How to Make Antivenom—And Why the World is Running Short

When Eric Bortz's monocled cobra bit him in January, he thought the pain would be the worst part. The dealer who sold the snake said its venom glands had been removed. Unfortunately for Bortz, that wasn't so. Within hours, the New Jersey man began to have trouble breathing and was rushed to a nearby hospital. But like most hospitals, this one was ill-equipped to treat such a specialized malady. So doctors transferred Bortz to Jacobi Medical Center in the Bronx, which specializes in snakebite treatment. Were it not for Jacobi's access to a wide array of antivenom through its partnership with the Bronx Zoo (which houses exotic snakes from around the world), Bortz could have died. Instead, he was treated and released days later.

However, 100,000 people worldwide each year are not so lucky. Despite the fact that humans learned how to make antivenom more than 100 years ago, there are critical shortages of virtually every kind of it, especially in developing countries. But why?

Making antivenom is a painstaking, resource-intensive, time-consuming process. It's not much different now than when it was first created in the 1890s by a protege of Louis Pasteur named Albert Calmette, who was living in present-day Vietnam when a flood forced monocled cobras into a village near Saigon, where they bit at least 40 people and killed four. Inspired by the then-new science of vaccinations, by 1896 Calmette had discovered the process of injecting horses with venom until they produced antibodies, taking the serum out of their blood and injecting it into snake-bitten humans as antivenom.

Leslie Boyer, a physician and head of the VIPER Institute at the University of Arizona, says the process is much improved a century later, but the steps remain largely the same. She and other antivenom experts walk us through how they create the antidote to the world's deadliest snakebites.

The first step is getting your hands on a lot of snakes, which are quarantined and monitored for weeks to months to ensure their good health. Before milking, put on protective gloves. Famed snake handler Bill Haast used his bare hands, but was eventually bitten on the right index finger, rendering him unable to wrangle serpents–his lifelong passion. Move the snake into a clean milking room. With some of the most deadly snakes, like banded kraits or black mambas, experts often use a short-acting anesthetic to calm the snake down.

Next, grab the snake with the thumb and index finger at the very back of the head, just behind the angle of the jaw where the venom glands reside. This allows you to press on the glands while preventing the snake from turning its head and striking you. Opening a snake's jaws may require gentle pressure, and with vipers, you might have to use forceps to swivel their fangs into the upright position and pull back the sheath covering the fang's hollow tip.

Take a vial and cover it with a rubber or plastic film. Then, snake in hand, push the fangs through the plastic (or let the snake simply strike on its own). Gently squeeze the glands to get out all the venom. In some cases, antivenom makers use a weak electric current to stimulate venom excretion. Carefully remove the fangs from the film. Snakes with fangs in the back of their mouths, such as colubrids, may require special tubes to bite into, which drain into a collection vial.

To get enough venom, each snake must be milked many times. For example, in 1965, the National Institutes of Health asked Haast, who founded the Miami Serpentarium, to produce 1 pint of coral snake venom. It took him, a man of unrivaled skill and patience, a total of three years and 69,000 milkings to get that much, from which the first and only American coral antivenom was made. Wyeth (now owned by Pfizer) produced this same antivenom until 2003, when it closed the factory. Since then the FDA–which must approve antivenom the same way it approves other drugs–has extended the expiration date of the scant remaining supplies three times because the supply threatens to run out soon.

Once milked, the venom must be cooled to below minus 20 Celsius and usually freeze-dried for easier storage and transport. Freeze-drying concentrates the venom and removes the water. It's important to clearly label the venom with the snake's species, any relevant subspecies and geographical origin, since venom can vary wildly between members of the same species, especially between young and old snakes (older ones are more venomous).

Horses are most commonly chosen as the animals to create antibodies because they thrive in many environments worldwide, have a large body mass, get along with each other and are forgiving. "When they see you coming at them with a needle two to three times, they don't attack you," Boyer says. "They're friendly animals with big veins and they have long lives." Goats and sheep can work well, too. People have also used donkeys, rabbits, cats, chickens, camels, rodents and even sharks. "Sharks make nice antibodies," Boyer says, "but obviously aren't easy to work with."

