In previous posts in this series, I discussed the impact on the occurrence of vaccine adverse events of giving multiple different vaccines to a pet at the same visit or different visits, We also need to consider the impact of giving multiple vaccines at once on overall response to vaccination.

There are some vague descriptions of concerns about overloading or exhausting the immune system, and the animal not being able to respond well because it’s being challenged with too many antigens at once. Although it’s been widely discussed, there is a distinct lack of evidence indicating that routine vaccine administration can overload the immune system.

The immune system is designed to handle multiple antigenic challenges at the same time. Right now, your immune system is detecting and reacting to myriad antigenic exposures. Our bodies encounter large antigen loads every day, and have massive amounts of antigen permanently residing in and on us as part of our bacterial, fungal and viral microbiomes. We don’t get exposed to a few antigens from a vaccine one day and then give the immune system a break for the year. The vaccine antigens are a comparatively major antigenic load, since we’re aiming to stimulate a strong immune response, but they are far from the only antigens the body encounters on a given day.

The immune system is quite capable of handling many antigens at once and immune exhaustion from vaccination doesn’t appear to be a relevant concern. An older but still relevant review of concerns about giving multiple vaccinations to children (Offit et al 2002) provides some insight on this. Based on estimates of circulating B-cell numbers, reproduction capacity, antigen loads and antibody production kinetics, they estimated that an infant has the theoretical capacity to respond to approximately 10,000 vaccines at once. Yes, it’s theoretical and based on various estimates, but even if it’s off by a lot, it still doesn’t support concerns about giving combinations of vaccines that we use in veterinary medicine.

While there are legitimate reasons to consider separating vaccines in some situations or limiting the number of vaccines for a particular animal, those largely revolve around managing known vaccine reaction issues. For routine purposes, there’s no concern about a decreased immune response from giving multiple vaccines at once.  

This post may look familiar, as it’s a repost of a piece from earlier this year, but it fits really well in this series (and it lets me be a bit lazy for the weekend).

Does Splitting Vaccines in Small Dogs Help Avoid Adverse Events?

The short answer: I don’t know, but probably not, and it could potentially do more harm than good.

I get asked a lot about splitting vaccines for pets, that is to say giving different vaccines at different visits instead of giving a bunch of vaccines all at the same time. The questions are often related to small breed dogs, which are more prone to adverse events following vaccination. Sometimes the questions are because a particular dog has had an adverse reaction to a vaccine in the past, and sometimes they’re because the owners are concerned about adverse reactions, even though their dog has never had one.

The theory behind the supposed benefits of splitting vaccines is that less antigenic stimulation would lead to a lower risk of adverse events. On one hand, that’s true. Data from a really large study of vaccination adverse events in dogs (Moore et al. 2023) showed that as you add more vaccines, the adverse event rate goes up (see graph below).

So, why do I say I don’t know if splitting vaccines helps avoid adverse events? Because we have to think about what happens to the dog over time, not just what happens after each vaccination visit. If we give only one vaccine today, we have a lower risk of an adverse reaction than if we gave two, but if the dog still needs the second vaccine, it will need to come back again for another vaccination visit, that also comes with its own risk of an adverse event.

Looking at the numbers from the graph above, let’s approximate the risks for a small breed dog that is due for DA2PP (distemper, adenovirus 2, parvo, parainfluenza, which are given together as a single injection) and rabies vaccines.

• That’s two vaccines. Based on the crude estimate from the graph, the risk of an adverse event would be roughly 27 in 10,000 if they are given at the same visit.
• If we only give DA2PP vaccine, the risk would be lower, at around 21 in 10,000, but the dog will still need to get a rabies vaccine.
• When the dog comes in for its second visit and we only give the rabies vaccine, the risk of an adverse event is once again 21 in 10,000.

If we look at the risk for a single vaccine visit, the risk is lower if we only give one vaccine (21 vs 27 in 10,000). However, if we look at the cumulative risk to this dog from receiving both vaccines on separate days, (21+21= 42 in 10,000) it’s actually higher than if we’d given them both at once.

