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Baculovirus protein balls. Source:

Viruses That Make Zombies and Vaccines

This week the FDA announced that they were approving a new kind of flu vaccine. Nestled in the articles was an odd fact: unlike traditional flu vaccines, the new kind, called Flublok, is produced by the cells of insects.

This is the kind of detail that you might skim over without giving it a thought. If you did pause to ponder, you might be puzzled: how could insects possibly make a vaccine against viruses that infect humans? The answer may surprise you. To make vaccines, scientists are tapping into a battle between viruses and insects that’s raging in forests and fields and backyards all around us. It’s an important lesson in how to find new ideas in biotechnology: first, leave biologists free to explore the weirdest corners of nature they can find.

The standard way to make flu vaccines dates back to the Eisenhower administration. Scientists inject flu viruses into chicken eggs. The viruses hack the molecular machinery inside the eggs for making proteins and genes. Instead of bird molecules, the egg makes new viruses. The scientists then isolate the new viruses, kill them, and then isolate proteins from the dead viruses to put in the vaccine. Those proteins then prime the immune system to recognize proteins produced by live viruses and fight them off.

Influenza viruses grow in chicken eggs thanks to the similarities of bird and mammal biology. In fact, all the flu strains that menace us humans got their start in birds. They crossed over to our species by evolving the ability to invade our cells, replicate efficiently inside of us, and spread in our coughs.

But using eggs has a lot of drawbacks. A single egg produces a single dose, which means that a supply of tens of millions of vaccines is a massive undertaking. Making matters worse, eggs need months make new viruses, so that vaccine makers need lots of time to build up a supply before the start of a new flu season. That means that they have to decide which flu strains to use long before they can actually see which flu strains are dominating a flu season. Sometimes this scientific clairvoyance fails, and a vaccine turns out to be badly matched for a particular flu season’s strains.

A lot of scientists have been casting around for a better way. One promising idea is to take advantage of the sinister sophistication of something called a baculovirus.

Baculoviruses are sprinkled abundantly on plant leaves. They even wind up in our food. In 1973, scientists found that cabbage from grocery stores was coated in baculoviruses. A single serving contained up to 100 million of them.

Fortunately, we have nothing to fear from baculoviruses because they make insects their victims, with each strain only infecting one or a few species at most. But woe to the caterpillar that takes a bite of a baculovirus-coated leaf. The virus swiftly infects its cells and makes vast numbers of new baculoviruses. Some of the viruses spread from cell to cell. Others stay where they’re produced, manufacturing giant balls made of a protein called polyhedrin. The viruses become lodged in these balls. Between the new viruses and the new polyhedrin balls, a caterpillar can become visibly swollen with its infection.

All viruses need a way to get to a new host to escape extinction. Baculoviruses have a particularly creepy way of doing so. They produce a protein that interferes with a caterpillar’s biology, apparently making it ravenous. Normally, caterpillars will rest at the base of plants. Infected caterpillars roam day and night, feeding their inner parasites. They eventually dissolve, raining virus-packed protein balls on the leaves below. The protein balls are tough and durable, helping the viruses stay viable until another unwitting host comes munching along.

We know all this thanks to a lot of scientists dedicating their careers to these peculiar viruses. One particularly important advance they made was figuring out how to rear insect cells in a dish. Rather than having to infect an entire insect, they could now observe viruses invading individual cells. Whether any practical good would come out of all this research nobody could say at first.

But soon ideas did arise. Farmers can now use baculoviruses as a pesticide, for example. And then a less obvious application of baculoviruses turned out to be much more powerful: engineering their protein balls.

It’s fairly straightforward to engineer the genes of a baculovirus, swapping a gene from another species into its genome. Scientists figured out how to swap foreign genes for the polyhedrin gene, so that when the baculovirus infected insect cells, it made balls made out of the foreign protein instead. Evolution, in other words, had produce a remarkably efficient protein factory.

Scientists began to use baculoviruses to churn out proteins that scientists could study in large quantities. Over 500 proteins have been produced from baculoviruses, and nearly half of papers on proteins from animals and plants depended on this method. Scientists have also started to make medically valuable proteins, which can treat cancers and other diseases. And most recently, scientists have started using baculoviruses to make vaccines against other viruses.

Take papillomaviruses, which cause cervical cancer. GlaxoSmithKline identified proteins from the most dangerous papillomavirus strains that triggered a strong response from the immune system. They engineered baculoviruses with the genes for those papillomavirus proteins. The baculovirus did what it always did: it hijacked caterpillar cells and produced lots of protein balls. But then GlaxoSmithKline could isolate the proteins, stick them in syringes, and protect millions of girls and women from a deadly cancer.

The new flu vaccine, made by Protein Sciences, is produced in much the same way. Protein Sciences selected a flu protein known to trigger a strong response from the immune system–known as hemagglutinin–and engineered it into baculoviruses. The baculoviruses then infected insect cells and made hemagglutinin balls. The scientists isolated the abundant hemagglutinin and turned it into vaccines.

It’s important to note that Flublok is not terribly impressive. According to the FDA, it was about 44.6 percent effective against all circulating influenza strains, not just the strains that matched the strains included in the vaccine. It’s only approved for people between 18 and 49, and it’s got a shelf life of 16 weeks.

The drawbacks of Flublok may have less to do with being made by baculoviruses than simply the molecule Protein Science chose to engineer into them. As I recently wrote in the New York Times, other scientists are investigating the potential of other flu proteins–or even just fragments of proteins–to trigger long-lasting protection against the flu.

As a general approach to making flu vaccines, baculoviruses have some advantages over chicken eggs. They are so efficient at making protein balls, and insect cells are so small, that the process can potentially churn out more vaccines in less space. And it’s a fast process, thanks to the fast work of baculoviruses. Protein Science needed only 3 weeks to go from the genetic sequence of hemagglutinin genes to vaccine production. Baculoviruses are promising for vaccines to other diseases as well; work is underway for vaccines against HIV and malaria.

These days, it’s very easy to make fun of scientific research with no obvious practical importance. But we can’t predict where in nature we will discover the ideas that will make our lives better. It’s hard enough to believe that a virus can make a catepillar its zombie. It’s harder still to believe that this zombie-master could potentially save us from diseases.

[Thanks to Helen Branswell for some very helpful insights about flu vaccines]