Prep the venom for injection by carefully measuring it out and mixing it with distilled water or a buffer solution. Then mix in some kind of adjuvant–a chemical that causes the horse's immune system to react and produce antibodies that bind to and neutralize the venom.

Inject a small amount (say a few milliliters) of the solution beneath the horse's skin, preferably on its rump or the back of its neck where lymph nodes and immune cells reside. It's usually a good idea to break up the shot into smaller doses in various locations to avoid causing an ulcer or sore on the skin and to maximize the surface area for an immune reaction. This part of the process can vary depending upon the type of antivenom, the company involved, the snake used and the sort of antibodies desired. The specific details are hush-hush. "These are closely guarded trade secrets by people who make antivenom worldwide–how much venom is administered in what fashion to get an immune response," Boyer says.

It's vital to have a trained veterinarian on hand to monitor the horse's health. If it tolerates the injection, you'll probably give it several more doses days or weeks apart. Antibodies in the horse's bloodstream peak after about eight to 10 weeks. At that point the horse is ready to be bled, which involves drawing 3 to 6 liters of blood from the jugular vein, according to WHO guidelines.

Use a centrifuge to filter the plasma, the liquid portion of the blood not including blood cells. The WHO recommends injecting the blood cells back into the horse, although horses can usually stay alive and healthy without this.

Now it's time to separate out the antivenom. Again, this multistep process varies by antivenom producer. Generally, it begins by getting rid of unwanted proteins. You do this by causing them to precipitate, or fall out, often by adjusting the plasma's pH or adding salts to the solution.

One of the last steps involves using an enzyme to break down the antibody into small parts and isolating its active ingredient. In the case of CroFab, the only FDA-licensed antivenom produced in the U.S. (which treats bites from all North American species except the coral snake), the sheep-derived antibodies are digested with the enzyme papain. Alvin Bronstein, medical director of the Rocky Mountain Poison Center, says this creates a small antibody with a much lower likelihood of causing an allergic reaction compared to its predecessor. "It's a revolutionary treatment for snakebite," he says.

Now that you've gone through all this effort, your antivenom still must be deemed safe and effective by the FDA, which can take another 10 years.

Once approved, the purified antibody product is freeze-dried or concentrated into powder or liquid form and put into vials for shipment. The antivenom usually needs to be refrigerated or frozen, which further hinders availability in developing countries where electricity may be unreliable. Once the product reaches an emergency room and a snakebite victim arrives, the vials are usually filled with saline solution and injected intravenously. If everything goes right, the antibodies then bind to and neutralize the venom, while the liver or kidneys clear out the excess chemicals.

All these steps certainly add up on the balance sheet. Mike Touger, an emergency medicine specialist at Jacobi, says his group has paid as much as $1600 per vial of CroFab, and Boyer says a snakebite that needs antivenom requires an average of 20 to 25 vials. Touger recalls the case of a man bitten by a timber rattlesnake, whose venom disrupts blood's ability to form clots; the man bled for three weeks and went through 30 vials of CroFab. "That's $30,000 in pharmacy costs alone," Touger says. The patient survived, as has everyone treated for venomous snakebites at Jacobi since the treatment center opened in 1981. But the time and money required to make antivenom, combined with the fact that most deadly snakebites happen in developing countries, has decreased the financial incentive for drug companies to produce more antivenom, contributing to a worldwide shortage.

There's one other, quirkier way to make antivenom–one that physicians don't exactly recommend. For decades Bill Haast, who died this June at the age of 100, milked about 100 snakes a day with his bare hands, and in 1948 began injecting himself with increasing doses of diluted cobra venom in order to develop his own immune resistance. At the time of his death (not caused by snakebite), he'd survived 172 bites from many of the world's deadliest snakes, including a blue krait, a king cobra and a Pakistani pit viper. He flew around the world to donate transfusions of his antibody-rich blood to treat 21 snakebite victims. Venezuela made him an honorary citizen after he traveled into the jungle to donate blood to a young snake-bitten boy. According to his wife Nancy, all 21 patients survived.