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Antivenom

Snakebite Treatment: Past, Present, and Future

The Antivenin Nearctic Crotalidae treated bites by crotalids such as cottonmouths (picture by Meg Jerrard on Unsplash)

The Antivenin Nearctic Crotalidae treated bites by crotalids such as cottonmouths (picture by Meg Jerrard on Unsplash)

Snakebites have challenged humans for centuries. Without a proper understanding of how snake venoms worked, physicians used the same ineffective treatments through much of history. These practices included manually sucking the venom out of a wound or serving Theriac, a concoction made of herbs, spices, opium, ground-up snakes, and even powdered mummies, to the victim. These remedies remained popular in western medicine into the seventeenth century.1

Antivenom, or antivenin, was developed in the 1890s as a new treatment for envenomation. Though who first created antivenom is heavily debated, most credit a French immunologist named Albert Calmette (1863-1933) who sought a treatment for cobra envenomations in Vietnam. Having witnessed a large number of monocle cobra bites after a heavy rainy season, he decided he had to act. He developed a new serum by injecting small, non-lethal doses of cobra venom into various animals; these animals went on to develop antibodies capable of neutralizing the venom. Calmette would then extract some blood from the animals and isolate the antibodies to purify into antivenom.2 This technique is still used in animals such as horses and goats to create antivenom today.3

Calmette’s discovery eventually led to commercial production of antivenoms. Three decades later, the HK Mulford Company of Philadelphia, overseen by the Antivenin Institute of America, began producing the first commercial antivenom in the United States. Their antivenom, called the Antivenin Nearctic Crotalidae, could treat the bites of various North American crotalids (copperheads, cottonmouths, and rattlesnakes). This versatility was possible because of the antivenom’s polyvalence–it contained antibodies effective against the venoms of numerous species.4

Antivenoms are now manufactured all over the world to treat all kinds of snakebites. However, the technology is far from perfect. Polyvalent antivenoms continue to be a work in progress today, and one of the main difficulties in creating a versatile and effective antivenom stems from the variation in venom across species. Elapids like cobras and taipans, for example, usually possess neurotoxic venom, while crotalids such as rattlesnakes and adders possess a completely different hemotoxic venom.

Due to significant diversity in venoms, drug companies must develop antivenoms specific to each snake species. Existing polyvalent antivenoms are limited and can only treat a few of the species most responsible for envenomations. For example, the main polyvalent antivenom produced in India only covers the “Big 4” snake species out of the 60 capable of envenoming humans. As a result, there is no antivenom treatment for people who have been bitten by many snakes not included in the “Big 4.” Without any other available treatment, doctors are forced to use this same antivenom on these patients, often leading to treatment failure. Furthermore, all Indian antivenom manufacturers source their venoms from one geographical population of each species, and because of variations within different populations of the same species, these antivenoms may not be very effective for patients of different locations.5 Similar issues exist with antivenoms produced around the world.

Current antivenom technology is limited due to the complexities of venom across and within species. However, scientists are creating new potential therapies with the goal of more effectively treating all snakebites. For example, the drug manufacturer Ophirex is conducting clinical trials for a PLA2 inhibitor, varespladib, which could treat snakebites from more species than any current treatment. Unlike traditional antivenom technology, the drug works by blocking PLA2 enzymes that play a major role in bleeding, tissue destruction, and paralysis. This class of enzymes are found in 95% of all snake venoms and may be the key to developing treatments that cover snakebites more broadly. Other small molecule therapeutics such as metalloproteinase inhibitors, aptamers, and chelators, among many others, are also currently being studied. As companies experiment with new therapies, antivenom technology will continue to grow and improve, hopefully resulting in better health outcomes for snakebite patients around the world.6

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How is Antivenom Made?

Snakebites are a global health crisis, affecting millions of people every year. Venomous snakes can deliver a lethal dose of venom with a single bite, making immediate treatment a matter of life or death. Thankfully, immunology pioneers in the 1890’s were the first to develop snake antivenom…and we still use the same process today!

Snake venom is a complex cocktail of various proteins, enzymes, and other substances, each with its unique effects on the human body. These venom components can cause severe tissue damage, interfere with blood clotting, can cause paralysis, and even lead to organ failure. Snake antivenom, on the other hand, is a specialized serum that contains antibodies capable of neutralizing the venom's toxic effects.

The steps for antivenom production.

