In the 1700s anyone alive knew that he or she would someday face King Smallpox. Once infected, a person had a 30 percent chance of dying, but even survivors might end up blind, deformed, or with permanent scars all over their bodies.
The normal attack route came through infected droplets landing on the membranes in the nose or mouth, but different civilizations learned that exposing people to the virus in other ways could prevent the disease. Some blew scabs from smallpox victims up their noses or took a scab or pus from an oozing smallpox lesion and scraped it onto someone’s arm. This process, called variolation, prevented illness in most, but because it used the same deadly virus, it risked giving the recipient smallpox disease instead. Between 1 and 3 percent of those who had received variolation died.
Edward Jenner, an English country doctor, observed that milkmaids had beautiful skin—at a time when smallpox left most people with pockmarked faces. He wondered whether the mild pustules milkmaids got on their hands from cowpox, a similar infection in cows, protected them against smallpox. He decided to test this theory on eight-year-old James Phipps, who was due to receive variolation. Jenner substituted some cowpox pus from a milkmaid instead of smallpox and scraped it onto James’s arm. Over the next several days, James developed a pustule from the cowpox. A couple of weeks later, Jenner tried it again but replaced cowpox with the actual smallpox virus (variolation) instead. This time James had no pustular response—the cowpox infection had made him immune to smallpox. Jenner then performed the same test on twenty-three other people. Success. He wrote up his findings. Despite initial skepticism from his medical colleagues, Jenner’s work gave birth to the first “vaccine” (from the Latin, vacca, for cow). Cowpox vaccination was adopted as a safer alternative to variolation. Jenner realized the significance of his 1796 finding, writing in a subsequent report, “It now becomes too manifest to admit of controversy, that the annihilation of the Small Pox, the most dreadful scourge of the human species, must be the final result of this practice.”1
Vaccination was the core of smallpox control and ultimately led to WHO’s global effort centuries later to wipe smallpox off the face of the earth. In 1980, when the World Health Assembly officially announced the eradication of smallpox, it asked all countries to turn their stocks of smallpox virus into repositories at the CDC or in the Soviet Union. After that, countries gradually stopped vaccinating against smallpox.
The unfortunate, unanticipated outcome of this public-health triumph was that as populations lost their immunity over time, smallpox’s attractiveness as a bioweapon increased. We at USAMRIID had been ringing alarm bells about smallpox for years, and our scientists initiated projects to develop new treatments and vaccines. Others began to take notice of the threat, which took many forms.
Had all countries really surrendered their smallpox stocks back in 1980, especially those that sponsor terrorism? What if someone unearthed smallpox from victims frozen in the permafrost or genetically engineered a new smallpox virus from a related virus or from scratch?
Understanding what happened in a vaccinated population in the former Yugoslavia provided a chilling example of smallpox’s potential. In 1972 a Yugoslavian man traveled on a pilgrimage to Mecca. On his way home, he passed through Iraq, where smallpox still occurred. After arriving home he may have felt ill but still invited friends over to tell them about his trip. Within two weeks eleven people developed smallpox—all unrecognized. Two weeks later over 150 more cases of smallpox exploded. The Yugoslavian government took extreme measures to shut down the epidemic by closing the borders, locking up the victims in a hotel in Sarajevo, and vaccinating the entire population of the country.
After the first Gulf War (1990–91), Iraq admitted that it had done research on camel pox virus—a close cousin to smallpox that causes disease in camels. Did Iraq intend to genetically engineer camel pox to make it act like smallpox? If the United States launched an invasion into Iraq, would Saddam Hussein unleash smallpox on U.S. forces or on the U.S. homeland?
We had no idea, but immediately after the anthrax letters of 2001, mindful of smallpox’s long reach and deadly capabilities, countries around the world scrambled for smallpox vaccine. By then the United States only had 15.3 million doses available for a population of over 280 million.
As the U.S. war machine started preparing for war with Iraq, the White House took notice of the specter of a weaponized smallpox attack. Vice President Dick Cheney pushed hard for action, and the CDC began to offer smallpox vaccine to civilian health-care providers, despite pushback from medical authorities. DoD preparations also kicked into gear.
