When Dr. Christina Klare saw the first sick cat in mid-December, she was surprised. The patient had been its healthy, "spicy" self during an annual exam only 11 days earlier. Now feverish and lethargic, it required overnight treatment at an emergency hospital for an unexplained ailment.
The cat recovered, but a few weeks later, Klare saw another one with a temperature of 105 degrees. And then another. On Jan. 18, she asked colleagues at the general practice where she works in Washington, D.C., whether anyone else was seeing cats with "fever of unknown origin." A couple had.
The next day, clients brought in three more lethargic, feverish cats.
"Trying to figure out what was going on took a huge emotional toll on our hospital," Klare said. But soon enough, scrutiny of the medical records yielded a possible clue: Around two weeks before showing signs of illness, each of the sick cats had received a vaccine the hospital was using for the first time.
The practice had begun administering Felocell 4 in mid-December as a substitute for its regular go-to, Felocell 3. Zoetis makes both. Felocell 3 is a version of a core vaccine recommended for all cats to protect against panleukopenia (cat distemper), calicivirus and rhinotracheitis. In late fall and early winter, that vaccine was on back order. As a substitute, Zoetis offered Felocell 4, which adds a modified live Chlamydia psittaci bacterium to the mix for protection against a respiratory tract disease that most often causes conjunctivitis.
The Felocell 4 product information indicates: "The use of this product has been associated with fever, anorexia, and lethargy in 1% of vaccinated cats, often occurring in clusters in association with multiple concurrent vaccinations."
Though they couldn't prove the cats' illnesses were side effects of Felocell 4, Klare and her colleagues stopped administering the vaccine on Jan. 19.
"From that day through the next three weeks, we were seeing at least one [vaccinated, sick] cat a day," Klare said. "It was awful. I've never seen anything like this. You are there to do no harm, and we felt we had hurt these cats." They notified their Zoetis representative of the decision. According to Klare, the rep supported the move and put them in touch with the company's adverse events department.
Within a few weeks of stopping administering Felocell 4, there were no new cases.
All told, 35 of 184 cats vaccinated with Felocell 4 at that clinic required some veterinary intervention. Most recovered. Two died – one at home, the other, euthanized due to severe anemia.
Zoetis told the VIN News Service in an emailed statement that a necropsy on the two cats that died "concluded there was no correlation between Vanguard Feline RCP+Ch use and the respective medical conditions of these two cats." (Felocell 4 was renamed Vanguard Feline RCP+Ch around the time of these cases.)
While the company did not directly acknowledge to VIN News that the nonfatal cases were vaccine reactions, Klare said she believes Zoetis covered treatment costs in the case of all affected clients who filed for reimbursement from the company. Zoetis said in its statement that it assesses each case reported to its medical information and product support team and may cover the costs of patient treatment based on a determination of "the appropriate support … which could range from diagnostic testing to monetary support."
As Klare and her colleagues wondered what was happening, veterinarians in other practices were seeing similar clusters of sick Felocell 4-vaccinated cats. Even as a direct connection between the sick cats and the vaccine has not been demonstrated, the veterinarians' experiences raise questions about the utility of the Chlamydia vaccine and highlight a lack of transparency in vaccine adverse event reporting in veterinary medicine.
Suddenly sick cats baffle multiple practices
Klare posted about the sick cats at her practice in late January on a message board of the Veterinary Information Network, an online community of veterinarians and parent of VIN News. She wanted to know if her experience was isolated. Klare said Zoetis gave her the impression in two meetings that hers was the only hospital reporting possible side effects.
Within a few weeks, seven other VIN members in seven geographically dispersed states — Illinois, Iowa, Michigan, New Hampshire, Ohio, Pennsylvania and Wisconsin — reported seeing cats with fever, painful mobility, lack of appetite and/or lethargy 10 to 14 days after receiving Felocell 4. Their stories were similar to Klare's.
In several cases, the time lag between shot and side effects initially threw veterinarians off the vaccine trail.
"I didn't suspect the vaccine," said Dr. Micah Youello, a practitioner in King of Prussia, Pennsylvania. "It seemed too long ago."
Still, out of an abundance of caution because he was using an unfamiliar vaccine, Youello called Zoetis after seeing his first sick cat. He said the company told him it sounded like a vaccine reaction, which can occur up to three weeks later.
At the suggestion of a Zoetis veterinarian, he promptly started the cat on antibiotics and fluids and delivered the news to the relieved owners, who had feared their 8-year-old cat had feline infectious peritonitis, an often fatal disease.
Youello treated four cats out of 25 vaccinated. "In 20 years as a veterinarian, I've never seen such a delayed reaction or had such a high proportion of animals affected," he said.
Dr. Jennifer Wehler in Michigan had a lower proportion of sick cats but more cases. She told VIN News her practice treated 23 cats out of about 200 vaccinated, starting in December.
