More and more pet owners are starting to question veterinarians and their staff about the need for vaccinating their pets due to misinformation on the internet, as well as sensationalized stories about pets who may, or may not, have experienced a vaccine reaction. Those in opposition of vaccines are passionate about their views, while those in favor are equally vehement on the subject. Is one side right and the other wrong, or is there common ground to be found? Likely a little of both. Not all is yet known about the immune system, and there is still research that needs to be done. As such, recommendations offered today are based on current information, with the full knowledge they could change in the future. Not what they used to be Vaccines were developed to help prevent infectious disease, which they do, and vaccine technology has advanced tremendously since the inception of vaccinology. Vaccine opponents often argue ingredients such as adjuvants (e.g. aluminum, mercury, formaldehyde, and foreign proteins) are reasons to not vaccinate, as they can be the cause of adverse advents. This was true in the past; however, many vaccines have been “purified” over the years through the removal of extraneous proteins. Some of the aforementioned adjuvants also have been discontinued in the production of some vaccines. These changes in production have made vaccines much less reactive for our patients over the years. Vaccines are safe, effective, and recommended for the majority of patients, but are there times when they can be harmful for some? While adverse reactions to vaccination can occur in many species, the rate of these reactions is low. The risk of not having immunity to common infectious organisms far outweighs the threat of developing serious illness as a result of vaccination. There are several retrospective studies that review the rate of reported post-vaccine adverse events. The likelihood of serious adverse events Technicians in the Kansas State University rabies laboratory stain slides to identify the rabies virus in the performance of the rabies fluorescent focus inhibition test (RFFIT) to determine rabies antibody titers. One study in Canada focusing on adverse reactions to vaccination in dogs and cats reported to the Canadian Food Inspection Agency’s (CFIA’s) Canadian Centre for Veterinary Biologics (CCVB) between January 1, 2010, and June 30, 2014, showed the rate of serious adverse events (SAEs) was small (Valli 2015). Allergic reactions represent the most common type of serious adverse event reported, with 2.663, 0.187, and 2.646 probable, possible, or unknown events per 10,000 doses of canine, feline, and rabies vaccines, respectively. Moore et al reported a total SAE rate of 13 per 10,000 vaccinated dogs in their large-scale (1,226,159 dogs) Banfield Hospital surveillance study. This represents a reaction rate of less than one percent (Moore et al. 2005). A flaw in these studies is that not all adverse events get reported, and some reactions may get reported as some other type of condition. However, one has to be aware a temporal association between vaccination and the development of a clinical sign does not necessarily equate to a cause-and-effect relationship between the vaccine and the illness. There can often be many other physical and/or behavioral issues occurring around the timespan when vaccines are given. An example of this would be a dog who receives a vaccine and develops vomiting and diarrhea a few hours later. This could be due to the vaccine or it may also have been due to dietary indiscretion that was caused from him getting into the garbage earlier in the day. Patients with a history of mild, acute post-vaccination reaction (e.g. facial swelling) are often treated with a single dose of diphenhydramine prior to vaccination. For patients experiencing a mild post-vaccination reaction requiring treatment, a single anti-inflammatory dose of a corticosteroid should be considered. However, there are some disease conditions where one should truly consider the need for vaccination. For example, patients with a history of having had a serious, acute vaccine-associated reaction (anaphylaxis) should not be revaccinated unless deemed necessary, and then only when the patient can be monitored for several hours post-vaccination. Pretreatment doses of corticosteroids +/- diphenhydramine are typically given as well. It is generally recommended to avoid the use of modified live vaccines in patients that are immunocompromised due to disease states or if they are undergoing some chemotherapy protocols. If vaccines are required, killed vaccines are recommended. American Animal Hospital Association’s (AAHA’s) 2017 AAHA Canine Vaccine Guidelines suggest not vaccinating animals with suspected delayed-onset post-vaccine reactions, such as immune-mediated hemolytic anemia (IMHA) or thrombocytopenia (IMT), as it has been suggested doing so could re-activate disease, even after they have recovered. The guidelines also go on to say vaccination has been anecdotally linked to immune-mediated disease in dogs, such as IMHA and IMT, but definitive studies demonstrating a clear cause-and-effect relationship have not been published. In veterinary medicine, the relationship between vaccine-associated immune-mediated disease and vaccination has been associated with adjuvant in inactivated (killed) vaccine (Cruz-Tapias et al. 2013, Esposito et al. 2014, Huang, Moore, and Scott-Moncrieff 2012, Roth 1999). In humans, there is a documented link between vaccines and immune-mediated diseases, such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Steps to minimize and/or manage SAEs Reassess the patient’s lifestyle to determine which vaccines are absolutely necessary. There are “lifestyle” calculators a client can complete for their pet that can be used to determine which vaccines are truly necessary. One example is AAHA’s Lifestyle-based Vaccine Calculator, which allows an owner to check off various lifestyle risk boxes that are appropriate for their pet. These are useful tools for clients who like to have more control in the decision-making process for their pets or are worried about over-vaccination; they also seem less like a vaccine sales pitch from their veterinarian. Allow longer intervals between core vaccine doses after completing an initial series and one-year booster to minimize the amount of given vaccines. Wait to give noncore vaccines to small-breed puppies (≤10 kg) two weeks after finishing core vaccines. Separate individual vaccine administration by at least three weeks if an adverse reaction was previously seen when multiple vaccines were given on the same day. Premedicate with diphenhydramine +/- a dose of corticosteroid in the case of more significant reactions. Administer a different brand of vaccine for the next scheduled boosters, as adjuvants differ between brands of vaccine. If it was a reaction to the adjuvant, a different brand may not trigger the reaction. Check vaccine titers for some diseases to see whether a vaccine is necessary. Why use vaccine titers? Kara Parsons, a fourth-year veterinary student at Kansas State University’s Pet Health Center, prepares a vaccine to give her patient. Vaccine titers have been gaining more acceptance over the past few years to reduce the frequency of vaccination. To be useful, two criteria need to be met: 1) One needs to be able to detect a measurable immunity (antibody) to the infectious agent causing the disease in a blood sample. 