune-suppressed people I shook hands with or hugged hello. Wearing a bandage on my arm for four weeks would reduce that risk, but not eliminate it.

I declined the offer. It seemed messy, complicated, and largely pointless. By the time my sore had healed, I would no longer even be working in the lab. Besides, I didn’t want to inadvertently give anyone a case of cowpox.

By page 17 of Elizabeth Fenn’s book on the great smallpox epidemic of 1775, I began to regret my decision. By page 74, with anthrax attacks on the rise, I sent out a panicky e-mail to my old boss to see if his lab still had any vaccine available. (They didn’t.) And by the time I finished Pox Americana, rattled Homeland Security Chief Tom Ridge had ordered 300 million new doses of smallpox vaccine to protect the nation, which had abandoned universal inoculation in 1972. Since early October, four Americans have died of inhalation anthrax, more than 20 sites across my city have been contaminated, and my doorman—who spends afternoons sorting bulk mail from D.C.’s Brentwood facility for 271 apartments—spent ten miserable days dizzy and sick from taking Cipro. A bioterrorist attack with smallpox—vials of which U.S. intelligence believes may be in the hands of various rogue nations—no longer seemed so farfetched.

The same reluctance that I once felt, and many still feel, about getting vaccinated, is now a hot topic of debate in Congress and (one hopes) inside the White House. Overcoming that reluctance and producing enough vaccine to protect the nation may be one of the keys to winning the war on terrorism, and saving countless lives. If so, it won’t be the first time smallpox, and government’s response to it, shapes the course of the nation. As Fenn’s extraordinary book points out, during the War of Independence, more men died of smallpox than musket fire. The British may even have used the virus as a weapon. And George Washington’s secret decision to inoculate his troops was crucial to winning the war.

Fenn’s book opens in 1751, with a 19-year-old Washington contracting smallpox while visiting his brother in Barbados. In his diary, he records the event on Nov. 17, “Was strongly attacked with the small Pox.” Not until Dec. 12 did he make another entry. “Rare was the diarist who kept writing through the throes of smallpox,” notes Fenn. “The void in Washington’s diary … speaks of a misery commonplace in years gone by but unfamiliar to the world today.”

Victims of smallpox showed no symptoms until 12 days after infection, at which point they began to suffer from “pre-eruptive symptoms”: severe headaches, excruciating backaches, fever, nausea, and malaise. Soon the telltale pustules (pus-filled blisters) began to form, first inside the mouth and nose, then on the face, neck, back, forearms, and feet. Patients were often wracked with severe anxiety, a symptom that did not bode well. Some—particularly Native Americans—died during this stage, without ever developing pustules. Others developed confluent smallpox, a condition with a 60 percent mortality rate in which the pustules ran into each other and sloughed off in great rotten sheets of skin. Hemorrhagic smallpox, a rarer form involved massive internal bleeding and was almost uniformly fatal. Even without these complications, smallpox often killed around one-third of its victims. Mortality was higher among infants, the elderly, the poorly nourished, or those, like the 18th-century Native Americans, who lived in genetically homogenous communities. Good nursing care during the month-long affliction markedly improved survival, but required the existence of already immune caretakers.

From the very beginning, attempts to prevent the spread of smallpox in North America were controversial. Puritan minister Cotton Mather’s house was firebombed in 1721 after he convinced Dr. Zabdiel Boylston to inoculate the uninfected during a smallpox outbreak in Boston. Often credited with introducing inoculation to America, Mather learned the procedure from his “Coromantee” slave, Onesimus. Inoculation had been widespread in Asia and Africa, but was largely unknown among Europeans until the early 18th century. New Englanders developed a particular hatred of the procedure and banned it in most towns. (Edward Jenner’s cowpox vaccine, the precursor of today’s, was not invented until 1796.)

Inoculation—a primitive and risky form of live-virus vaccination that involved intentionally giving individuals a mild case of smallpox to prevent them from acquiring a more deadly form “the natural way”—was a double-edged sword. Inoculees gained immunity but also became temporarily infectious and could easily spark outbreaks unless quarantined for the duration of their induced illness. Far too often, the early Americans were loath to allow such infringements on their “liberty,” writes Fenn, and the infectious inoculees—including such historical notables as Abigail Adams—would circulate freely, leaving a trail of disease in their wake. Inoculation was also a class issue. The procedure was expensive, and during their infectious period, the rich often transmitted their affliction to the uninoculated poor, who couldn’t afford the procedure.

When the War of Independence broke out in 1775, the Continental Army at first dug in its heels and forbade inoculation for fear of spreading the disease and incapacitating the fighting forces. “The Surgeons of the Army are forbid, under the severest penalty, to inoculate any person,” according to General Benedict Arnold’s February 1776 orders. Officers found submitting to inoculation would be “immediately cashiered” and privates “punished at the discretion of a Court-Martial.” Yet troops were so desperate to avoid the scourge that they’d inoculate themselves in secret with pinpricks under their nails.