"A number of my staff doctors came to me saying, ‘I have another fever of unknown origin cat,' " she said. "I thought, ‘That's weird.' " One doctor saw three such cats in one day.
As the owner of the practice, Wehler was responsible for investigating. She reviewed all the patients' charts, and when the possibility of a vaccine reaction came to mind, "We stopped using the vaccine right then and there," she said.
Klare, Wehler and Youello were shocked at the number of sick cats they saw — 19%, 11.5% and 16%, respectively. The proportions seemed way out of line with the vaccine product information, which reports side effects in 1% of vaccinated cats.
Dr. Joseph Griffioen, a veterinarian in Iowa, had one cat become sick following its Felocell 4 vaccination in January. He explained on the VIN message board discussion of the reactions that high incident rates at individual practices aren't necessarily inconsistent with the product information, which gives an overall rate.
"The 1% isn't going to be a uniform distribution," he wrote. "Generally, you might see a few in a burst and then not see any for several years."
Griffioen has used the combined Chlamydia vaccine over the years, and he said he remembers at least one instance of four or five cats having side effects around the same time.
Zoetis uses the term "clusters" to describe this phenomenon on the product label. The company told VIN News: "Our ongoing pharmacovigilance has not shown any changes in overall adverse event rates and remain in line with the safety and efficacy data reported on label."
So, while the experience of seeing a cluster of sick cats is "wrenching," as one practitioner put it, statistically, it may not be out of the ordinary.
A case of hot batches?
A practice in Illinois owned by Dr. Julie Hahn counted seven cats out of 50 that got sick within two weeks of vaccination. Hahn said that when she pressed Zoetis on the high incidence at her clinic, she was told that side effects tend to show up in clusters, but wasn't told why that happens.
VIN News, too, asked Zoetis why side effects occur in clusters. The company did not respond to the question.
Vaccines like Felocell 4 use an attenuated, or weakened, bacterium to trigger an immune response that trains the body to fight against natural infection. Hahn and other veterinarians believe that the animals were sickened by the modified live Chlamydia in Felocell 4, and that side effects cluster because the potency of the bacterium is not uniform.
As Griffioen put it: "It's inevitable one batch might be a little hotter — contain more antigen — than another."
Similarly, Dr. Richard Ford, an emeritus professor at North Carolina State College of Veterinary Medicine who helped write American Animal Hospital Association (AAHA) and American Association of Feline Practitioners (AAFP) vaccine guidelines, said: "During the manufacturing process, variation in the degree to which the antigenic bacteria are attenuated, as well as the number of bacteria per dose, could lead to a more reactogenic response in some cats following vaccination."
Such a response "could include transient fever, lethargy, myalgia/arthralgia [muscle and joint pain], inappetence, etc.," Ford said. To an owner, he added, it would look like their cat became "acutely ill" after being vaccinated.
VIN News determined that at least five unrelated practices out of eight reporting sick cats used vaccines with the same lot number.
Dr. Steve Valeika, a veterinarian and epidemiologist in North Carolina, said an investigation would be needed to determine what caused the cats' illness. However, he said the delay in the onset of clinical signs suggests the modified live Chlamydia was the cause. "[B]ecause you're causing a low level of infection, it just takes seven to 14 days for it to incubate and cause this," he said.
"I'm not saying with a high degree of certainty this is what happened," Valeika said. "But this is a reasonable hypothesis to pursue, and seems like a leading hypothesis."
Hahn, in Illinois, said: "[Zoetis] did not admit it was a batch issue or that they had a lot of calls on it." She added that though she's disappointed in the lack of explanation, she remains a loyal Zoetis customer.
The company did not respond to a question from VIN News on whether it had seen any adverse reaction reporting trends indicating an issue with production.
Whether to vaccinate against Chlamydia, and when
The species of Chlamydia that affects cats is Chlamydia felis. It is spread through contact with discharge from an infected eye, often between a queen and her kittens. The bacterium predominantly causes conjunctivitis.
Valeika said affected cats' eyes will "look like little pink puffballs." Though it may look terrible, chlamydiosis isn't usually a serious condition. Less common signs include fever, respiratory signs, lethargy, decreased appetite and, in really bad cases, pneumonia. For the most part, infection is easily treated with eye medication or oral doxycycline for a few weeks, he said.
Valeika said he's never used a Chlamydia vaccine.
Vaccine guidelines from the AAHA, AAFP and the World Small Animal Veterinary Association list Chlamydia as a non-core vaccine. The recommended use is narrow: as a control program in multi-cat households where infection is confirmed.
Ford does not recommend routine use of the vaccine for a host of reasons. First, he says, infections are uncommon, especially among household cats.