How solid are these numbers? It’s hard to say. The data are crude, but they are the best we have. It makes sense, though. Splitting vaccines would have to drop the risk by at least 50% to achieve a net benefit when we have to add extra vaccination events to ensure the dog gets all the vaccines it needs. This also doesn’t consider the added stress, hassle and normal general malaise the pet can get after vaccination, which happens twice if the vaccines are split. I got my flu and COVID-19 vaccines at the same time. I did that on purpose because I’d rather have one episode of having a sore arm and maybe feeling crappy than two episodes. The same presumably applies to our canine patients.

It’s not that there are no valid reasons for splitting vaccines. It’s possible that some dogs that are particularly reactive to vaccines would benefit more from this strategy. We just don’t know.

The main benefit of splitting vaccines is to understand which vaccine may be causing a reaction in the dog if they have one. If I give DA2PP one day and the dog is fine, then follow up with rabies vaccine and the dog has a reaction, that’s useful because it suggests we have to focus on issues with the rabies vaccine. However, even that isn’t a guarantee of the cause, as many vaccine reactions are just random, non-repeatable events that don’t indicate long term risk.

So, split away if you want, but realize that’s it’s a bit more complicated than it might seem at first glance. It might not be reducing the risk to the dog, and it may actually be increasing it.

Earlier this week (in part 2 of this series) I covered minimal intervals for giving pets different vaccines (when they’re not given on the same day). This post will cover intervals for giving boosters of the same vaccine, particularly in pets being vaccinated for the first time (I covered boosters for overdue pets in part 1).

Some vaccines, such as our core modified live vaccines for dogs and cats, are highly effective even with just one dose. That means if an animal is healthy and old enough to no longer have circulating maternal antibodies (which can interfere vaccine response), it really only needs one dose of vaccine, not a series. Other vaccines (e.g. leptospirosis, Lyme disease, feline leukemia) require a “primer” and a “booster” dose to achieve an effective response; the label recommendation for these is typically to give the booster 2-4 weeks after the first dose.

We use a 2-4 week interval because we know it’s long enough to work as a booster, but also relatively short so the animal is protected as soon as possible; however, that doesn’t mean that a different interval won’t also work. The vaccine manufacturers don’t test how well their vaccines work at a whole bunch of different intervals (as it’s expensive and requires more animals to do more challenge trials), so we don’t have clear data on what happens if we miss the recommended booster interval. To make a decision in these cases, we need to consider how the immune system responds to serial doses of the same vaccine.

Longer than label booster intervals

If we are starting a vaccine series and miss the recommended interval, that doesn’t mean we need to restart it. It just means the animal was not protected as soon as it could have been, since it took longer to get that important second dose.

• If an adult dog got its first leptospirosis vaccine, missed the booster at 4 weeks and instead came in 6 weeks after the first dose, it can just have a single booster now without having to “restart the series.” The immune system hasn’t forgotten the primer dose, and the booster will work fine. For further discussion and details, see the part 1 post from earlier this week on overdue pets.

A longer interval between boosters may actually produce an even better immune response in some cases. The best interval to use for this may actually be 3-6 months, not 2-4 weeks, but that would mean the animal in question isn’t fully protected for a lot longer. By boosting earlier, we might be sacrificing a little bit in terms of the maximum degree of protection, but we get the animal protected sooner, which is a logical trade (and remember that the 2-4 week interval has been tested by the vaccine manufacturer so we know it works well enough).

The take home message is not to get hung up on a 2-4 week vaccine series, as long as the animal gets that all-important booster (and the sooner it gets it thereafter, the sooner it’s protected).

Shorter than label booster intervals

There are some plausible concerns with shorter intervals, but unfortunately we have no data to either support or refute them. There’s also lots of grey, because the immune system doesn’t suddenly change on day 14 after the first dose of a vaccine. The immune response is on a continuum to which we are trying to apply a specific breakpoint that will work for most of the population. So a booster on day 12 or 13 likely isn’t a big deal, but an even shorter interval could be problematic because of the the way the immune system responds and creates memory. Following vaccination, we want the body to produce antibodies in the short term for immediate protection, AND establish a robust pool of immune cells that will be able to quickly ramp up antibody production again in the future on subsequent exposure to the pathogen (or a booster vaccine).

