Let's Review

New research on Zenrelia and vaccines shows adult dogs mount normal immune responses to core vaccines. Here's what the evidence actually shows—and what you should tell clients.

Here's What You Actually Need to Know

A rigorous 2025 peer-reviewed study showed that previously vaccinated adult dogs receiving Zenrelia™ (ilunocitinib) mounted normal, protective antibody responses to core vaccines—rabies, distemper, parvo, and adenovirus.

All of them.

If that surprises you, you're not alone. When Zenrelia launched in September 2024, it came with a black box warning that stopped veterinarians in their tracks:

"WARNING: VACCINE-INDUCED DISEASE AND INADEQUATE IMMUNE RESPONSE TO VACCINES."

Black box warnings are the FDA's strongest safety alert—reserved for serious, potentially fatal risks. They're not suggestions. When you see one, you pay attention.

This one specifically warned of:

• Risk of fatal vaccine-induced disease from modified live virus vaccines
• Inadequate immune response to any vaccine, including rabies
• Recommendation to discontinue Zenrelia for 28 days to 3 months before vaccination and withhold for 28 days after vaccination

That language created real problems for clinicians—and for dog owners trying to figure out what to do. Zenrelia is a nonselective JAK inhibitor — a class of drugs that modulates immune signaling — and asking whether that affects vaccine responses is exactly the right clinical question. The original safety data showed 4 out of 6 dogs on Zenrelia failed to mount adequate rabies responses, and two dogs died during the study. From a regulatory standpoint, that absolutely triggered the strongest possible warning. From a "person who cares about dogs" standpoint, this is a firm NO WAY. 

However, as concerning as all of that is — and it is concerning — that safety study bore almost no resemblance to the dogs we actually treat. These weren't itchy Labradoodles on a normal dose. They were unvaccinated puppies on supratherapeutic doses in a facility that had active disease outbreaks. The dogs in the study had never seen a vaccine in their lives. Most of our patients have been vaccinated every year since puppyhood.

But, most veterinarians saw 'fatal vaccine-induced disease' and did exactly what any good clinician would do: they said 'absolutely not, I am not risking my patient's life.' Which is the right instinct! The problem was that the warning didn't come with the context that might have changed the calculus — that the study was a mess, that the dogs weren't remotely comparable to clinical patients, and that the question of what happens in a healthy, previously vaccinated adult dog had never actually been answered

Now we have data from clinically relevant patients: previously vaccinated, immunologically mature, healthy dogs. The results directly answer the question everyone has been asking.

This article covers what went wrong in the original study, what the new research actually shows, and what it means for the dogs in your care—whether you're a veterinarian managing these cases or a pet owner trying to sort through conflicting information.

Why This Felt So Confusing

 If the Zenrelia vaccine situation had you avoiding the drug or just hoping vaccine appointments wouldn't come up — you were not alone. 

Veterinarians were stuck in an impossible position. The warning sounded catastrophic, but we had real life practice in front of us. Many had some version of this internal dialogue:

"This warning sounds like a diseaster. I do not want to endanger my patients. Is this real?"

"This seems like a massive inefficiency every time an allergic dog is due for vaccines. Not to mention, I feel terrible making my patient flare up just to get a booster."

"I have a 7-year-old Lab who's been vaccinated her whole life. Does this warning actually apply to her?"

Allergy cases are already draining—they're chronic, relapsing, and can be emotionally charged for everyone involved. When a regulatory warning lands that feels simultaneously alarming and clinically disconnected from your actual patients, that's genuinely hard to navigate.

Pet owners weren't having an easier time. Between online communities circulating worst-case scenarios and veterinarians who were themselves uncertain how to advise, a lot of people were either stopping a medication that was working well for their dog or feeling anxious every time vaccination came up. 

The FDA did what it was supposed to do with the data it had. The frustrating part is that the data couldn't answer the question anyone actually needed answered — and now, finally, we have data that can.

What Actually Happened: The Original Study

The boxed vaccine warning didn't come from realistic clinical failures in vaccinated dogs with atopic dermatitis. It came from a laboratory safety study. This was the kind of study that's designed to stress-test a drug under extreme conditions, not to model what happens in a normal veterinary practice.

Here's what that study actually looked like:

The dogs were young, purpose-bred beagles around 10 months old. They had never been vaccinated and had no immune memory for core diseases. They were given ilunocitinib at both the label dose and three times the label dose. Then they received a primary vaccination series—not boosters, but first-time vaccines—starting on day 28. This matters, because a dog receiving its very first rabies vaccine has a completely different immunological challenge than a dog that's been vaccinated annually for six years.