Step 1: Venom Collection: To produce snake antivenom, venomous snakes are carefully selected and milked for their venom. This process involves stimulating the snake's venom glands while safely collecting the venom drops. Expert herpetologists or trained professionals perform this task, ensuring minimal harm to the snake and themselves.

Step 2: Venom Dilution: Once collected, the venom is carefully diluted. This step is crucial to reduce its toxicity and make it safe for subsequent use in the production of antivenom. Dilution also helps in standardizing the venom concentration for consistent batch production.

Step 3: Animal Immunization: Next comes the immunization stage. The diluted venom is injected into a host animal, often horses, although other animals like sheep or goats can also be used. Horses have proven to be particularly effective in producing large quantities of antibodies. The injected venom stimulates the animal's immune system to produce a defensive response, generating specific antibodies to combat the venom toxins.

Step 4: Antibody Harvesting: Over a period of several weeks, the host animal's immune system produces a significant quantity of antibodies against the venom. Regular blood samples are collected from the animal, typically from the jugular vein, and processed to separate the serum, which contains the valuable antibodies. The animal's well-being is closely monitored throughout the process, and steps are taken to ensure their comfort and health.

Step 5: Purification and Standardization: The harvested serum is subjected to purification techniques to remove any impurities and concentrate the desired antibodies. Various purification methods, such as chromatography and filtration, are employed to achieve this. The purified antibodies are then analyzed and standardized to ensure consistent quality and potency.

Step 6: Testing and Packaging: The final step involves rigorous testing of the antivenom to assess its effectiveness and safety. The antivenom is tested for its ability to neutralize the venom's toxic effects through in vitro assays and in vivo tests. Once the product meets the required standards, it is packaged into vials or ampoules, ready for distribution to hospitals and healthcare facilities.

The production of snake antivenom is a complex and intricate process that involves careful venom collection, animal immunization, antibody harvesting, purification, standardization, and extensive testing. Thanks to the efforts of scientists, herpetologists, and veterinary professionals, snake antivenom plays a vital role in saving countless lives affected by snakebites. As research and technology continue to advance, the development of more effective and accessible antivenoms holds great promise in reducing the global burden of snakebite fatalities.

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Veterinary Experts Do Not Recommend The Rattlesnake Vaccine

Every spring, as the weather warms up, we want to shed our winter coats and get out with the dogs onto trails and into open spaces. Unfortunately, as our pooches explore the environment with their noses, they may encounter snakes coming out of brumation.

This can cause concerns for dog owners. Many will ask their vets, “What can I do?” Unfortunately, some vets will recommend the rattlesnake vaccine. Touted to “buy time” getting to an emergency clinic or even to ward off the envenomation, the rattlesnake vaccine is an often used but poorly supported treatment for dogs.

The rattlesnake vaccine uses inactivated western diamondback rattlesnake (Crotalus atrox) venom. The manufacturers claim it “is intended to help create an immunity to protect your dog against the effects of western diamondback rattlesnake venom.” However, there is no evidence to support the vaccine being effective, and some data suggest it could be harmful by causing an allergic reaction to snake venom.

The American Animal Hospital Association (AAHA) recently released a statement highlighting the lack of evidence of vaccine (toxoid) efficacy. Read It Here.

Key points from the AAHA’s statement:

1.      There is NO published data supporting the efficacy of the vaccine in dogs.

2.      In a study that was performed in mice, where mice were given 50-1,500 TIMES the dose of the toxoid given to dogs during routine vaccination, survival following exposure to snake venom was still not guaranteed, and some vaccinated mice actually died or required euthanasia earlier than unvaccinated mice exposed to the same amount of venom.

3.      Adverse reactions, including anaphylaxis, have been reported in vaccinated dogs.

4.      Though the manufacturers make claims of cross-protection (protection from envenomation by pit viper species other than the western diamondback rattlesnake, the species used in the production of the toxoid), there are no data to support this claim.

From the AAHA: “Veterinarians choosing to use this toxoid should be aware of the lack of peer-reviewed published data. Polyvalent antivenin therapy is an alternative to vaccination in suspect cases of rattlesnake bite.”

The vaccine did not prove effective in a retrospective study looking at 272 cases of rattlesnake envenomations in dogs. Read It Here.

