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Flu Pandemic Preparedness: Growing Vaccines In a Greenhouse

Feb 07, 2012

If you were to ask the average person what the number one killer of mankind has been throughout history, they might throw out some ideas. Famine? Heart disease? War? Good guesses, but they'd be wrong. That dubious honor can be laid at the feet (figuratively speaking) of a very, very tiny killer: a virus.

Viral infections have killed more people on earth since the dawn of humanity than most other culprits combined. Some of them are well-known. The worst outbreak of the bubonic plague - also called the "Black Death" - occurred in the middle of the fourteenth century, and it killed 25 million people in Europe in five years, literally wiping out one-third of the continent's population. Subsequent outbreaks, which continued through the following centuries (and the black plague is still around today), killed millions more.

Then there's a much more common virus. While most people don't find the flu too threatening -- you get it every few years, you drink a lot of fluids and feel lousy for a week -- influenza has been, throughout history, humanity's number one murderer. The Black Death pales in comparison to the global Spanish flu pandemic of the early twentieth century. That outbreak, which occurred between 1918 and 1920, killed more people than World War One (which was no slouch in the killing department, taking somewhere between 20 and 40 million lives). The

Spanish flu, often cited as the most devastating epidemic in recorded world history, killed between 50 and 100 million people - more people in a single year than all four years of the black plague pandemic of 1347 to 1351 - and infected half a billion. More than one quarter, or 27 percent, of people on earth were infected by the Spanish flu, and between 10 and 20 percent of those infected died. The number of deaths was so high that the average life span in the U.S. was temporarily reduced by 10 years.

At that time, there were no vaccines for the flu, so the virus was allowed to spread unchecked across the planet, particularly in populations that lived in crowded, less-than-sanitary conditions (i.e., most of the world, at that time). Nor were there anti-viral medications or ventilators to help save the lives of those worst affected by the virus.

The U.S. recently experienced a small taste of what a flu pandemic could be like. In early 2009, a novel strain of the Influenza A/H1N1 virus arrived from Mexico and spread rapidly, infecting 59 million Americans and hospitalizing 265,000 from April 2009 until February 2010, according to the Centers for Disease Control (CDC). About 12,000 people died, some of them young and healthy people, along with the usual victims: the very old, the very young, the immuno-compromised and many pregnant women, who were disproportionately sickened by the virus. The nation was lucky: this particular strain of flu was not as dangerous as it could have been, and most healthy people who were infected did not become dangerously ill. (It's interesting to note, however, that the Spanish flu pandemic was also caused by the H1N1 strain.)

This flu outbreak helped underscore the fact that the U.S. is poorly prepared for a pandemic. Thanks to difficulties with the vaccine production process, the first doses of the A/H1N1 vaccine took 26 weeks to produce. It took 38 weeks to produce enough vaccine to immunize half the population, and sufficient vaccine to protect the entire country took nearly a year: 48 weeks, to be precise.

Currently, about 115 million people get immunized against the seasonal flu: only about one-third of the country. Should a dangerous flu virus - think avian or swine - mutate and threaten the nation in the future, that's not nearly enough to protect the country via the "herd immunity" that vaccination offers. Given that each American would need a vaccination, and children often require two doses, the number would need to hit somewhere around 600 million - and that vaccine would need to be created quickly, given how fast viruses mutate. Current vaccine production processes just aren't up to it, says the CDC.

Vaccine production today isn't exactly a high-tech process - in fact, it's been the same for more than 50 years, and it certainly isn't very green. Generally, the process uses what's called the "attenuated method," which involves growing the new strain of virus in chicken eggs. After it's grown, the virus is killed (obviously, injecting people with the live virus would give them the disease the vaccine is supposed to prevent). Even dead, the virus is able to act as an antigen that can teach the body's immune system to recognize the virus so in the future, when a person is exposed to the real deal, his or her immune system would produce an immediate response. In some cases, the viruses are grown in cell cultures, but the idea is essentially the same as with the attenuated method.

The current production processes is slow, taking between six and eight months to ramp up production after a pharmaceutical company receives the gene sequence of a new virus strain. It's inefficient, and because it's not particularly profitable, the U.S. government has to kick in subsidies to induce companies to even engage in vaccine production. Aware of this, the U.S. government set aside $1 billion in research and development money in 2006 to try and encourage the development of new methods of vaccine production. It ramped up its efforts in 2010 in response to the failure of the vaccine production system during the avian flu scare. (A failure that can be accounted for in this report.)

So how far have we gotten? Not very, but some progress has been made.

In December of 2011, the U.S. Department of Health and Human Services, in partnership with pharmaceutical company Novartis, dedicated a new facility in North Carolina that will skip the current egg method of vaccine production and instead use the cultured animal cell method. The goal of the facility is "pandemic readiness," and the new plant, once fully operational, will theoretically be able to quickly produce about a quarter of the vaccine that would be required by the U.S. in the event of a future pandemic. While the facility was initially created for the production of influenza vaccine, its cell-based technology methods could be adapted to produce vaccines for infectious diseases in an emergency: both those of the known variety (smallpox, for instance) and the unknown and yet-to-be mutated.

