When the first recipe failed, as evidenced by the fact the monkeys were still alive, Raines had to go back to the computer modeling and revise her assumptions.
She manipulated the genes in the tularemia and created a bio-hazard that had to be restrained within the cement walls of the BSL-4 facility. With formula in hand she produced the new strain in glass. The aerosolized delivery produced inhalation tularemia without breaking the strength of the bacteria. The pre-clinical animal trial was successful. All four rhesus monkeys were infected and symptomatic within three to five days, and dead with complications from pneumonia within a week. The vaccine did not preserve their immunity. The monkeys were not immune from the tularemia.
Raines then had to produce a new vaccine, one that would keep the next group of monkeys alive.
It took great skill for Raines to successfully produce a lethal strain of tularemia, but creating the new super vaccine would require innovation normally reserved for Nobel winners. Evolving and translating the procedures Raines was developing in her basic BSL-4 research laboratory into a process that could be scaled up in a manufacturing environment to make millions of doses would require as much luck as it would skill.
Success would require a scientist with dedication and a willingness to be patient. There would be failure and disappointment. No one was more patient or dedicated than Lieutenant Colonel Leslie Raines.
When the first four monkeys were rolled into her BSL-4, she knew they were in a death chamber. Raines went above and beyond the enrichment requirements that her staff gave the four rhesus monkeys and made sure they had extra treats to eat and toys to play with while they waited for a lethal dose of tularemia. If millions of people and animals were going to live, she knew that four monkeys had to die first.
When Raines got the great news that the rhesus monkeys had died, she suited up and went into the BSL-4 and quietly thanked the non-human primates and stroked their fur from the openings in the cages. Raines was an animal lover at heart, but her mind was full of science.
Sixteen more dead monkeys cut her to her soul. She hadn’t found the right vaccine formula yet. She hadn’t found the correct immune response mechanism. She killed those monkeys, and she felt horrible, personally responsible.
Losing the animals she was desperately trying to save gnawed at her relentlessly. She worked many nights until 0400 hours, slept on the couch and got back into the lab by 0600. She was moody, short and irritable. Nothing else mattered. She couldn’t even comprehend a tularemia bio-weapon killing millions of people.
She had to save the next four rhesus monkeys.
Maybe it’s the adjuvants, she reasoned.
A small-molecule drug had a molecular weight of less than 1,000, whereas the virus-like particle Raines was using as the basis of her new vaccine was more than 10,000-fold greater in size. The dosage amount would be based on both weight and biological potency.
In the four failed vaccine tests that caused 16 dead rhesus monkeys, Raines took scrupulous notes. Every procedure, piece of equipment and data discovered was documented. Raines knew each process had to be described and characterized in great detail, including the nature and performance of the specific equipment used for every step of the process. The requirements created an essential rigidity to her approach which was necessarily unforgiving of an error in judgment. Any misstep along the way could result in a very time-consuming and expensive correction in the manufacturing process as soon as the vaccine product candidate left the Fort Detrick BSL-4 and landed in France at LyonBio.
In normal vaccine development, Raines and her team might have required five-to-nine years in repetitive pre-clinical trials. The FDA would demand the studies prior to moving the vaccine for rapid evaluation in human clinical trials.
But developing a vaccine for a bio-weapon was different than a vaccine intended for universal pediatric use. A bioterrorism threat was an emergency situation and testing for efficacy was not always as practical, and not always possible.
LyonBio was equipped to be the pilot plant for the Phase 1 human clinical trials that might not ever happen. Bulk preparation of the Phase 3 final vaccine for full-scale manufacturing was the most likely scenario.
But if Raines couldn’t save four rhesus monkeys, none of it would matter anyway.
Qazvin University of Medical Sciences
Ghods Hospital
Markazi Province, Iran
Ghods Hospital, built in 1991, was a fairly small, but modern regional hospital. Iranian doctors were well-trained, and the equipment in the hospitals was quite modern. Even though the Islamic Republic of Iran was estranged and isolated from the west, the universities, hospitals and businesses were anything but third world.
Markazi Province was Kazi’s favorite province in Iran. It was also his family name. Literally translated, Markazi meant central, as in the central province of Iran. With Azak as the capital city of the province, more than 1.3 million people called Markazi home.
Kazi fashioned himself as being middle of the road, in the center. He was born in Pakistan to Iranian immigrant parents, then raised in Iran by his ultra religious grandparents, and educated in the United States before his career took him to The Netherlands, Pakistan and back to Markazi Province in Iran.
Kazi’s parents were murdered in cold blood by Pakistani terrorists in 1981. They broke into the house in the middle of the night looking for food and money. He always assumed the thieves allowed him to live because he was only a 12-month old infant at the time. He couldn’t remember anything about his first year in Pakistan. He never heard his mother’s screams as the men slit her throat or the single gunshot that was fired into his father’s head.
His grandfather flew to Islamabad to collect him from the orphanage. Forty-eight hours after his parents were murdered he was living in Markazi Province with a grandfather he had never met.
Kazi’s grandfather was a highly educated man and worked as the Dean at the Arak University of Medical Sciences. AUMS did train some doctors, but their specialty was research, especially training doctors who were both clinicians and basic science researchers.
Kazi spent his formative years playing in his grandfather’s lab, mixing chemicals together and dissecting every dead animal he could get his hands on. Kazi was fascinated with the similarity and interconnectivity of organs, between both humans and animals.
Kazi’s grandfather, Qazvin, was also a religious zealot. He was a member of a secret and clandestine religious group which he co-founded with several others in 1953 called the Hojjatieh Society. They were an underground messianic sect which hoped to quicken the coming of the apocalypse in order to hasten the return of the Mahdi, the future redeemer of Islam who had been hidden through occultation since the 7th century.
Qazvin and the others wanted to bring back the Imam through violence rather than waiting piously for the Imam’s eventual return on his own schedule. But after the Iranian Revolution began, the Hojjatieh Society was banned and persecuted by Ayatollah Khomeini’s government. The Hojjatieh rejected both democratic and Islamic forms of government. They preferred to wait and be governed by the Islamic Messiah. Any form of government to the Hojjatieh was illegitimate or unnecessary at best. They were not interested in democratic reforms or totalitarian regimes. They wanted no government at all.