• Antibodies are initially produced by immature plasma cells (plasmablasts). For long term immunity, the plasmablasts need to mature into “adult” plasma cells in germinal centres in the lymph nodes, and there also needs to be a population of specific T-helper lymphocytes that help signal plasma cell production. That all takes time. If a booster vaccine is given too soon in the process, the response occurs without the help of those germinal centres and with fewer helper T cells, so instead of producing plasma cells and memory B-cells (that help produce durable immunity with rapid response in the future), the response just produces more short term plasmablasts.

Pre- and post-exposure rabies vaccination in people provides an interesting comparison. After a rabies exposure, a person is given a series of vaccine doses over a very short period (days 0, 3, 7 and 14) because the main goal is rapid immediate protection (to intercept any virus already in the body), not establishing long term protection against future exposures (but there will still be some, of course). For pre-exposure rabies vaccination in people, the first two doses are given no less than 7 days apart, with another dose usually between day 21 or 28 from the first dose, which is the more effective strategy for establishing long term protection.

Picture this: A dog is due for its leptospirosis vaccine booster at two weeks, but it comes in early. Do you give it the booster, or tell the owner to come back at the two week mark?

• If it’s possible to have the dog come back, that would be ideal, so we’re following the label instructions and don’t need to think about the other issues.
• Sometimes we’re concerned that the owner won’t bring the dog back because it’s too much hassle. Potentially suboptimal vaccination is usually better than no vaccination, and I don’t want to pass up an opportunity to protect an animal, so if that’s the case consider how early might be too early:
  • 10-14 days after the first dose: Likely won’t make a big difference. I’d have little concern with giving the booster right away.
  • 7-10 days after the first dose: Probably also fine. While we don’t have veterinary data, human vaccine schedules show that effective boosting can occur over this interval.
  • Less than 7 days after the first dose: Questionable. The animal may still have a good short term response, but may not develop robust, long term immunity. If two doses are inadvertently given this close together, I’d consider the second dose potentially ineffective and recommend an additional booster at least two weeks later. The rare situation where it might be worthwhile to booster right away is if someone had a puppy that got a dose of leptospirosis vaccine at 12 weeks of age and came in 6 days later because they were going camping today for a few weeks. I’d consider giving the puppy the booster then (to try to give the dog more short term immunity for the camping trip when it’s at high risk of exposure), but I’d recommend a third dose later on to be confident in the long term protection.

I admit that a lot of this is based on some best guesses and extrapolation. As is often a challenge in veterinary medicine, we don’t often have directly relevant high level data to help guide us in these situations. Nonetheless, it’s important to reassess old habits and historical approaches and consider what evidence and data we do have, to help us make the best decisions we can.

TL;DR: There’s no proven premedication strategy that reliably prevents adverse reactions to vaccines; instead focus on patient risk assessment, appropriate vaccine selection, close monitoring, and prompt treatment if an adverse event occurs.  

Vaccine adverse events (AEs) in pets are uncommon, but that doesn’t mean their inconsequential. Clients (and veterinarians) worry about them a lot. Adverse events following vaccination can range from very mild (like feeling crappy for a day or two after getting a flu shot) to life-threatening anaphylaxis.

Some worry about pets that have had an AE in the past. Others worry even when the animal doesn’t have a history of an AE. In either case, premedication is sometimes used to try to reduce the risk of an AE – but does it actually make a difference to the animal, or does it just make us feel better?

For both prevention and treatment, it’s important to be aware of the different mechanisms that drive different types of AEs. For the purpose of this post, we can group these into four broad categories:

1. Inflammatory reactions: These include localized pain and swelling around the injection site, and systemic signs like fever and malaise. These are essentially exuberant “normal” responses to a vaccine, based on what we would expect the body to do. These reactions are typically mild and self-limiting, but can still make the animal feel pretty rough the day after (as many people experience after their own vaccines).
2. Anaphylaxis: This is the most sudden, dramatic and life-threatening type of reaction. It’s a rapid-onset, immune-mediated reaction driven by immunoglobulin E (IgE), which leads to profound systemic mast cell and basophil degranulation, releasing massive amounts of histamine into the body.
3. Localized / non-anaphylactic allergic reactions: These are true allergic reactions that develop minutes to hours after vaccination, but they’re actually quite rare. They are likely a response to non-target antigens in components of the vaccine (e.g. trace components, stabilizers), not the actual vaccine antigen itself.
4. Immune mediated inflammatory reactions: There are a few types of these, the onset of which typically occurs several hours to days after vaccination. They can vary in severity, from little nodules at the site of injection to severe systemic consequences to widespread immune complex formation.

