A Valley Fever vaccine for dogs may be available soon. Before we discuss the vaccine, let’s review Valley Fever.
Valley Fever is not simply a fever, but a potentially deadly illness that is tricky to diagnose and treat. Indeed, many of us think “virus” when we “read” fever. Valley Fever is not caused by a virus, but by either the Coccidioides immitis or Coccidioides posadasii fungus. These fungi do not thrive in humid climates, but in the arid soil found in Mexico and the Southwest United States. Once the soil is disturbed, the fungal spores are released into the atmosphere, can be easily inhaled, transform in the body, and cause pulmonary and/or disseminated Coccidioidomycosis (Valley Fever) disease in humans and animals. On top of all of that, these fungi are spreading across the West due to climate change. The only good news is that it does not transmit from animal-to-animal, human-to-human, or even animal-to-human.
Confluence of Factors
Valley Fever is perplexing as to why some people and animals develop debilitating symptoms compared to others. Researchers believe it is a confluence of factors that involve immunocompetency, environment, lifestyle, existing illnesses, and genetics. For instance, we know that people with HIV have weakened immune systems and are more likely to develop severe disease to all types of fungi – including Coccidioides. Dogs that spend 80% or more of their time outdoors were 4.9 times more likely to be infected. It has been surmised that Chihuahuas are potentially less susceptible to severe illness because they grew up in the area and developed a genetic mutation over generations against the disease. However, we do not know for sure about this yet.
TGen was actively recruiting dogs for potential genetic testing for Valley Fever.
Signs
The signs of pulmonary Valley Fever in dogs are coughing, fever, weight loss, lack of appetite, and lack of energy. Infected humans can exhibit similar signs.
Disseminated Valley Fever can affect one or many parts of the body including the central nervous system and bones. Signs of disseminated Valley Fever are lameness or swelling of limbs, skin lesions, back or neck pain, with or without weakness/paralysis, seizures and other manifestations of brain swelling, soft abscess-like swelling under the skin, swollen lymph nodes, non-healing skin wounds that ooze fluid, eye inflammation with pain or cloudiness, unexpected heart failure in a young dog and swollen testicles. Note that pregnant dogs and humans are more seriously ill.
Are you wondering how any companion dog parent could let their dog become so ill? First, the pulmonary form usually occurs within three weeks of inhalation. However, the fungi can lay dormant in the body for up to three years before signs occur. Plus, dogs with the disseminated form may never develop pulmonary signs or they might have been treated for another suspected illness such as kennel cough.
Diagnostics
Dogs that develop signs of Valley Fever and live in – or have traveled to endemic areas – definitely should be tested for it. We rely on titer tests that measure the IgG antibodies mounted against the disease. However, the results may be negative and so testing should be performed again 3-4 weeks later. The results are also more of a gauge about exposure and can take a few days to return. Finally, antibody titer tests look at a humoral immunity response instead of a cellular response (T-cells). A T-cell response is what is needed to combat a fungal infection.
Confirmation of the disease should be made with an additional test, which may include a chest x-ray, bone and joint x-rays, culture of fluid or tissue samples, biopsies or aspirates, or even a CT or MRI scan of the brain or spinal cord depending on the symptoms.
Treatment
Valley Fever is treated with antifungal medications such as itraconazole or fluconazole usually for prolonged periods (months); ketoconazole is no longer the preferred drug. If itraconazole or fluconazole fail to work, other fungistatic medications may be used. Antifungals are problematic as they can lead to liver failure. Unfortunately, there is really no established treatment time, flareups could occur that require restarting treatment, or medication may need to be prescribed for the entire length of a companion dog’s life.
Cost
According to the University of Arizona’s Valley Fever Center of Excellence (VFCE), companion dog parents spend approximately $60 million annually on diagnosis, treatment and follow-up care. Bear in mind, that figure only covers Central and Southern Arizona. The average cost of care for an individual companion dog is high – between $15,000 and $30,000.
As an aside, we are impressed with the VFCE organization. It is comprised of medical doctors of immunobiology, veterinarians, and professors of plant pathology. It is an exemplary pillar of wholistic one medicine.
The team would like more non-Arizonan companion pet parents whose dogs have been diagnosed within the past 30 days with Valley Fever, and are taking an oral antifungal to participate in its WOOF Study. For companion dogs that have been taking fluconazole (an oral antifungal) for more than 30 days and were diagnosed with Valley Fever, please consider participating in its Fluconazole study. You may find links to the studies here. We encourage everyone whose companion dogs meet these requirements to participate in one of these studies because it helps all dogs that may be diagnosed with Valley Fever in the future.
Fungal Vaccines
At the present time, no fungal vaccines are available on the market for companion dogs and cats. In fact, no fungal vaccines are approved by the Food and Drug Administration for humans right now either.
Indeed, several challenges exist with the development of fungal vaccines. For instance, we need to mount particular T-cell responses – not an antibody response. This is because people at risk for severe fungal infections are immunocompromised and T-cell deficient. While scientists are working to create many fungal vaccines, the majority of experiments appear to have stopped after those in mice for a number of reasons such as lack of funding or test failure.
Valley Fever Vaccine
The genesis of the development of the Valley Fever Vaccine for dogs (and possibly humans) is a testament to communication and collaboration. Scientists on the East Coast of the United States noticed that a gene, CPS1, was associated with more diseases. They mentioned this to the VFCE team at the University of Arizona. So, VFCE sequenced the genome of Coccidioides posadasii and found CPS1. In a snapshot, they deleted the gene. Once they did that, they discovered that pathogenicity was reduced, although the antigenic properties remained.
