Every so often this question crosses our desks, “Dear Dr. Dodds, My dog and I are spending a lot of time in the desert and I am concerned about snake bites here, as spring nears. I have seen a rattlesnake vaccine offered in the area. What do you think about it?”
The short answer: We do not advise it.
“Why,” you ask? We will get to that. First, let’s start with the basics.
Rattlesnakes
There are approximately 32 species of rattlesnakes in North America and over 80 subspecies.
What is the rattlesnake vaccine?
The rattlesnake vaccines for both animals are killed (inactivated) toxoid vaccines made from the venom of the Western Diamondback rattlesnake (Crotalus atrox). The “toxoid” part should not alarm you – venom from any snake is a toxic substance. Other toxoid vaccines exist such as that for tetanus.
History of rattlesnake vaccine
The United States Department of Agriculture (USDA) conditionally approved the canine rattlesnake vaccine on November 14, 2004, and the equine version on May 21, 2010.
To receive the conditional approval, both vaccines were subjected to safety studies. Basically, the purpose of the studies was to demonstrate the lack of adverse events linked to the vaccination and tolerability to the vaccine in the animals.
The information regarding the canine vaccine is sparse. The Summary of Studies Supporting USDA Product Licensure states, “Study data were evaluated by USDA-APHIS prior to product licensure and met regulatory standards for acceptance at the time of submission. Study data, however, are no longer available.”
Study data for approval in horses is still available:
- Product Administration: Three doses given one month apart.
- Observation: 30 minutes post vaccination, daily for 2 days, and weekly thereafter
- Results: 39 horses (6%) had some type of abnormality. 37 had injection site reactions, while 2 had systemic reactions; (1 horse had Diarrhea at 72 hours, and 1 horse had sore front feet at 24 hours). Both systemic reactions were resolved within 1 day. All of the injection site reactions were resolved within 3 weeks (with most resolved by 2 weeks).
No challenge studies were conducted to receive conditional licensure for either animal. A challenge study gives the subject the vaccination and then challenges the subject with the offending substance such as a virus or bacterium. In this instance, the substance would be venom. Challenge studies not only discover if an animal mounted an adequate or mitigating protective response to exposure or severe infection, but also any adverse events.
Still over a decade on the market, no rattlesnake vaccine challenge studies have been conducted with either animal. It should be noted that the American Association of Equine Practitioners (AAEP) states that efficacy and potency test studies are in progress.
Mode of action and cross-protection claims
In an undated document uploaded to Researchgate in 2016, the manufacturer made some claims that were not peer-reviewed, and not backed up with science or any data. We gleaned from it that the vaccine will supposedly “buy time” between envenomation and emergency treatment, and reduce severity of symptoms…so long as emergency treatment is “prompt” even with vaccinated animals but not in all cases depending on a variety of factors.
According to the American Animal Hospital Association (AAHA), the manufacturer claims cross-protection against envenomation by the Western Diamondback and other pit vipers for dogs.
Regarding horses, the AAEP states:
“The vaccine label claims possible protection against the venoms of the Western rattlesnake (including the prairie, Great Basin, Northern and Southern Pacific varieties), sidewinder, timber rattlesnake, massasauga, and the copperhead. Partial protection may be obtained against Eastern diamondback rattlesnake venom. This vaccine does not provide protection against venom from the water moccasin (cottonmouth), Mojave rattlesnake or coral snake.”
Remember, these are unverified claims by the manufacturer.
Challenge study with mice
The only challenge study to date involved mice. According to the researchers:
- vaccination improved survival rate and survival time after challenge exposure with Western Diamondback rattlesnake venom;
- may offer limited protection against Northern Pacific rattlesnake venom; and,
- did not provide significant cross-protection against rattlesnake venom.
Not all venom is the same.
We have always known that venom is a complex substance. Published studies from 2013 and on (after the conditional vaccine licenses were granted) revealed greater complexity than once thought.
Historically, venom was broken down into four categories based on its effects on the recipients: neurotoxic, myotoxic, hemotoxic and cytotoxic.
For instance, the Southern Pacific rattlesnake (Crotalus helleri) venom was typically considered hemotoxic, whereas the Mojave rattlesnake (Crotalus scutulatus scutulatus) venom attacked the brain and nervous systems (neurotoxic). The neurotoxic venoms are still considered the most lethal.
But, these categories were blurred…and continue to be. Neurotoxic venom has been discovered in Southern Pacific rattlesnakes of the same subspecies as the hemotoxic-producing ones.
Another example is the timber rattlesnake (Crotalus horridus) venom which could be classified as a cocktail depending on the snake’s location and environment:
- neurotoxic venom is found around the Georgia-Florida border;
- mainly hemotoxic is amongst the snakes to the north and midwestern parts of the United States and north Florida; and,
- a cocktail of hemotoxic and neurotoxic has a combined action of its components and is present in those snakes along Florida’s northern border; and,
- Type C venom is weaker than the other three and does not contain any of those components.
To add confusion to the mix, potency levels of each category or hybrid can vary greatly.
Currently, scientists are unraveling the multitude of factors including why the venom type, cocktail, and toxicity levels are widely varying within and between species. Sex? Location? Evolution? Survival? Age? Diet?
By the way, the Western Diamondback’s venom – which is used to make the vaccine – is considered hemotoxic and the snake can be found in Southern California, Arizona, New Mexico, Nevada, Oklahoma and Texas.
Where’s the science?
Most of the science involves peer-reviewed retrospective analyses that are not funded by the manufacturer.
Witsil et al. reviewed 272 cases of rattlesnake envenomation in dogs and came to this conclusion:
- Although the vaccine manufacturer cites evidence during the product’s licensing process of formation of protective antibodies against rattlesnake venom in dogs, no canine challenge studies or peer-reviewed studies have been released documenting the vaccine’s clinical efficacy.