Below is a list of some of the strategies that are commonly used to try to prevent or treat vaccine AEs, and whether they do or don’t make sense, depending on the mechanisms involved.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Anti-inflammatories are usually the first approach to treating reactions that result in inflammation and pain. For pain, malaise or fever after a flu shot, many people would likely take ibuprofen (an NSAID). The same is generally true for dogs and cats: if they feel rough after vaccination, an appropriate dose of an NSAID will help them feel better. This is something we do in response to a problem, it is not something we should be trying to use as a preventative. The US CDC’s Epidemiology and Prevention of Vaccine-Preventable Diseases (also known as the “Pink Book”) includes a chapter on vaccine administration, which states: “The prophylactic use of antipyretics (e.g., acetaminophen and ibuprofen) before or at the time of vaccination is not recommended. There is no evidence these will decrease the pain associated with an injection. In addition, some studies have suggested these medications might suppress the immune response to some vaccine antigens.”

Antihistamines

As the name suggests, these drugs are meant to address histamine-based reactions that cause issues like hives (but not anaphylaxis – that requires epinephrine). In dogs and cats, diphenhydramine (Benadryl) is the most frequently used antihistamine. Unfortunately, oral absorption (bioavailability) of this drug is poor and unpredictable in dogs, and the half life is short, so it’s effects can be unpredictable, limited and short term, which makes it an unreliable choice for treatment and particularly bad for prophylaxis (because there’s a good chance if you give it in advance that it may be gone by the time a reaction starts). The short half-life also increases the risk of “rebound” signs, e.g. if the histamine release persists after the drug concentrations fall. Intravenous diphenhydramine is useful for initial short-term treatment of severe reactions. Cetirizine is a better choice for an oral antihistamine, since it’s more potent, has better bioavailability and lasts longer.

Nonetheless, as for NSAIDs, antihistamines are for treatment of AEs, not prevention. In humans, they specifically recommend against pre-treating with antihistamines before vaccination. There’s no evidence that they help prevent AEs. The US CDC’s guidance for preparing for the potential management of anaphylaxis at COVID-19 vaccination sites addresses this quite clearly: “Administration of antihistamines to COVID-19 vaccine recipients prior to vaccination to prevent allergic reactions is not recommended. Antihistamines do not prevent anaphylaxis, and their prophylactic use may mask cutaneous symptoms, which could lead to a delay in the diagnosis and management of anaphylaxis.”

Corticosteroids

These drugs have potent anti-inflammatory effects, and at higher doses they can even suppress the immune system. They are a core component of treatment of immune-mediated diseases. However, at both anti-inflammatory or immunosuppressive doses, they can cause a variety of adverse (side) effects. We’re not going to prevent an immune-mediated reaction with an anti-inflammatory dose of steroids, and it makes no sense to give an immunosuppressive dose of steroids prior to a vaccine (as it would inhibit the good immune response the vaccine is trying to induce). While corticosteroids are critical for treatment of vaccine AEs, they have no role in prevention, and quite realistically could do more harm than good if used prophylactically.

Epinephrine

Epinephrine is an essential emergency drug for short term treatment of imminently life-threatening, active anaphylaxis. It cannot be used to prevent reactions.

Anti-nausea medications

One anti-nausea medication in particular (maropitant) is sometimes administered prior to vaccination of pets, particularly cats. If the animal gets nauseated in response to vaccination, it might help to give maropitant in advance (similar to a person taking gravol before a car ride to prevent motion sickness). There’s no real downside to this, other than cost, and the effort of trying to get the medication into the animal (which is sometimes no small feat with cats). Whether or not the level of nausea makes it worthwhile depends on the individual animal and whether there’s a known history of nausea after vaccination, but this drug would not interfere with the vaccine response in any way.

What CAN we do to reduce the occurrence and impact of vaccine AEs in pets?