After laboratory trials with mice, VFCE – in conjunction with Anivive LifeSciences – set up a challenge study with dogs. A challenge study consists of a control group and vaccinated groups that are then literally challenged with the microbe. In this case, it was the fungus, Coccidioides posadasii. (We understand why challenge trials are not acceptable to a lot of people, but they are required for U.S. Department of Agriculture (USDA) approval and licensing.)
Prior to the challenge, groups of 6 dogs were randomly given: control (saline-injection twice); Prime-only of 1 x 105; Prime/Booster of 1 x 104; Prime/Booster of 5 x 104; and, Prime/Booster of 1 x 105.
The majority of all dogs from all groups had localized swelling at the injection site that resolved within two weeks. The good news is that no gross lesions were detected.
The dogs were then challenged with a large dose (10,000) spores of the fungi. In natural settings, dogs and humans are usually only exposed to 1-50 spores at a time.
After the challenge, four dogs developed clinical signs of illness such as coughing, fatigue, fever and weight loss. All of those dogs were either control or prime-only.
Radiographs were performed. 3 out of the 6 prime-only dogs and all 6 control dogs had abnormalities. 5 out of the 18 prime-booster dogs also had abnormalities that were characterized as less severe than the others, and were believed to be due to post-anesthesia and nebulization.
The researchers also looked at gross lesions. These were limited to the thoracic cavity. All control and prime-only dogs had lesions, whereas 6 out of the 18 prime-booster group had them.
Histologically, 12/18 prime-booster dogs had pyogranulomatous lesions in the lungs and/or lymph nodes that were characteristic of coccidioidomycosis, but spherules were identified in sections from only two dogs, indicating that organisms were sparse or absent. Remember, dogs were being challenged with 40x the amount they would be exposed to in nature, for reasons that are unclear.
Only 2 out of 18 prime-booster dogs had a positive IgG titer for coccidiomycosis. The positive IgG titer confirms that the vaccine will not interfere with titer test results. A limitation of this study is that it did not measure the cellular immunity response.
Another limitation is that no one knows the duration of vaccine immunity.
We found this study to be well-designed overall, except for two items: while they did not challenge with Coccidioides immitis, they did discover that this vaccine will protect against C. immitis in mice, as this fungus is unique to California whereas C. posadasii is more widespread.
Secondly, our more important concern is that the team did not measure their cellular immune response, which is the response that elicits protection against fungal infections. Note that T-cell immunity is fairly standard practice in laboratory experiments and has become more standardized in clinical medicine due to the SARS-CoV-2 (COVID-19) outbreak.
Our one question is: what dosage are they recommending for the commercial vaccine?
Next Steps
The team has completed a couple more studies required by the USDA which regulates and approves all veterinary vaccines. VFCE is seeking community dogs for the next study, which is tentatively slated to begin in late 2023. If you would like to participate and have your companion dog vaccinated against Valley Fever, please complete the VFCE form and they will contact you when they are ready to launch. You do not have to live in an endemic area to participate.
Our Thoughts on the Valley Fever Vaccine
Fungal vaccines are a challenge, and a new challenge at that. But, we have to start somewhere.
The Valley Fever vaccine will be a future non-core vaccine based on environment, lifestyle, and possibly breed. This is a discussion for you to have with your veterinarian.
Currently, we do not have an opinion on the efficacy and safety of Valley Fever vaccine and will wait for more evidence.
References
Dodds, W. Jean. “Is Blastomycosis the Same as Valley Fever?” Pet Health Resource, Tumblr, 13 May 2018, https://drjeandoddspethealthresource.tumblr.com/post/173856437686/is-blastomycosis-the-same-as-valley-fever#.Y9_9CHbMLIV.
Dodds, W. Jean. “Valley Fever on the Rise.” Pet Health Resource, Tumblr, 29 Apr. 2018, https://drjeandoddspethealthresource.tumblr.com/post/173415318831/valley-fever-on-the-rise#.Y9_9JXbMLIV.
Galgiani, John N et al. “Vaccines to Prevent Coccidioidomycosis: A Gene-Deletion Mutant of Coccidioides Posadasii as a Viable Candidate for Human Trials.” Journal of Fungi (Basel, Switzerland) vol. 8,8 838. 10 Aug. 2022, doi:10.3390/jof8080838, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9410110/.
Medici, Natasha P, and Maurizio Del Poeta. “New insights on the development of fungal vaccines: from immunity to recent challenges.” Memorias do Instituto Oswaldo Cruz vol. 110,8 (2015): 966-73, doi:10.1590/0074-02760150335, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708015/.
Oliveira, Lorena V N et al. “Vaccines for human fungal diseases: close but still a long way to go.” NPJ Vaccines vol. 6,1 33. 3 Mar. 2021, doi:10.1038/s41541-021-00294-8, https://www.nature.com/articles/s41541-021-00294-8.
“Ongoing Research.” Valley Fever Center for Excellence, University of Arizona, Nov. 2021, https://vfce.arizona.edu/valley-fever-dogs/research-valley-fever-dogs/ongoing-research.
Shubitz, Lisa F et al. “Δcps1 vaccine protects dogs against experimentally induced coccidioidomycosis.” Vaccine vol. 39,47 (2021): 6894-6901, doi:10.1016/j.vaccine.2021.10.029, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186468/.
“Valley Fever.” Anivive Lifesciences, https://www.anivive.com/valley-fever.
Ward, Rebecca A et al. “The Known Unknowns of the Immune Response to Coccidioides.” Journal of Fungi (Basel, Switzerland) vol. 7,5 377. 11 May. 2021, doi:10.3390/jof7050377, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151481/.