Then things went sideways in the facility itself. ⬅️

Two infectious disease outbreaks occurred during what was supposed to be a controlled, bio-secure study. First, Cystoisospora canis—a coccidial parasite—spread through the facility, causing gastrointestinal disease ranging from mild to severe. Second, and more significantly, Canine Adenovirus Type 1 (CAV-1) got in. CAV-1 is the virus that causes infectious canine hepatitis, and it's not the same as CAV-2, the vaccine strain. They're genetically distinct. CAV-1 is highly contagious and notoriously difficult to eliminate with routine disinfectants.

Four out of six dogs on Zenrelia failed to mount adequate rabies titers by day 88—though some improved by day 116 as they recovered from illness. Two dogs were euthanized: one from severe coccidiosis with a colonic intussusception (day 52), and one from necrotizing hepatitis and pancreatitis (day 54). That second dog had developed clinical signs of hepatitis—including vomiting blood—before receiving its first modified live vaccine. Post-mortem PCR confirmed CAV-1. Natural infection. Not the vaccine virus.

[I just need a moment of silence for these poor dogs 💔. I feel like people are talking about this all without taking a moment to say how sad and awkward it is to think about dogs as test subjects and not pets that we kiss a lot and dress up for Halloween. I am thankful for these dogs, and for their gifts to science. But, I am sorry for these dogs and all they went through.]

The FDA originally concluded that Dog #2's death was vaccine-induced adenoviral hepatitis secondary to Zenrelia-induced immunosuppression. But, after reviewing Elanco's additional PCR data in September 2025, the FDA acknowledged: "Given the presence of Cystoisospora canis infections in multiple dogs, a natural adenoviral infection, such as ICH, could have occurred. The totality of evidence supports removal of the risk of fatal vaccine-induced disease from modified live virus vaccines from the labeling."

That "vaccine-induced fatality" language was eventually removed from the label. 

What we can say with confidence about that original study: these were not healthy dogs, the facility was not well-controlled, the animals were battling multiple concurrent infections, and the doses included a 3× supratherapeutic level that nobody should use clinically. The decision to issue a black box warning based on those results was appropriate with the knowledge available. But, that original study did not tell us what happens when you vaccinate a healthy, previously vaccinated adult dog [our typical allergic patient] on Zenrelia.

The New Evidence: What the Booster Study Showed

In late 2024, researchers finally studied the right population. The results were published in peer-reviewed form in 2025 as Fent et al. in BMC Veterinary Research.

(A quick note on citations: this study was first presented as a conference abstract at the ISCAID 2024 Symposium in Vancouver, Canada, with Stephen King as lead author. The peer-reviewed publication lists Fent as first author. They're the same study—I'll refer to it as Fent et al. 2025 throughout.)

What they did:

68 previously vaccinated, immunologically mature beagle dogs were randomized into three groups: untreated controls, Zenrelia at the label dose, and Zenrelia at three times the label dose. All dogs were treated daily for 56 days. On day 28—while actively receiving the drug—they were given core booster vaccines: killed rabies, CAV-2, CDV, and CPV. Antibody titers were measured before vaccination and at 15 and 28 days post-vaccination.

This was a formally powered non-inferiority trial, meaning it was designed specifically to detect whether the treated groups performed meaningfully worse than controls—with pre-specified statistical thresholds.

What they found:

For rabies, CAV-2, and CPV: 100% of dogs in every group achieved protective titers at both time points.

For distemper (CDV): 96–100% of dogs reached protective titers at day 43 (15 days post-vaccination). By day 56, titers had declined toward pre-vaccination levels—in all three groups, including the untreated controls. This is normal vaccine kinetics, not a drug effect. The authors note it's consistent with other canine vaccine studies, and the day 56 CDV titers were statistically equivalent between treated and untreated animals.

No serious adverse events. The mild GI and skin findings were distributed evenly across all groups.

Both ilunocitinib groups—at 1× and 3× the label dose—met the non-inferiority criteria against controls for all four vaccines on the primary endpoint.

Dogs on Zenrelia, even at triple the therapeutic dose, responded to vaccines the same way untreated dogs did. Okay. Here we are. 

What About the Primary Vaccination Study?