In response to the need for faster and more efficient vaccine production methods, a number of other companies backed with venture capital money have sought to develop newer methods. San Francisco-based Vaxart (profiled here by the Wall Street Journal in 2009) is testing vaccines produced with their proprietary manufacturing process and created in weeks instead of months. (Their process is not based on the egg method, which creates shelf-unstable vaccines that can go bad quickly, or the animal cell culture method.) Another benefit of Vaxart's technologies is that most of their vaccines are delivered orally, which has several benefits. For starters, it makes immunization easier and overcomes the objections of the needle-phobic, leading to more widespread immunization, and it helps combat something called "anti-vector immune response." If you've been exposed to diseases caused by adenoviruses in the past (common complaints like ear infections, tonsillitis, croup and pneumonia), a vaccine that uses the adenovirus as a vector will often trigger an immune response in the body, meaning that it fights off the immunization as it would a disease, rendering it less effective.

While private enterprise looks for a ground-breaking (not to mention patentable) solutions, one government agency well known for its forward-looking support for innovation has turned its significant resources toward the problem. The Defense Advanced Research Projects Agency (known and loved as DARPA) has a colorful past that includes, among other activities, development of ARPANET, the precursor to the Internet, as well as technologies in aerospace, computing and networking, space technologies, GPS, weapons, robotics and other areas.

DARPA, being an agency devoted to defense, has set its sights on next-generation vaccine production for one overriding reason: to ensure there is a way to defend against viruses that might have been intentionally created. Should a terrorist group find a way to mutate a particularly dangerous virus and let it loose on the public, it could devastate the globe in months without ever firing a shot or detonating a bomb. And as of right now, the U.S. is ill-equipped to meet the threat, a point that was driven home by 2009's avian flu vaccine debacle.

DARPA, for its part, has settled its sights (and its cash) on an entirely new vaccine production process: one that's very green. Literally.

Project GreenVax, led by Texas Plant-Expressed Vaccine Consortium (TPVC) and a company called G-Con LLC, is seeking to grow vaccines in plants instead of in eggs. By infecting plants (initially, tobacco plants) with viruses, the process literally "grows" the viruses. The plants are later harvested and ground up, at which time researchers can separate the grown antigens to create the vaccine. The process has has the potential to produce a lot of vaccine at low cost. Project GreenVax is currently operating on a $61 million grant from both the TPVC and DARPA. Research is conducted at the project's specially designed modular facility located at the Texas A&M Health Science Center in Bryant, Texas. It has one overriding goal: to find a process that will create a lot of vaccine very quickly almost anywhere.

"We have major problems with vaccine production and manufacturing in our country," Dr. Brett Giror, the vice chancellor of Strategic Initiatives at Texas A&M University, told KXAN news, an NBC affiliate.

Giror says that while current vaccine production methods create safe and effective vaccines, they just can't create sufficient quantity quickly enough in the event of a pandemic, particularly if the threat is man-made.

"Biology is the threat of the future," said Giror. "Terrorist groups like al Qaeda have sophisticated personnel who will never build an aircraft to fight the U.S. but could modify an existing bacteria or virus in a way that could be deadly to us."

According to Project GreenVax, the most important element in a new vaccine process is scale: how many doses can be made within a short amount of time in response to any particular pandemic. The group says it would be in a position to make as much as one kilogram of vaccine protein - which translates to as many as 10 million doses - in one month. While the researchers know they can make vaccines out of plants, the process is currently done on a small scale - a few thousand - which will help too few people to be effective. The project needs to find a way to scale from regional to national to global.

Most processes you design in a lab "just don't scale," says Giror. "You just can't get there from here." GreenVax is trying to change that by implementing new processes for purification that would be cost-effective and could scale up in the way required.

One of the biggest challenges for the group was getting that many grow lights assembled - the usual lights one would use in a green house, for example, or to grow college "party favors" in a foil-lined closet (remember that guy in the dorm?). Standard grow lights aren't efficient on a large scale: their photons disperse too easily and they make too much heat. In response, Project GreenVax has come up with the world's first LED solution that optimizes the wavelengths the plants need, doubling the amount of photons that land on the plants, which has been shown to greatly increase plant biomass from traditional grow lights.

Another challenge the project has overcome is production facilities. If you need a lot of vaccine quickly, you can't expect to be able to build a

factory from scratch, or modify an existing one, in time to meet your needs. Project GreenVax has created the world's first modular clean rooms: facilities that can be assembled quickly from pre-fabricated walls, floors, ceilings and furniture, which can then be filled with the growing plants and lab resources to make the green vaccines. The clean rooms are not only modular and easy to assemble, they can be moved easily too, thanks to air bearings that work a bit like an air hockey table - a cushion of air can be activated underneath so the clean rooms can be moved easily. (You can see a YouTube video of the modular units in action here).

The world was lucky in 2009. While many people dismiss discussions of flu pandemics as alarmist, they apparently don't realize that from one year to another, there is absolutely nothing but chance standing between us and a flu strain as virulent as the one that devastated the planet in 1918, killing as many as one in 10 of the people who contracted it. It would be nice to know that this time, we have twenty-first century technology on our side.