Colonel Charles Hoke, an army infectious disease doctor with light brown hair and a boyish grin, ran the program that funded infectious disease research in military laboratories. His long, distinguished career included a tour with the CDC’s Epidemic Intelligence Service and running research studies in Thailand on dengue fever, Japanese encephalitis, and influenza. On a Thursday afternoon in July 2002, he received the dreaded phone call from his boss, the chief of Staff to the commanding general at Fort Detrick’s headquarters, that every military officer knows can come at any time.
“Colonel Hoke. You have been selected to be the army’s representative on the Select Agents Response Task Force (SARTF), and you will report for duty at the Office of the Surgeon General on Tuesday next week.” Colonel Hoke argued that he was essential in his current job and couldn’t leave, adding, “I will need to hear this from the general.” The general got on the phone. “Yes, Colonel Hoke, those are my instructions.” Colonel Hoke asked, “Do you have any special guidance?” “Yes,” the general responded, “do the best job you can.”
Colonel Hoke hung up and immediately placed a call to an old friend at the surgeon general’s office. “Is there any way I can get out of this assignment?” Colonel Hoke asked. “No problem, Charles,” his friend told him. “All you need to do is convince the commanding general of MRMC [Medical Research and Materiel Command], the head of the Army Medical Department, and the surgeon general that someone else is better qualified, and you’re free.”
Colonel Hoke relented.
On Monday he cleared out his office at Fort Detrick. On Tuesday he reported to the army surgeon general’s office to support Colonel John Grabenstein at the SARTF, whose primary mission was developing a plan to protect U.S. forces from smallpox. A key element: immunize U.S. forces in advance of an anticipated invasion of Iraq. John Grabenstein, a pharmacist with a broad forehead, steel-blue eyes, and a presidential look reminiscent of John Quincy Adams, was the right man to lead the SARTF. He brought a laser focus to the SARTF after spending the prior two years running the army’s anthrax vaccination program.
John said, “We’re just moving papers as fast as we can do it and trying to get everything put together,” and one day Dr. Hoke and another medical colleague showed up, “briefcases in hand” at the cubicle farm supporting the army surgeon general and said, “We’re here for the SARTF.” John asked, “What’s that?” Apparently, no one had bothered to inform him that he was in charge of the SARTF. Nevertheless, Dr. Hoke had a piece of paper authorizing him to be there, so John put him to work.
Once on board Dr. Hoke immediately understood the stakes. Not only was there a threat to the Unites States’ completely susceptible military population, but the safety of the homeland was also at stake. Soldiers infected on the battlefield risked bringing the virus home and lighting the flame that could spread a wildfire across the United States and to the world beyond.
But vaccinating the U.S. military forces had just gotten harder. In the late fall of 2001, Wyeth Pharmaceuticals lost its license for the vaccine, even though it had considerable quantities of vaccine in storage. The smallpox vaccine has three components: the dried vaccine in a vial; a second, smaller vial containing liquid (the diluent), which mixes with the vaccine to liquefy it for vaccination; and a two-and-one-half-inch-long specialized needle (the bifurcated needle) that looks like a miniature, two-pronged pitchfork. Unless all the components are functional, the vaccine can’t be used. In 2001 the diluent became the Achilles heel when it failed testing.
Overnight, no one inside or outside of the military could use the vaccine, even though the vaccine itself still worked. The Office of the Vice President pushed strongly to get a new vaccine into the national stockpile, but until a new diluent and bifurcated needles could be remanufactured, the vaccine became “investigational,” subject to all the FDA’s rigorous requirements for conducting a research study.
Just like Jenner had done in the 1700s, the smallpox vaccine is still administered differently than other vaccines. Instead of being injected deep into the muscle with a long needle, the bifurcated needle is dipped into the vaccine solution, and it captures the exact amount of liquid in between its two tiny prongs to give a single vaccine dose. The vaccinator then wipes the liquid on the upper arm and pierces the skin multiple times with the needle at the same location to carry the vaccine into the skin with each penetration. Over the next week or so, the live virus in the vaccine replicates in the skin, and the patient develops a pus-filled blister at the site, like eight-year old James Phipps developed in the 1700s. This blister is a good sign: it indicates that the patient has a “take” and is therefore becoming immune. A scar eventually develops, leaving a permanent record of successful vaccination.