A separate publication (Fent et al., BMC Vet Res. 2025;21:461) looked at primary vaccination in seronegative, vaccine-naïve dogs—a fundamentally different question from what we're discussing here. That study's implications are a separate conversation I'll cover in a future post. The key point is that adult booster responses and primary puppy vaccination are not interchangeable scenarios, and the booster data doesn't speak to the naïve puppy question or vice versa.

This Does Not Apply to Puppies

This needs to be stated plainly.

Zenrelia is not FDA-approved for dogs under 12 months of age, full stop. The booster study enrolled previously vaccinated, immunologically mature dogs. It did not evaluate primary vaccination or younger animals. Nothing in this research supports using Zenrelia in puppies who are still working through their initial vaccination series.

If your dog is under 12 months old, or if you're managing a dog who hasn't yet completed a puppy vaccine series, Zenrelia isn't appropriate. There are ways to treat young dogs, and Zenrelia is not one of those ways. 

Everything discussed here applies exclusively to previously vaccinated dogs 12 months of age or older.

Do not use this medication off-label. 

Why Your Patient Didn't Look Like the Warning

Safety studies are deliberately extreme. Young animals, supratherapeutic doses, worst-case conditions—that's the point. You want to know what the drug could do before it reaches real patients.

The problem comes when those extreme-condition results get applied to routine clinical situations without context. The dog that triggered the fatal disease warning was a never-vaccinated 10-month-old on triple the therapeutic dose, sick with two concurrent infections, who showed signs of hepatitis before ever receiving a vaccine. That is not the typical allergic dog in your exam room.

The dog in your exam room is four years old. She's been vaccinated every year since she was a puppy. She's itchy, she has atopic dermatitis, but she's otherwise healthy. Her rabies booster is due. She just started Zenrelia and for the first time in years, she's sleeping through the night without licking her paws and scratching.

Until somewhat recently, nobody could give you a straight answer, because the data didn't exist. Now it does.

Previously vaccinated adult dogs on Zenrelia respond normally to booster vaccines. You're not going to harm your patients by giving routine boosters while they're on Zenrelia—assuming they're otherwise healthy adults with a current vaccination history.

Zenrelia is still an immunomodulator, and appropriate clinical judgment still applies. But the specific fear—that you'd give a routine booster and the dog wouldn't respond—isn't supported by the evidence we have.

So What Should You Actually Do?

Previously vaccinated adult dogs (≥12 months): Core booster vaccines can be administered while dogs are on Zenrelia. Protective immune responses are expected. No mandatory washout period is supported by current evidence—though see the note on the label below.

Puppies or vaccine-naïve dogs: Zenrelia should not be used. Complete the vaccination series first.

Dogs with poorly controlled allergic inflammation: This is where Inflammation First™ thinking applies—managing the inflammatory state appropriately before layering in other decisions. I cover this in depth in my courses.

Important note: The current label still recommends a 28-day to 3-month washout period before vaccination. Veterinarians can and should make evidence-based decisions within the veterinarian-client-patient relationship that may differ from label recommendations when clinically appropriate—but that decision should be documented and the client informed.

On the Washout Question

The 28-day washout recommendation came from early regulatory caution and theoretical immunologic concerns, at a time when there was simply no data on booster responses.

The Fent et al. 2025 study vaccinated dogs who were actively on the drug, and they responded normally. Given that context, a decision to pause Zenrelia comes down to weighing the low current evidence of vaccine risk against the very real, very predictable risk of an allergic flare. For most previously vaccinated adult patients, that calculus is clear. Every patient is different, and you know yours.

What to Say When Clients Ask

A note before these examples: every clinical decision needs to happen within your VCPR, based on the individual patient in front of you. The current FDA-approved label still recommends a washout period. These scripts are starting points for conversations, not blanket protocols.

"Is it safe to vaccinate my dog on Zenrelia?"

"A 2025 study found that previously vaccinated adult dogs on Zenrelia developed normal, protective immunity to core vaccines—the responses were indistinguishable from dogs not on the drug. The current product label still recommends stopping the medication before vaccination, so we need to talk about what makes sense for your dog specifically."

"Should we stop Zenrelia before vaccines?"

"The label does recommend a washout period, but the research picture has gotten clearer. The 2025 study vaccinated dogs while they were actively on Zenrelia and found normal responses. For a previously vaccinated adult dog who's doing well on the medication, the risk of stopping and triggering a flare may outweigh the theoretical vaccine risk—but that's a conversation for your dog's specific situation."

"I just saw the warning—did I mess up by vaccinating my dog last week?"

