Paul McKellips - Jericho 3

Even though the public demand for safe and effective vaccines remained strong, very few of the major pharmaceutical companies had the knowledge or facilities required to develop and manufacture new vaccine products. Most of the traditional work focused on small-molecule drugs and therapeutic proteins.

Raines had no choice but to choose an offshore firm. There were too many restrictions on which additives could be introduced into American-made vaccines. The complexity of the technology, the need for specialized facilities and the endless regulatory hurdles were major obstacles in the US. And with the emergence of an expanding animal rights movement that was waging effective battles on all five fronts — political, legal, social, violence, and psychological — basic science was anything but basic in America.

At her core, Raines was a biomedical researcher, a basic scientist. Raines started with in silica modeling. She used the finest Silicon Valley computers and software programs and looked for ways to exploit naturally occurring tularemia into a lethal bio-weapon. Based on some vulnerable areas she discovered within the gene make-up of tularemia, she cooked up an in vitro recipe that she hoped would be vaccine-resistant. In vitro was the research conducted in a Petri dish or within glass. Raines developed both her toxin and her vaccine inside test tubes. She had to find a delivery mechanism that would spread an aerosolized version of the bacteria that could be inhaled. Aerosolized tularemia was tricky. If the bacteria broke down too much during physical alteration, it would lose its potency. Raines then needed to test both the toxin and the vaccine in a living organism. She gave the existing baseline vaccine to four rhesus monkeys and delivered the inhalation tularemia. It was a pre-clinical animal trial, or what was called in vivo research conducted within a living organism.

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.