The crisis in the nation’s flu vaccine supply has led to renewed calls to modernize a half-century-old manufacturing system that relies on millions of chicken eggs and a lot of educated guesswork.

Because it takes at least six months to produce the annual flu vaccine, no manufacturer can replace the 46 million shots Chiron Corp. won’t ship this season.

Citing manufacturing problems, British regulators on Tuesday shut down Chiron’s factory in England where roughly 46 million doses destined for the United States had been made.

That leaves the nation with only 58 million shots for the more than 100 million people most vulnerable to the flu, according the Centers for Disease Control and Prevention.

“In the face of a pandemic, this is exactly what we will be faced with,” said Dr. Robert Webster, a leading flu expert at St. Jude Children’s Research Hospital in Memphis, Tenn. “This is unacceptable in the United States. It is a bloody scandal.”

Experts said the shortfall has exposed a clumsy manufacturing system woefully unprepared for emergencies such as the 1918 flu pandemic - a public health crisis that scientists warn could happen again at any moment.

The manufacturing process could be improved by genetically engineering flu strains and brewing vaccines in human and monkey cells instead of chicken eggs, many scientists and health officials argue.

But efforts to update the system are still dogged by scientific problems, intellectual property tangles and market forces.

In the 1970s, there were as many as 25 flu vaccine makers. Today, there are only two major suppliers for the world.

That’s because vaccine-making is a risky business with high levels of liability and low profit margins that most pharmaceutical companies avoid.

Webster is developing a genetic engineering technique called “reverse genetics” that also promises to take much of the initial guesswork out of vaccine development and could shave weeks, even months from the process.

Webster uses reverse genetics to build from scratch perfect flu strains that reproduce reliably and quickly. His work is being tested in people now, a process and he and many others believe will replace the laborious trial-and-error process now used to grow “seed strains” to start the annual vaccine-making process.

Each February, World Health Organization doctors meet with an international team of virologists to identify the flu strains they think will hit the following winter. They then brew these flu strains in chicken eggs to create a safe “seed vaccine.”

It can take weeks or months for the eggs to yield the seed vaccine, and until the vaccine makers receive the seed and related biological material from the WHO, they can’t begin the manufacturing process in earnest.

What’s more, keeping and raising the chickens needed for their eggs is a tedious and decidedly low-tech approach to fighting the flu.

Drug companies and academic researchers say they could reduce the lead time and prepare more effective vaccines by incubating the virus in human and monkey cells rather than eggs and by using reverse genetics to remove much of the guesswork of preventing a disease that kills an average of 36,000 Americans and hospitalizes another 114,000 a year.

However, such advances are being slowed by technical problems and intellectual concerns. Three different groups of researchers and companies, including Gaithersburg, Md.-based biotechnology company MedImmune Inc., hold key patents to reverse genetics processes.

MedImmune said it allows government scientists around the world who are developing vaccines for pandemics to use its technology for free. But MedImmune does require companies attempting to profit from vaccine manufacturing to pay royalties if reverse genetics is used.

Not a single vaccine developer has entered into a commercial relationship with MedImmune, spokeswoman Jamie Lacey said.

Further, the cell-based processes still have some technical hurdles to overcome, including guarding against passing cancer or other illnesses on to healthy people getting flu shots.

Several companies, including Emeryville, Calif.-based Chiron, are experimenting with a specialized monkey cell that has yielded positive results in early testing.

Using the monkey cells isn’t new - they’ve have already been used to make a polio vaccine approved in the United States, and a smallpox vaccine using monkey cells is in the works. And while people allergic to eggs are advised not to take flu shots, allergic reactions aren’t expected to result from the monkey process, since the cells have been purified to eliminate all genetic traces of monkeys from the resulting vaccines.

Still, none of the new technologies under development is close to supplanting the egg-based system anytime soon. However flawed, eggs have supplied the nation’s flu vaccine for more than 50 years and changing systems will be time consuming and expensive.