In Europe and England, smallpox was endemic, and people usually caught it during their youths, when they were most likely to survive the infection. (Those infected between ages five and 14 have the lowest mortality rate.) With the bulk of its army thus rendered naturally immune, the British did not need to worry about either seizing smallpox-infested towns or inoculating the small percentage of its forces not infected as children.

The Americans soon learned they could scarcely battle two enemies at once—smallpox and the British. The disastrous experience of the siege of Quebec in 1775, when smallpox ravaged up to one-third of the assembled Americans, began to change the Americans’ minds about inoculation. Captain Lemuel Roberts concisely captured the problem during the retreat from Quebec by boat: “My pock had become so sore and troublesome that my clothes stuck fast to my body, especially my feet; and it became a severe trial of my fortitude, to bear my disorder and assist in managing the boat.”

Wave after wave of smallpox decimated the soldiers during the first two years of the war. New recruits would come down with the disease immediately upon enlistment, and thousands of potential fighters stayed away for fear of infection. By the winter of 1777 (the winter of Valley Forge), Gen. George Washington made a momentous decision to inoculate all new recruits and finally halt the pestilence’s progress. The inoculation campaign had to be conducted with great secrecy. Though it would protect soldiers in the long run and decrease fear of enlistment, it would also incapacitate large numbers for weeks at a time, rendering the Continentals vulnerable to assault. Ultimately, however, it became clear that the spread of smallpox through the ranks presented a graver threat to the army—and would kill more individuals—than the Redcoats. Recruits were quarantined in camps and inoculated before being sent out to fight.

“Washington’s unheralded and little-recognized resolution to inoculate the Continental forces must surely rank with the most important decisions of the war,” writes Fenn. “The general had outflanked his enemy”.

After the inoculations were complete, the Continentals were able to fight at full strength without fear of the epidemic. This was critically important in the Southern campaign in the final years of the war. Irregular militias refused to march on Charleston, South Carolina, to retake the town because smallpox was loose there. But an inoculated army of soldiers paid to fight was able to engage in battles that had scared off the militias—and to withstand the British attempts at biological warfare that preceded the surrender at Yorktown.

One of the saddest episodes of the war involved Virginia’s Ethiopian regiment, comprised entirely of Loyalist blacks and escaped slaves promised freedom for fighting with the British. “Within these days past, I have marched by 18 or 20 Negroes that lay dead by the way-side, putrifying with the small pox,” wrote a Connecticut soldier pursuing the British eastward from Richmond in the summer of 1781. “These poor creatures, having no care taken of them, many crawl’d into the bushes about & died, where they lie infecting the air around with an intolerable stench & great danger.” The Americans believed this abandonment was a deliberate attempt to infect the Continentals. “The British have sent from Yorktown a large number of Negroes, sick with the small pox,” wrote one eyewitness. “Lord Cornwallis’s attempt to spread the smallpox among the inhabitants in the vicinity of York, has been reduced to a certainty and must render him contemptible in the eyes of every civilized nation,” opined the Pennsylvania Gazette.

Thomas Jefferson later estimated that of 30,000 Virginia slaves who joined the British in search of liberty, “about 27,000 died of the small pox and camp fever.”

The scourge did not end with the war. Nor was it restricted to the former British colonies along the Eastern seaboard. It struck 44,286 in Mexico City in 1779. It rewrote the balance of power for the Plains Indians, decimating the village-dwelling Arikaras and Mandans and allowing the nomadic Sioux to seize control of the prairie. In the Pacific Northwest, it attacked villages so strongly that when English captain George Vancouver led an expedition in 1792 to the area, he found village upon deserted village with “human skulls, and other bones, promiscuously scattered about.”

Some sections of the latter half of Pox Americana will be of greater interest to historians than general readers. Passages cataloging in detail where the pox went and precisely whom it killed are necessary for a work of history but also get a bit dry. Meanwhile, the illustrations and pictures, though striking, often float unexplained or unconnected to the text. But these are minor quibbles. Pox Americana is a considerable achievement and an extraordinary work of history that uncovers an episode that reshaped America as surely as the War of Independence.

As for me, I signed up to do my bit for the war effort—and hopefully acquire some immunity—by trying to join the National Institutes of Health study of a diluted smallpox vaccine. (Unfortunately, I didn’t make the cut.) If the study can prove that a diluted dose works, we could potentially expand our existing stock of smallpox vaccine from 15 million doses to 75 or maybe even 150 million doses—a making-the-best-of-it strategy of which George Washington would have been proud.