My division at USAMRIID joined the smallpox vaccine preparation effort because giving the vaccine was a unique skill set that few people still had back in 2001. We were the only place in the DoD and one of the few in the country with any recent experience giving smallpox vaccine, because we gave it to our lab workers conducting research on monkeypox and smallpox.2
While the SARTF continued with its preparations, the Armed Forces Epidemiology Board (AFEB), a highly respected scientific advisory panel for the DoD made up of civilian experts, weighed in and endorsed “the development of policies and contingency plans for use of smallpox vaccine for military personnel.” The AFEB also noted that “any use of investigational smallpox vaccine should be done on a voluntary basis.”
That sounded great—on the surface. Giving a licensed vaccine to the forces is easy. Soldiers in basic training are like pincushions and get loads of them. Line them up, roll up their sleeves, and inject them “double barreled” in both arms in a human assembly line. “Investigational products” are different. They come wrapped in red tape with a whole different set of rules—and paperwork. It’s not like issuing flak jackets. We cannot force soldiers to take them—not even in the military. Every soldier must read and sign a two-dozen-page consent form—and that’s after you have sat them down and presented the vaccine’s risks and benefits. It’s hard to imagine adhering to this legal procedure while dodging enemy bullets. Soldiers had the right to refuse—even when facing an imminent threat. Such a complex process is no way to protect an army.
Dr. Hoke blasted me and a couple of USAMRIID colleagues an urgent note on July 16 about the march toward vaccinating the forces with an investigational product, stressing, “I’m trying to keep on the table that there is a vast difference between what can be done now [with an unlicensed vaccine] and [later] once there is a licensed vaccine. As hard as I try, there is the most incredible pressure to come up with a plan.” The SARTF was moving forward with the assumption that the vaccine would be relicensed in time for the war, but the team had to develop a contingency plan just in case there was a glitch. “Shit happens” is a way of life in the military, and things going wrong has to be part of the daily calculations.
Among ourselves and the SARTF, we discussed the possible need to request a presidential waiver of informed consent; otherwise, we couldn’t guarantee protection of the forces. Those of us at USAMRIID just didn’t believe that the decision makers at the highest level understood the challenge of what they were asking for—vaccinating the forces with an investigational vaccine—but we also knew that having the president waive informed consent was unlikely because it would be a political death trap.
The military generally tries to align its policies for protecting the health and autonomy of soldiers with civilian public health organizations like the CDC and the FDA, but occasionally, war operations present unique challenges without simple solutions. The military and the FDA had been burned before, during the first Gulf War, when soldiers were injected with vaccines without knowing what they were receiving. The specter of Gulf War Syndrome loomed over the effort, because vaccines had been considered a potential cause of that illness until they were later discounted. John Grabenstein at the SARTF knew that if the DoD had to vaccinate soldiers with an IND vaccine, it had to do it right. He said, “There was never any discussion of ‘we’ll give them a one-page summary, or we’ll hoodwink them, we’ll try and pull the wool over their eyes’; there was always respect for informed consent.” The main issue was how that could be achieved, but there was no good way to handle all the required FDA paperwork and tracking who got vaccinated. John recalls thinking, “Imagine if it’s a ten- or twenty-page consent form and it’s a half a million people, so how many pages is that and what are we going to do with all that paper?” For five hundred thousand soldiers, a twenty-pager translates to ten million pages, twenty thousand reams, and fifty tons of twenty-pound bond paper! There were no portable electronic solutions then.
The chief of the Allergy-Immunology Department at Walter Reed’s National Vaccine Healthcare Center emailed that she had “grave concerns about the implementation issues . . . making anthrax [vaccine] look like kindergarten” compared with smallpox vaccine. “The risk of failure, if not done in a way that facilitates compliance and success, is high. . . . We have the potential to lose a lot of trust in vaccine programs in general if we do not do this right.”