Key findings from the study:

1.      There was no evidence that vaccination lessened morbidity or mortality.

2.      No measurable benefit could be identified associated with rattlesnake vaccination.

From this case series: “Vaccination for protection of the general canine population from rattlesnake envenomation cannot be recommended by these authors.”

Furthermore, the rattlesnake vaccine toxoid may predispose snakebitten dogs to anaphylaxis by providing the necessary sensitizing exposure to snake venom antigens. Read It Here.

Key findings from the study:

1.      There are no peer-reviewed publications providing evidence of clinical efficacy in snakebitten dogs.

2.      Anaphylaxis requires prior sensitization to an antigen; it is proposed that repeated vaccinations with the rattlesnake toxoid vaccine serve as a sensitization event to snake venom.

From the authors: “These dogs had previously been vaccinated with the C. atrox toxoid vaccine on more than one occasion, which may have served as the initial sensitization required for the development of anaphylaxis.”

Snakebites are medical emergencies for pets and humans alike. Effective antivenom is the only thing that can neutralize venom and improve outcomes.

If you would like to learn more about veterinary ativenoms, please see this post by Dr. Cory Woliver (A Primer on Antivenoms Used by Veterinarians).

If you found this article helpful, please consider donating to ASF today. Every donation is 100% tax deductible and goes directly to patient care in Africa.

A Primer on Antivenoms Used by Veterinarians

Many people ask about the antivenoms that are used for envenomations in dogs and cats, so here is your immunology lesson for the week.

We have three veterinary-specific products available to us: Venom Vet, Rattler, and ACP. These are all licensed to be used for ALL North American pit viper bites (rattlesnakes, copperheads, and cottonmouths). It is rare to use CroFab or Anavip (the human pit viper antivenoms) in veterinary medicine due to the cost and the fact that there are labeled products for animals, but either could be used in animals. Coral snake antivenom is a human product that we use on animals and is different from pit viper antivenom.

All veterinary antivenom products are derived from horses. Basically, venom is collected from snakes and injected into horses. This process is repeated a number of times. After enough time has passed for the venom to generate an immune response (antibody production), a sample of the horses’ blood is collected and filtered to harvest the antibodies.

Antivenom is a product derived from those horse antibodies. These antibodies or antibody fragments are what work to neutralize the venom. Antibodies look sort of like a Y. The top part is called the Fab (fragment antigen binding) region.  The bottom part is called the Fc (fragment crystallizable) region. Collectively, the entire antibody is referred to as an IgG molecule.

https://ruo.mbl.co.jp/bio/e/support/method/antibody-structure.html

Antivenom can either be made using the whole antibody or just a region of the antibody. The larger the molecule size, the longer the half-life, meaning the antivenom stays in circulation longer. Full IgG molecules are larger than F(ab)2 pieces (the top of the Y, minus the Fc). The upside of IgG antivenoms is that because they stay in circulation longer, you may end up needing less total antivenom. The downside is that with the Fc fragment still attached, you have a higher risk of hypersensitivity reactions.

The Venom Vet product is an F(ab)2 molecule. This means that the most reactive part of the antibody (the Fc portion) has been removed, so there should be fewer allergic reactions in theory. ACP is a whole IgG molecule, making it theoretically more likely to cause an allergic reaction. Rattler is also whole IgG, but instead of being a small, highly concentrated volume of antibodies, it is 50ml of equine plasma. Due to Rattler being plasma from a different species, there is a larger theoretical chance of allergic reaction. The coral snake antivenom is also an IgG product.

Overall, reactions to these products are rare. Usually, fewer than 10% of cases. If allergic (hypersensitivity) reactions occur, they are treatable, whether it is hives or anaphylaxis. You can treat these reactions with Benadryl and/or epinephrine. The reason allergic reactions happen is because there are foreign (horse) proteins in the antivenom. Studies have shown that all of these products have the same efficacy but varying allergic reaction rates. Lower reaction rates have been noted for F(ab)2 products (2.5-3.5%) compared to IgG (7.2-9.3%). But all are good products; if your pet needs antivenom, any of these is a solid option.

Average costs for these products range from about $300-1,000 per vial. If you live in an area with venomous snakes, you should consider getting pet insurance or putting aside some money in case of a bite to a pet, as total envenomation treatment costs can range from about $800-10,000+ depending on how bad the bite is.

Cory Woliver, DVM

University of Florida

If you found this article helpful, please consider donating to ASF today. Every donation is 100% tax deductible and goes directly to patient care in Africa.