I focus on two things:

• Carefully assessing vaccination needs (so we don’t give more vaccines than we really need to)
• Being ready to treat AEs (because they will happen)

Our standard approaches to vaccination are geared toward the general population, and they typically err on the side of more vaccination for the protection of the pet from disease, because disease exposure is the bigger risk. If an animal has a true increased risk of an AE, the cost:benefit ratio of giving more vaccines may change. If the risk of a vaccine AE is realtively high, and the value of the vaccine is relatively low (in terms of disease prevention), it might make more sense to skip that vaccine.

• For example, in an adult dog at risk for a vaccine AE that I know had at least one DAPP vaccine at 16 weeks of age or older, I’d be comfortable foregoing additional doses of that vaccine. But the value of other vaccines in the same dog (e.g. leptospirosis) would be higher, so I’d push more to have those done anyway. There’s no one-size-fits-all approach; one needs to consider the risks and benefits to the pet, and the owner’s preferences and risk aversity.
• Note that splitting vaccines up across multiple appointments also doesn’t really help decrease the overall incidence of AEs (I’ve covered this before, but I’ll rehash it in another post soon).

Beyond that, have a plan for treating AEs promptly when they do occur.

• If a pet is feeling rough after vaccination, providing short-term NSAID treatment is reasonable.
• If a pet is having what looks like a true histamine-based reaction (e.g. hives), an antihistamine is indicated (e.g. injectable diphenhydramine for a quick effect, followed by oral cetirizine for a more reliable and prolonged effect (compared to oral diphenhydramine)).
• If a pet is having a true immune-mediated reaction (which is rare), then immunosuppressive doses of steroids are needed (but not something we want to do unless we have to, because of the potential complications).
• If there’s any hint that anaphylaxis might be occurring, get the epinephrine and don’t let the animal out of your sight.

The greater the concern about the risk of an AE and the greater the risk of a severe AE, the closer the animal should be monitored. That might mean vaccinating them in the morning and keeping them under close observation in the clinic during the day, or ensuring they are at home with someone to observe them. If there’s a really high risk of anaphylaxis (but enough of a need for the vaccine to still take that risk), it might even be worth having an IV catheter in place and having a dose of epinephrine standing by, along with close observation and a plan for what else to do if the animal has a severe reaction.

Picture this: An owner takes their dog to a veterinarian for routine vaccines. The veterinarian recommends a DAPP vaccine (distemper, adenovirus, parvovirus, parainfluenza), as well as vaccination for rabies and leptospirosis. After some discussion, the owner declines the lepto vaccine, but proceeds with the others. The next day, they call back after doing some reading, having decided they’d like to have the dog vaccinated for lepto after all. When can the dog receive the additional vaccine?

A lot of veterinarians would likely recommend waiting at least two weeks, because that’s the minimum interval for boosters for many of our canine vaccines. It’s a pretty well entrenched dogma that’s been propagated through teaching, continuing education talks and reviews for years, but if you try to trace back that recommendation, you eventually hit a dead end.

• It’s sometimes stated that the immune system can get overwhelmed or overloaded if too many vaccines are given close together, but there’s no hard evidence that happens. People and animals are bombarded by antigenic stimuli every day, so out immune systems are designed to be ready to go 24/7.

There’s actually no clear immunological basis for a universal 14-day minimum interval between administration of different vaccines (vs boosters of the same vaccine) in dogs and cats, or that giving different vaccines closer together than this results in clinically relevant vaccine failure. In human medicine (where they have a lot more data), there’s no recommendation for a minimum interval between most vaccines, with a few exceptions that don’t apply to pet vaccines.