"Your dog got a booster, and the 2025 study was specifically about dogs in exactly that situation—previously vaccinated adults getting boosters while on Zenrelia. They all developed protective immunity. I'm not concerned about what happened with your dog."

"My breeder/Facebook group says Zenrelia destroys the immune system."

"I completely understand why that's circulating—the original black box warning language was alarming. And, there are a lot of opinions around management of inflammation. Zenrelia does affect immune signaling, which is how it helps with itch. But the 2025 research showed that dogs on Zenrelia responded to vaccines exactly the same way untreated dogs did. We monitor carefully, and I'll tell you specifically what I watch for in [pet's name]."

"Should I separate vaccines while on Zenrelia?"

"The study gave all four core vaccines together on the same day while dogs were on Zenrelia, and every dog responded normally to all of them. There's no evidence we need to separate them. That said, if [pet's name] has had vaccine reactions in the past, spacing them out is always a reasonable conversation."

"Should I titer instead of vaccinating?"

"Titering tells us what antibody levels look like right now from previous vaccines—it's useful information, but it's a different question from whether it's safe to vaccinate while on Zenrelia. The 2025 study answered that second question directly for previously vaccinated adults. Whether you titer, vaccinate, or do a washout period is something we should decide together based on [pet's name]'s full picture."

If You Already Did This

If you've vaccinated previously vaccinated adult dogs while they were on Zenrelia, the Fent et al. 2025 study supports that decision. You weighed your patient's individual needs, made a defensible call with the information you had at the time, and the subsequent research suggests you were right about that population.

Ultimately, this is how medicine works. We make the best decision we can with what we know, we stay current with the evidence, and we update when new data arrives. Here we are. 

What This Situation Revealed

The anxiety this black box warning created came from the right place. Veterinarians want to get it right. Pet owners wanted to protect their dogs. Nobody wanted to be the person who missed something important.

There's been a lot of noise—online communities demonizing Zenrelia, accusations that veterinarians are prescribing recklessly, fear-mongering that treats every new drug like a time bomb. That noise isn't evidence, and it isn't serving anyone's dogs well.

The Fent et al. 2025 study was rigorous, properly powered, and designed to test the actual patient population we treat. Previously vaccinated adult dogs on Zenrelia mounted normal vaccine responses. That's what the data shows—and it's worth trusting the data.

Zenrelia isn't risk-free. It's an immunomodulator, and clinical judgment still applies. But "clinical judgment" means using evidence to inform decisions—and the evidence here is reassuring.

I'm genuinely proud of how veterinarians have handled this since Zenrelia launched. Cautious, thoughtful, willing to sit with uncertainty rather than ignore it. That's the job, and people did it well.

Key Takeaways

✓ Previously vaccinated adult dogs on Zenrelia mount normal vaccine responses to core vaccines
✓ The original warning came from a compromised safety study, not from clinical failures in real patients
✓ The "fatal vaccine-induced disease" language was removed from the label in September 2025
✓ Zenrelia is not labeled for dogs under 12 months—this is non-negotiable
✓ The CDV day-56 titer decline happened equally in treated and untreated dogs; it's vaccine kinetics, not a drug effect
✓ A washout period isn't supported by current evidence, though it remains on the label
✓ If you already vaccinated adult dogs on Zenrelia, the evidence says you made a reasonable call

Why This Matters Beyond One Drug

Allergy cases demand constant micro-decisions under uncertainty. Every visit: which drug, which warning, how do I explain this to a worried client, what if I'm wrong? That pressure doesn't stop with Zenrelia.

Making intentional, evidence-based decisions—rather than reactive ones—is a skill, and it's exactly what I teach in Itch to Answer™, my comprehensive course on canine atopic dermatitis diagnosis and treatment.

If you want to make solid medical management decisions, or if you're struggling to explain complex dermatology to anxious clients in a way that builds trust rather than more anxiety—this course is for you.

Launching late April 2026. Get on the waitlist: https://www.theallergicdog.com/subscribe

Frequently Asked Questions

Can I vaccinate my dog while they're on Zenrelia? A 2025 peer-reviewed study found that previously vaccinated adult dogs (≥12 months) on Zenrelia mounted normal immune responses to core vaccines. The current FDA label still recommends discontinuing Zenrelia 28 days to 3 months before vaccination. Talk with your veterinarian about what makes sense for your dog's specific history.

Is Zenrelia safe for puppies? No—Zenrelia is not FDA-approved for dogs under 12 months. The research only evaluated booster responses in previously vaccinated adults. Puppies should complete their vaccination series before starting Zenrelia.