My colleagues at our sister lab, the Walter Reed Army Institute of Research (WRAIR), put it even more bluntly: “The assumption that this entire process can be accomplished under the rubric of a clinical research protocol is flawed. . . . The IND regulations are not intended for mass public health interventions of the type envisioned by this plan.”
The DoD drove on anyway, but Colonel Hoke did his best to sound a note of caution to the planners.
On August 24, 2002, the army surgeon general signed a memo directing our command to develop a protocol to dilute the existing smallpox vaccine fivefold, which could expand the limited national stockpile. We took on this task, along with our other contingency vaccine protocols. USAMRIID’s higher-level command was further directed to prepare a plan to vaccinate one thousand volunteers, with an expansion to thirty-thousand, if needed.3
But this small number would not solve the problem for the DoD. Vaccinating one thousand volunteers is one thing. Trying to vaccinate half a million forces with an investigational product would spell disaster, but waiting for a licensed vaccine would take time. We didn’t have time to wait, which risked delaying the launch date for war in the Iraqi desert into the middle of the summer. That would be a problem.
With leadership from the White House and the Office of the Vice President, in consultation with experts such as Dr. D. A. Henderson, who led the global smallpox eradication effort, and retired army major general Philip Russell, a respected scientist and vaccine developer, who met frequently with the vice president, the pieces led by the SARTF began to fall into place. Colonel Hoke started to get some traction with the challenges and risks of using an investigational vaccine. The DoD joined forces with the FDA and Wyeth. As Phil Russell said, “We pushed really hard [on Wyeth], and they went all out to bring those lots out of deep storage and get them approved for use.” Wyeth assigned a former army physician-scientist to lead the effort to methodically conduct studies and assemble the documents and information needed to get the vaccine relicensed. The Wyeth team worked around the clock, and the FDA reviewed the documents from them in real time. But John Grabenstein is quick to point out that “nobody ever brought undue influence on the FDA.” Phil Russell said, “At that point in time, interagency differences were set aside. Everybody was on the same page and wanted to get the jobs done.”
On September 12 a new directive came from the Pentagon to form smallpox epidemiologic response teams and treatment teams. I worked with the USAMRIID commander to assign our different docs, nurses, and technicians to the respective teams.
The SARTF’s preparedness effort culminated in organizing a “DoD Smallpox Preparedness Conference” for the team members from October 29 to November 1, 2002, in a hotel near the Pentagon. Masterfully orchestrated to fly under the media radar, hundreds of DoD medical personnel from around the country converged for training on smallpox recognition, learning how to vaccinate, managing vaccine reactions, and getting vaccinated themselves. Our USAMRIID nurses gave hands-on training, while vaccinating the care providers. I lectured to a hotel ballroom full of military docs and nurses from the army, navy, and air force on how to vaccinate using an investigational protocol. Even as I lectured, I couldn’t help thinking that this was a fool’s errand. I just wasn’t convinced that we could pull off vaccinating an invasion force with an investigational vaccine. There had to be a better way.
John Grabenstein recalls, “We were living, eating, and breathing biodefense stuff, contingency planning, but there remained a concern that if they couldn’t get a presidential waiver and they had to give the vaccine under IND, how could they do it? Well, you then need some specialists, dedicated people who can do the training, . . . explain the risks and benefits,” and accomplish all the other tasks of giving an IND vaccine. At a meeting one afternoon, John said that a Specialized Medical Augmentation and Response Team (SMART) for biodefense was needed to do this.
As the winter of 2002 arrived, the DoD figured out its “better way.” John’s idea of a SMART team took hold. The army was scouting for a field-ready “dream team” of experienced medical officers who understood infectious diseases, bioweapons, investigational vaccines, and how to give them. War preparations continued, but the work on a smallpox vaccine was only the beginning.
In my mind I heard the unmistakable, ominous “WHOP-WHOP-WHOP” sound of Blackhawk helicopters just over the horizon. They were coming for me.