• According to the US CDC guidance on Timing and Spacing of Immunobiologics: “There is no evidence that non-live vaccines interfere with the immune response to other non-live vaccines or to live vaccines. Any non-live vaccine can be administered either simultaneously or at any time before or after a different non-live vaccine or live vaccine. The 2 exceptions are a 4-week interval between PCV13 and MenACWY-D in a person with anatomic asplenia and the separation of doses between PCV13 and PPSV23. (These exceptions are not applicable to dogs and cats of course).
• Regarding live vaccines, the CDC guidance goes on to say: Limited data are available regarding interference between live vaccines used in the United States. The immune response to one live-virus vaccine might be impaired if administered within 28 days (i.e., 4 weeks) of another live-virus vaccine. In a study conducted in 2 U.S. health maintenance organizations, the risk for varicella vaccine failure (i.e., varicella disease in a vaccinated person) among persons who received varicella vaccine within 28 days of MMR vaccination was threefold higher than among persons who received varicella vaccine >28 days after MMR vaccination. Another study determined that the response to yellow fever vaccine is not affected by monovalent measles vaccine administered 1–27 days earlier. The effect of nonsimultaneous administration of rubella, mumps, varicella, and yellow fever vaccines is unknown.”

Based on this, the concern is only with serial administration of multiple injectable modified live vaccines, and it likely only affects some of these vaccines, not all of them. Combination core vaccines for pets (DAPP for dogs, FVRCP for cats) include modified live components, but the other vaccines we use (for lepto, Lyme disease, feline leukemia, and some rabies vaccines) are non-live vaccines. There are some modified live feline chlamydia vaccines, but those are typically part of FVRCP vaccines. (If there was a chlamydia-only live vaccine, I’d consider spacing it by at least 4 weeks from an FVRCP vaccine, but I don’t know if that would actually be necessary). We don’t otherwise need to worry about giving different modified live vaccines close together because the products don’t exist.

So in my opinion the dog in our initial scenario can be vaccinated for lepto at any time with no additional concerns about “interference” or poor response because of the vaccines the dog received at the initial appointment. If the owner is told to wait, there’s a good chance life will get in the way and a later appointment won’t get booked. I wouldn’t want to miss an opportunity to vaccinate the dog, so I’d have them come back as soon as they are able. That also helps the dog get protection as soon as possible.

Now let’s think about non-injectable vaccines. Picture this instead: Same dog, same owner, same recommendations. This time the owner calls back the next day and says they will be boarding the dog later this year, so they want to get it a “kennel cough” vaccine. You recommend a mucosal (oral or intranasal) vaccine, since they are more effective than injectable kennel cough vaccines. When can the dog receive an oral or intranasal vaccine?

Mucosal (oral, nasal) vaccines that we use for “kennel cough” (typically Bordetella bronchiseptica, canine parainfluenza virus, canine adenovirus in various combinations) in dogs are modified live vaccines, so there might be some issues to consider with regard to minimum vaccination intervals, but we have a complete lack of data on the impact in pets.

• In humans, the CDC guidance says “Two or more injectable or nasally administered live vaccines not administered on the same day should be separated by at least 4 weeks, to minimize the potential risk for interference. If 2 such vaccines are separated by < 4 weeks, the second vaccine administered should not be counted and the dose should be repeated at least 4 weeks later. On the day a live injectable or intranasal vaccine will be administered, providers should ensure that no live injectable or intranasal vaccine was given in the previous 28 days.”

This is the one situation where there might be a biologically plausible argument for a minimum interval between different vaccines, but whether it actually has a clinically significant impact is another question. We have no idea if it’s an issue for pets, but this scenario could occur with dogs given a modified live core vaccine and then a modified live intranasal or oral vaccine less than 4 weeks apart. I’ve never really considered this to be a big concern, as I’d typically be more concerned about missing the opportunity to protect the dog against a vaccine-preventable disease, but I don’t think we can ignore it completely.

So in the scenario with the newly vaccinated dog and the owner now requesting a kennel cough vaccine, I’d consider how important the vaccine is in the very short term and over the next several months. If the dog won’t be boarded for a few months, I’d recommend waiting 4 weeks for the kennel cough vaccine out of abundance of caution, to try to get the best response possible on the first dose. If the dog is going into a high risk environment (e.g. boarding) soon, then I’d give the vaccine right away, but also recommend another dose 4 (or more) weeks later based on the theoretical potential for a poorer response to the first dose. That may be overkill, but it’s the one scenario with a plausible basis for setting a minimum dosing interval between different vaccines.