Do I need to stop Zenrelia before my dog's vaccines? The label recommends a 28-day to 3-month washout. The 2025 study suggests this may not be necessary for previously vaccinated adults, but it's a decision to make with your veterinarian based on your dog's full picture.

What vaccines were tested? Rabies, CAV-2 (adenovirus), CDV (distemper), and CPV (parvovirus)—the core vaccine panel. All dogs on Zenrelia achieved protective antibody levels.

I heard the distemper results were different—what happened? Distemper (CDV) titers peaked at 96–100% protective at day 43 in all groups—including untreated controls. By day 56, titers declined toward pre-vaccination levels across all groups equally. That's normal vaccine kinetics; antibody levels after boosters don't stay permanently elevated. The formal non-inferiority analysis confirmed the treated dogs' responses were equivalent to controls.

What about non-core vaccines like leptospirosis or Lyme? The 2025 study only evaluated core vaccines. There's no published data yet on non-core vaccine responses in dogs on Zenrelia. Clinical judgment applies.

Should vaccines be separated if my dog is on Zenrelia? The study gave all four core vaccines together on the same day, and all dogs responded normally. No evidence suggests separation is necessary, though individual history matters.

My dog was already vaccinated while on Zenrelia. Should I be worried? If your dog is a previously vaccinated adult, the 2025 study is directly reassuring. Talk with your veterinarian if you have specific concerns.

Why did the FDA warning change in 2025? The FDA removed "fatal vaccine-induced disease from modified live virus vaccines" from the label after reviewing PCR data showing the dog deaths in the original study were attributable to natural infectious disease outbreaks, not the vaccine. The inadequate immune response warning technically remains on the label, though the 2025 booster study showed normal responses.

What should I do if my veterinarian recommends stopping Zenrelia before vaccines? That's a reasonable approach that follows label guidance. Other veterinarians are making individualized decisions based on the 2025 evidence. Both positions are defensible—talk it through with your vet to decide what's right for your dog.

About the Author

Dr. Meagan Painter is a Board Certified Veterinary Dermatologist (DACVD) at MSPCA's Angell-West in Waltham, MA. She founded The Allergic Dog™ after realizing that the gap wasn't knowledge—most veterinarians know plenty—it was having a practical framework to work from when cases get complicated and clients get anxious. She lives in Massachusetts with her husband, daughter, a Boston Terrier, a cat named Chips, and a hamster who loves banana chips. Her best work happens at 4:30am, before anyone is awake and before she heads to work. Dedicated, fun, and uniquely suited to help allergic dogs. 🐾

References

1. Fent GM, Jacela J, Plazola-Ortiz R, Olps J, McCandless EE, Toutain CE, O'Kelley S, King S. Immunologic response to first booster vaccination in dogs treated with Zenrelia™ (ilunocitinib tablets) at up to three times the recommended therapeutic dose compared to untreated controls. BMC Veterinary Research. 2025;21:481. https://doi.org/10.1186/s12917-025-04929-z (Presented as conference abstract at ISCAID Symposium, Vancouver, Canada, October 13–16, 2024.)

2. Fent GM, Despa S, Gabor L, Earll M, McCandless EE, O'Kelley S, et al. Response to primary canine core vaccination in 10-month-old seronegative dogs treated with three times the recommended therapeutic dose of Ilunocitinib tablets (Zenrelia™). BMC Veterinary Research. 2025;21:461. https://doi.org/10.1186/s12917-025-04896-5

3. U.S. Food and Drug Administration. Freedom of Information Summary: Zenrelia (ilunocitinib tablets). Original New Animal Drug Application. September 19, 2024. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/15865

4. U.S. Food and Drug Administration. Dear Veterinarian Letter regarding important safety information associated with the use of Zenrelia (ilunocitinib tablets). September 2024. https://www.fda.gov/animal-veterinary/product-safety-information/dear-veterinarian-letter-regarding-important-safety-information-associated-use-zenrelia-ilunocitinib

5. Elanco Animal Health. Elanco Announces FDA Approves Improved Zenrelia™ Label, Removing Vaccine-Induced Disease Language. Press release. September 23, 2025. https://www.elanco.com/us/newsroom/press-releases/elanco-announces-FDA-update-of-zenrelia-label

6. Zenrelia (ilunocitinib tablets) [package insert]. Greenfield, IN: Elanco US Inc; 2025.