Every year some 100,000 people die all over the world after being bitten by a venomous snake. Depending on the toxicity of the venom and how much venom is injected into the body, a snakebite will cause tingling, muscle weakness, nausea swallowing difficulties, excess saliva and potentially fatal breathing problems. To avoid getting killed, a snakebite victim must immediately go to a hospital for antivenom treatment. If the patient is brought in due time and, of course, if the hospital has the corresponding antivenom in stock, there’s an almost 100% chance she will survive. As you might have guessed, the prevailing reason why so many people die from venomous snakebites, even though a hospital is nearby, is because there isn’t enough antivenom to spare. In this post, you’ll learn how antivenom is made, what are the challenges and why it’s so precious.

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Photo: P. Mirtschin, Venom Supplies

The first antivenom

It’s amazing to find out that antivenoms were first introduced only some 100 years ago – until then people could only rely on their own immune system to survive, which most often than not didn’t cut it. Albert Calmette, a protege of the famous Louis Pasteur, made the first antivenom serum in 1896 in present-day Vietnam after a  flood forced monocled cobras into a village near Saigon, where they bit at least 40 people and killed four. A man of science, Calmette wasn’t satisfied with hope alone to save those unfortunate enough to get bitten, so taking inspiration from the then innovative vaccination wave, he took on the mission to make antivenom. He eventually discovered a process by which horses were injected with venom to produce antibodies, whose blood was then extracted and injected in the snake-bitten victim. Today, although much improved over the century, the process remains more or less the same.

How to make antivenom

In a typical antivenom institute, various species of snakes are bred, cared for and constantly monitored to ensure these are in good health. When the time is ripe, professionals introduce the snakes, which can include some of the deadliest like banded kraits or black mamba, into a milking room. The snake is grabbed 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 the snake milker to press the snake’s glands without allowing the snake to turn and bite – even so, many professional snake handlers can get bitten hundreds of times during their career.

The quantity of venom even season professionals can milk is very small, though, so snakes have to be milked many, many times to produce a useful amount. For instance,  it took a total of three years and 69,000 milkings to get one single pint of coral snake venom.  Once milked, the venom must be cooled to below minus 20 Celsius and usually freeze-dried for easier storage and transport. This process also concentrates the venom and removes water. Of course, each vial of venom needs to be correctly labeled with the snake’s species, geographical position and so on. Then comes the immunization part.

Traditionally, horses are used to create antibodies because they thrive in many environments worldwide, have a large body mass, get along with each other and are familiar with humans so they don’t get easily scared by needles. Goats and sheep are also used, as well as donkeys, rabbits, cats, chickens, camels, rodents. Some institutes even experiment with sharks. The antivenom produced from sharks is quite effective, but they’re rarely used for obvious reasons.

Before injecting the animal, chemists carefully measure the venom and mix it with distilled water or some other buffer solution. Most importantly, an adjuvant is added to the solution so the horse’s immune system reacts and produces antibodies that bind to and neutralize the venom. A veterinarian supervises the process at all times so that the horse or other animals of choice remains in healthy condition. Antibodies in the horse’s bloodstream usually peak in about eight to ten weeks. At this point, the horse is ready to have its blood harvested – typically 3 to 6 liters of blood is drained from the jugular vein.

Blood vials are centrifuged for purification. Photo: USFWS/Southeast/Flickr

Blood vials are centrifuged for purification. Photo: USFWS/Southeast/Flickr

The next step in the antivenom fabrication process is purification. The blood is centrifuged to filter the plasma – the liquid portion of blood that doesn’t contain blood cells – to allow the antivenom to be separated. During this step, producers typically employ their own methods and many keep them a trading secret. Typically, though, unwanted proteins are discarded through precipitation, 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 antibodies and isolate the active ingredients. The last step involves checking, usually by an outside regulatory body like the FDA in the United States. Once approved, the samples are concentrated under powder or liquid form, frozen and shipped to hospitals where they’re most needed.

As you can see, the process is extremely complicated, expensive and of little yield. For instance, a typical antivenom vial costs $1500 to $2200, but a snakebite requires between 20 and 25 vials to be neutralized. If you add these up, a man bitten in the US by a viper or some other venomous snake would have to drop some $30,000 in pharmacy costs alone. Yet most snake bites occur in developing countries, especially in rural areas of the tropics. Because the costs and energy required to produce antivenom are so large, producers don’t make enough because it’s not financially feasible, despite high demand for the product. As such, these people rarely get treated in hospitals, where antivenom is in little or no supply.

How to turn yourself into an antivenom

Antivenom isn’t the only way to survive a highly venomous snakebite. An alternate route, which works only for those that are constantly exposed to the risk of being bitten by venomous snakes, is to build tolerance. For instance, humans have been intentionally exposing themselves to poisons for millennia. The first account of such practice may be found in the story of king Mithridates, the ruler of Pontus, a region of in Asia Minor. Mithridates was openly opposed to the Romans, and in those times the weapon of choice for assassinating the upper class was poison. Paranoid of getting killed after every morsel of food, Mithridates eventually became a veritable scientist and poison control expert. The details are sketchy and have been lost in time – some say he poisoned ducks, then drank of those who survive. Nevertheless, he discovered that by gradually exposing himself to a nonlethal dose of poison, say arsenic, he would eventually build up immunity – up to a point. Ironically, he killed himself by ingesting an immense amount of poison, after suffering a decisive defeat at the hands of the Romans. The practice is now commonly known as mithridatism, and can work just as well for snake venom.

Haast handling a nervous cobra. Photo: bilhaast.com

Haast handling a nervous cobra. Photo: bilhaast.com

Bill Haast, a famous snake handler who died at age 100 was known for milking up to 100 snakes a day. At this rate, you can imagine he would get bitten often. Realizing this, he first started in 1948 injecting himself with increasing doses of diluted cobra venom in order to develop his own immune resistance. By the time he died  – of natural causes, we need to add – Haast had survived 172 bites from many of the world’s deadliest snakes, including a blue krait, a king cobra, and a Pakistani pit viper. Actually, he even flew around the world and donated his blood for direct transfusion, thus saving 21 victims.

 

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