To sum up another very long blog post:

• There is no scientific basis for a minimum interval between giving different non-live vaccines to dogs and cats.
• The only scenario in which a minimum interval between different vaccines could plausibly matter is sequential administration of multiple modified live vaccines, which doesn’t come up very often in pets anyway, and the potential for interference it based only on extrapolation from human medicine, with no evidence that it is clinically relevant in dogs or cats.

This also raises questions about vaccination of pets in shelters. Shelters vaccinate frequently using modified live vaccines, including kennel cough vaccines for dogs. Does that mean those dogs may be suboptimally vaccinated in some situations, OR can we consider shelters a natural model that shows this kind of interference actually isn’t a concern? An interesting point for discussion, but shelter vaccination strategies are fodder for a separate post.

Don’t forget to check out the new paired resource from the Ontario Animal Health Network (OAHN): Vaccination Timing and Intervals in Dogs and Cats (infosheet and infotable). If you don’t have an OAHN login, veterinarians and RVTs can sign up for free.

Let’s face it, approaches to vaccination in companion animals are based partly on direct evidence, partly on extrapolation from other species, partly on expert opinion, and partly on “this is what we do because it’s what we’ve always done.” The evidence base for much of what we do is incomplete, and for a lot of things the evidence base is actually sparse to non-existent. We typically have good basic information about most of our vaccines and what happens with them in the specific “textbook” scenarios, but we also need to know what to do when animals and owners don’t follow the textbook (which happens a lot).

Label instructions on vaccines have traditionally described those ideal / textbook scenarios, but more recently they are getting much less specific. That’s useful in some ways, because it provides room for flexibility and gets away from rigorous, dogmatic approaches, but it doesn’t necessarily help someone know what to do instead.

That’s where veterinary vaccination guidelines can be useful too, and these have been critical to the advancement of preventive care over the years, but they also need to evolve. Current veterinary vaccination guidelines have a lot of recommendations that aren’t supported by any data, but sometimes we have to make recommendations even when we have very little evidence. More recent approaches to guideline development use rigourous evidence synthesis (to make sure we are basing decisions on what’s known, not just the parts we like) and provide insight into how certain we are about each recommendation: Some recommendations are very clearly evidence-based and solid; many are reasonable but not strongly supported by evidence; some need to be rethought altogether. If there’s no transparency about what we know versus what we think versus what we’re guessing, it can lead to confusion and other issues (like guesses being treated as fact).

• That’s me wearing my guideline methodologists hat, but I’ll take that off now, since I’m about to make some recommendations without that degree of evidence synthesis and structured decision-making process. It’s a blog post, after all. But hopefully it might entice some of the groups that make those guidelines to evolve.

Today I’m going to tackle what to do with pets that are overdue for their scheduled vaccine boosters. (I’ll try to cover some of the other scenarios in subsequent posts – this one will be long enough as it is!) Vaccines usually have recommended re-dosing intervals. In the past these have typically been very specific (e.g. every 12 months), but the trend is now toward much looser statements. For example, one Canadian canine vaccine label now reads “Historically, annual revaccination with this product has been recommended. The need for annual booster vaccination has not been established for this product. For advice on revaccination frequency, consult your veterinarian.”

Here’s an example: An 8-year-old Bichon (let’s call him Teddy) was vaccinated as a puppy, and then got core (distemper, parvovirus) and rabies vaccines at approximately 1 year of age, and then again 3 years later (around 4 years of age). He was due for re-vaccination a year ago (7 years old). Teddy was also consistently vaccinated against leptospirosis every year, but missed that one last year too.

What do we do with Teddy?

• To be honest, my thoughts on this have evolved as I’ve put more time into looking at evidence and thinking about vaccination. I’ll admit I had a lot of ingrained approaches that were based on historical norms and not data and evidence. Changing behaviours is hard for people, and even I’m not immune to that, but we have to evolve.

A common response to this scenario would be to say that Teddy is well overdue for everything, so we need to restart all of his vaccine “series,” meaning a dose now and (for some of the vaccines) as booster in a few weeks. But that doesn’t make sense to me immunologically. Most (not all) of our canine vaccines are quite good at what they do, and the immune system of most animals has an effective long term memory. While protection against some diseases may wane over time (which is why the boosters are still needed), the ability to respond well to a booster vaccine often endures for much longer (a concept sometimes referred to as boostability).