- In view of the results of this study, in dogs with rattlesnake envenomation, there is no evidence that use of glucocorticoids, diphenhydramine, prophylactic antibiotics, or vaccination lessen morbidity or mortality.
Petras et al. proves the validity and necessity of challenge studies for all vaccines prior to approval – conditional or not:
- In this case series, two patients presented for rattlesnake envenomation in concurrent anaphylactic shock with no previous sensitization event. It is hypothesized in both patients that the previous sensitization event was from repeat vaccinations with atrox toxoid vaccine.
- This case report documents suspected anaphylaxis in two canine patients after first time envenomation by a rattlesnake. Both patients were previously vaccinated by the Crotalus atrox toxoid, which is hypothesized to be the initial inciting trigger.
Leonard et al.:
- No statistically significant difference in morbidity or mortality between vaccinated and unvaccinated dogs was found. The findings of this study did not identify a significantly protective effect of previous vaccination in the cases of moderate to severe rattlesnake envenomation that require treatment with antivenin.
Gilliam et al. appears to have the only study involving horses:
- Our study objectives were to measure antivenom antibody titers in rattlesnake-bitten horses and compare them to titers in horses vaccinated with the rattlesnake venom vaccine.
- Antivenom antibody titer development was variable following natural envenomation and vaccination, and vaccine-induced titers were lower than natural envenomation titers.
- Based on existing literature, circulating titers may offer some protection against the systemic effects of envenomation; however, the ability of these titers to protect horses from the adverse effects of envenomation has not been tested in vivo.
To be fair to the manufacturer, the obscure, un-peer reviewed, undated paper provides rationalizations and apparent contradictions. For instance, some companion pet parents of vaccinated animals waited too long to seek emergency care or the venom could have overwhelmed the “protective effects” of the vaccine.
HOWEVER…The several efficacious peer-reviewed studies referenced above show that the manufacturer’s claims are weak, have caveats, and are unsubstantiated.
Experience
Dr. Dodds has observed several serious adverse events involving sloughing of skin and muscle at and below the vaccination injection site.
The business perspective
The rattlesnake vaccines were developed by a small vaccine manufacturer. In our view, if these vaccines were actually viable and proven to work, one of the larger veterinary pharmaceutical companies likely would have purchased the proprietary vaccines and marketed them by now or would have developed their own.
Additional References
Cates, Charles C et al. “Comparison of the protective effect of a commercially available western diamondback rattlesnake toxoid vaccine for dogs against envenomation of mice with western diamondback rattlesnake (Crotalus atrox), northern Pacific rattlesnake (Crotalus oreganus oreganus), and southern Pacific rattlesnake (Crotalus oreganus helleri) venom.” American journal of veterinary research vol. 76,3 (2015): 272-9. doi:10.2460/ajvr.76.3.272, https://avmajournals.avma.org/view/journals/ajvr/76/3/ajvr.76.3.272.xml.
Gilliam, Lyndi L et al. “Antibody responses to natural rattlesnake envenomation and a rattlesnake toxoid vaccine in horses.” Clinical and vaccine immunology : CVI vol. 20,5 (2013): 732-7. doi:10.1128/CVI.00004-13, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647753/.
Levine, Michael et al. “Neurotoxicity Associated With the Southern Pacific Rattlesnake (Crotalushelleri).” Annals of emergency medicine vol. 81,3 (2023): 318-322. doi:10.1016/j.annemergmed.2022.08.020, https://pubmed.ncbi.nlm.nih.gov/36253294/.
Leonard, McGee J et al. “Effects of the canine rattlesnake vaccine in moderate to severe cases of canine crotalid envenomation.” Veterinary medicine (Auckland, N.Z.) vol. 5 153-158. 31 Oct. 2014, doi:10.2147/VMRR.S69216, https://pmc.ncbi.nlm.nih.gov/articles/PMC7337165/.
Petras, Kaelyn E et al. “Suspected anaphylaxis and lack of clinical protection associated with envenomation in two dogs previously vaccinated with Crotalus atrox toxoid.” Toxicon : official journal of the International Society on Toxinology vol. 142 (2018): 30-33. doi:10.1016/j.toxicon.2017.12.044, https://pubmed.ncbi.nlm.nih.gov/29248468/.
Rokyta, Darin R et al. “The genesis of an exceptionally lethal venom in the timber rattlesnake (Crotalus horridus) revealed through comparative venom-gland transcriptomics.” BMC genomics vol. 14 394. 12 Jun. 2013, doi:10.1186/1471-2164-14-394, https://pmc.ncbi.nlm.nih.gov/articles/PMC3701607/.
Sunagar, Kartik et al. “Intraspecific venom variation in the medically significant Southern Pacific Rattlesnake (Crotalus oreganus helleri): biodiscovery, clinical and evolutionary implications.” Journal of proteomics vol. 99 (2014): 68-83. doi:10.1016/j.jprot.2014.01.013, https://pubmed.ncbi.nlm.nih.gov/24463169/.
Witsil, Amanda J et al. “272 cases of rattlesnake envenomation in dogs: Demographics and treatment including safety of F(ab’)2 antivenom use in 236 patients.” Toxicon : official journal of the International Society on Toxinology vol. 105 (2015): 19-26. doi:10.1016/j.toxicon.2015.08.028, https://pubmed.ncbi.nlm.nih.gov/26341419/.
Woliver, Cory, and Michael Schaer. “Neurologic and hematologic sequalae following a timber rattlesnake (Crotalus horridus) envenomation in a dachshund.” Toxicon: X vol. 18 100156. 18 Apr. 2023, doi:10.1016/j.toxcx.2023.100156, https://pmc.ncbi.nlm.nih.gov/articles/PMC10165130/.