Moreover, he said, the antigen is injected, which induces a systemic immune response, whereas the infection is local, typically limited to the conjunctiva. Therefore, he said, the protective value of the antigen is likely to be limited. "Vaccination is not expected to induce robust local immunity" to the affected part of the eye, Ford said.
Ford added that the nature of infection caused by the Chlamydia bacterium is difficult to defeat with vaccine-induced antibodies.
So why is it incorporated into a core vaccine?
"I think the reason is that nobody's going to buy it as a standalone vaccine," Ford speculated, adding that there are no standalone, or monovalent, Chlamydia vaccines available in the United States.
Asked for what purpose Chlamydia was added to a core vaccine and to what segment it is marketed, Zoetis replied only: "Veterinarians make vaccine decisions based on their assessment of patient risks and benefits" and echoed the AAHA and AAFP recommendation for use in a multi-cat household with confirmed infections.
Zoetis said it is confident that Felocell 4, now named Vanguard RCP+Ch, "which has been on the market for over 30 years with millions of doses administered by veterinarians across the country, remains an effective and safe option for cats when used according to label."
Veterinarians out of the information loop
For several of the veterinarians caught up in treating clusters of sick cats this winter, the challenges were made worse by feeling in the dark. They said once they learned that other veterinarians were in a similar pickle and began sharing information and advice, it was a huge relief. In veterinary medicine, there is no public database they could have consulted to see if other practices were reporting problems.
Vaccine adverse reaction reporting protocols are very different between veterinary and human medicine.
While veterinarians are encouraged to report suspected vaccine adverse reactions to the companies responsible for the product, companies only recently have been required to report that information to the federal government. According to Mike Stepien, a spokesperson for the U.S. Department of Agriculture Animal and Plant Health Inspection Service, the requirement took effect on Feb. 17, 2021.
Despite the new reporting requirement, adverse events involving a specific product are not public information — on the contrary, it's considered confidential business information, Stepien said. Requests about animal vaccine adverse events must be submitted through a Freedom of Information Act request, which may be declined, he said. VIN News lodged a request on April 4 for adverse event reports on Felocell 4; the response is pending.
"In my experience, it is a one-way communication thing from the veterinarian who had or experienced this adverse event to the manufacturer," Ford said. "And the manufacturer is under no obligation to say, 'Oh, yeah, we've had 13 cases of left ears falling off with our vaccine.' "
Zoetis said it "strictly adheres to the reporting requirements set by all regulatory agencies, including the USDA. The health and safety of animals is the top priority for Zoetis and the report of an adverse event is taken very seriously."
The situation in human medicine is almost diametrically opposite, as many Americans learned when Covid-19 vaccines became available. Anyone can report side effects after vaccination to the Vaccine Adverse Event Reporting System (VAERS). Health care providers are required to report certain adverse events, and vaccine manufacturers are required to report all adverse events that come to their attention.
VAERS is co-managed by the U.S. Centers for Disease Control and Prevention and the U.S. Food and Drug Administration. The reports are available to the public.
According to the reporting system site, "VAERS is not designed to determine if a vaccine caused a health problem, but is especially useful for detecting unusual or unexpected patterns of adverse event reporting that might indicate a possible safety problem with a vaccine."
Valeika said that in addition to serving as an early warning signaling system for scientists, "the fact that [VAERS] is transparent and public serves the function of making it impossible for people to say there is a cover-up."
But, he laments, there is a downside. "Because it's public, anyone can go in and pull the data and … say 'according to CDC data, 87,000 people have died from the COVID vaccine' … and that's complete nonsense. It's based on what's reported, not what's proven to be the case."
Such cherry-picking of the data has been used to fuel vaccine hesitancy. "The transparency is, I think, worth the abuse," Valeika said, "although sometimes I wonder about that position."
Meanwhile, the lack of public reporting on vaccine reactions in animal health has serious consequences — especially in the bigger picture. Ford points to the fact that certain vaccines are known to cause fibrosarcoma, a type of cancer, in some cats. However, more than 30 years since the serious side effect was recognized, it's unclear what in the vaccines is causing the cancer. "If there were a robust reporting process … we would have a lot better information — actionable information," he said. "We just don't have it in veterinary medicine."
Edie Lau contributed to this report.
Update: Reports of adverse reactions associated with Felocell 4 vaccinations surged in the winter of 2021-22, judging from copies of reports provided by the USDA in response to a Freedom of Information Act request by the VIN News. The spike in reports corresponds with the timing of sick vaccinated cats at eight hospitals cited in this article. In total, USDA received 529 reports of adverse reactions to Felocell 4 from January 2018 to March 11, 2022. Among reports that specify the date of vaccination (not all do), nearly 300 are for cats vaccinated between Nov. 1 and March 1.
VIN News Service commentaries are opinion pieces presenting insights, personal experiences and/or perspectives on topical issues by members of the veterinary community. To submit a commentary for consideration, email firstname.lastname@example.org.