In human medicine, there are very few situations where it is recommended to restart a vaccine series, and none of them apply to the kinds of vaccines we use in dogs and cats. If a person misses their scheduled booster and is overdue – whether by a day, a year, or 10 years – the recommendation is typically to simply revaccinate them. According to the US CDC guidance on Timing and Spacing of Immunobiologics: “Vaccination providers should administer vaccines as close to the recommended intervals as possible. However, intervals between doses that are longer than recommended typically do not reduce final antibody concentrations, although protection might not be attained until the recommended number of doses has been administered. With some exceptions (e.g. oral typhoid vaccine) an interruption in the vaccination schedule does not require restarting the entire series of a vaccine or toxoid or addition of extra doses.”

So for Teddy, I’d recommend simply revaccinating him as usual, with the exception of the rabies vaccine… That exception is due to regulatory issues around rabies vaccine, because regulators don’t like to take any chances when it comes to very deadly zoonotic diseases (which is somewhat understandable).

• Rabies vaccine works very well, and many animals respond extremely well to a booster vaccine even if they’re overdue by several years (Moore et al. 2015), but it’s impossible to know (in advance) which animals will and which won’t respond well to a booster, or how long an animal may be protected beyond what has been tested by the vaccine manufacturer. But even rabies vaccines labels have become less prescriptive; for example, one such label now says “Duration of Immunity is at least 3 years after a repeat dose” but does not specify an interval for the repeated dose.
• A pet’s rabies vaccination status therefore impacts what happens if that animal is potentially exposed to rabies. Different jurisdictions have different rules about this; Ontario’s rabies management guidelines for domestic animals are one example. If an overdue dog like Teddy was revaccinated today, I would have absolutely no concern about the dog being protected for at least the next 3 years, but some regulators would only consider that booster valid for 1 year. So if Teddy was exposed to a bat or an abnormal raccoon 18 months from now, that could mean a long confinement period (instead of easy observation).
• Knowing what the rules are in your local area is important. Some jurisdictions now may worry less about the previous vaccination intervals (but knowing the pet has had previous rabies vaccines at some point), and focus mainly on the interval from the last dose (e.g. within 3 years). Some will accept a 3-year duration of immunity if there are only short lapses in the history (e.g. as long as the dog was boostered within 3 months of when it was due). Some remain very strict, meaning as soon as a pet is overdue, it’s next rabies vaccine is only good for 1 year, and only after getting another booster within 12 months can the pet go back on the 3 year revaccination schedule. While it could be helpful for regulators to have some more flexibility, “regulation” and “flexibility” are difficult concepts to marry along with “consistency”.
• Animals that travel overseas may encounter the strictest rabies vaccination requirements. Border authorities may look very closely at vaccination history, any lapse in vaccination (even by a day) could invalidate a claim to a 3 year duration of immunity (meaning if it’s been more than 1 year since the pet’s last vaccine, it will be stopped at the border).

Knowing what rules may apply to a certain pet (based on where it lives or where it may travel) is key. If in doubt, I’d revaccinate Teddy now and give a booster in a year, even though it’s likely overkill for many pets (but better than a rabies quarantine or interrupting the owner’s vacation plans).

Even if we get veterinarians (and owners) on board with the immunological basis for not needing to restart vaccine series in overdue pets, some veterinarians will still worry about liability and vaccinating “off label.” But consider that giving a single dose now is no more off-label than restarting a series, because neither of those scenarios is described on the label (or even in the R&D from the vaccine manufacturer). Yet we convince ourselves that the historical norm (e.g. what we did before, as per the label) is the safer / better approach, but we don’t know if that’s actually true.

For me, at this point, overdue animals are easy: Vaccine them as you normally would, but also think about (and discuss with the owner) if the pet might run into any regulatory issues if it’s not revaccinated again in 1 year (instead of 3 years).

I’ll be a little more concise (I almost promise) when I cover other vaccination scenarios (stay tuned). For more information (and a sneak peak of what’s to come), check out the new paired resource from the Ontario Animal Health Network (OAHN): Vaccination Timing and Intervals in Dogs and Cats (infosheet and infotable). If you don’t have an OAHN login, veterinarians and RVTs can sign up for free.