2) There needs to have been challenge studies performed with the virulent organism to associate protection with a specific titer level. Vaccine titers are not an effective means for assessing protection for some diseases. In general, these are for the diseases included in the noncore vaccine category, as their specific protective level of antibodies have not been determined. The antibody response following vaccination with these vaccines tends to be short-lived and generally does not correlate with protection, as many do not produce sterilizing immunity (i.e. prevention of infection following exposure). Noncore vaccines also are known as lifestyle vaccines, and administered based on risk determined by geographic location and activities. For dogs, leptospirosis, Borrelia (Lyme), Bordetella, canine parainfluenza, and canine influenza are risk-based vaccines. For cats, feline leukemia virus (FeLV), Chlamydophila (chlamydia), and Bordetella vaccines are administered to cats with greater risk of exposure. Vaccine titers can be useful for determining the need for DA2P (canine distemper, Adenovirus-2, and canine parvovirus) and feline panleukopenia, as a positive antibody result to these correlates well with protective (sterile) immunity. These are considered core vaccines. Although feline rhinotracheitis and calicivirus also fall in the core category for cats, and antibodies can be measured, vaccination does not result in sterilizing immunity, making titers less useful for these diseases; however, many titer panels include all three of these feline viruses. After the patient has completed their initial series of the core vaccines and a booster one year later, annual titers can be determined thereafter to assess the need for continued boosters. Many cats and dogs have post-vaccine titers to the core diseases that last many years, and sometimes a lifetime (Schultz 2006). Several years ago, the American Association of Feline Practitioners (AAFP) and AAHA recommended increasing the vaccine interval for DA2P and FVRCP (feline viral rhinotracheitis, calicivirus, panleukopenia) from one year to three years based on titer-testing results (Scherk et al. 2013, Ford et al. 2017). Conversely, it must be noted titers also have identified patients that needed a booster vaccination sooner than every three years. As such, they are useful for detecting the need for boosters for both animals that don’t need vaccination as well as those that do. Because animals needing boosters may also be recognized, annual titer testing should be considered. Titers and rabies Rabies is a core vaccine, and titers can be determined, but the use of titers in lieu of rabies vaccination is not as straightforward. Rabies vaccination is required for dogs (and often cats as well) in most states and/or municipalities as part of rabies control and prevention policies. Rabies is zoonotic, and control in rabies vectors is the most efficient method in preventing human rabies deaths (World Health Organization 2018, Ma et al. 2018). Rabies control laws currently do not include the use of titers in place of vaccination (Brown et al. 2016). The other complicating factor is there is no agreed standard titer value that is considered protective. Not all laboratories that determine titers are accredited and not all test methods are accurate. For a disease with such great significance with regard to public health, it is important to use a lab that is accredited and has quality-control measures in place. Peer-reviewed publications examining rabies vaccine protection through challenge studies provide the best information on what level of circulating rabies antibody is correlated with protection from clinical rabies. Challenge is often performed via the intracerebral route, which is an extreme challenge route of exposure for pets. Many of these studies have used the mouse neutralization test (MNT) or the rapid fluorescent focus inhibition test (RFFIT) for measurement of antibodies. In summary, we find from review of these papers that currently vaccinated dogs and cats with rabies antibody levels above 0.5 IU/mL survive more frequently than those with levels below 0.5 IU/mL (Bunn and Ridpath 1984, Aubert 1992). However, there have been cases reported, though rare, of an animal succumbing to challenge with a level above 0.5 IU/mL, so the correlation is not perfect. The probability of survival increases with higher IU/mL values up to around 1.0 IU/mL, meaning an animal with a level of 1.0 IU/mL has as good a probability of survival as an animal with a level of 10.0 IU/mL (Bunn and Ridpath 1984). This correlation of protection has been found to be similar in several species (Moore 2017). Review of the published studies pointed out the difficulty in comparing rabies serology between studies if the same laboratory test method and cut-off level were not used (Moore 2017). Survival from challenge There is very limited published data on dogs and cats “out of date” for their rabies vaccination and survival from challenge. One paper looking at dogs at five years and cats at four years post-vaccination showed fair correlation of rabies antibody level and survival from challenge, with 54 percent of dogs and 87 percent of cats with detectable rabies antibody just before challenge. The study also showed 92 percent of dogs and 100 percent of cats surviving (Lawson and Crawley 1972). The challenge studies also show the timing of the blood draw is important in predicting survival, as is evidenced in the out-of-date vaccination study above. Correlation is best if the time period from vaccination to titer check is earlier rather than later after vaccination, with the peak period at 21 to 30 days post-vaccination (Moore 2017). Several publications report dogs under one year of age with only a puppy rabies vaccine tend to have levels of antibody below 0.5 IU/mL more than other age groups. This indicates the timing of vaccination can influence the immune response if maternal antibodies are present (Wallace et al. 2017, Kennedy et al. 2007). The above findings emphasize that if rabies titer testing can be used in lieu of vaccination, a number of standards will need to be established, the most important of which being the level of rabies antibody, timing of blood draw after vaccination, and approved test (Moore 2017). Some states are starting to consider laws in support of the use of titers in those animals that have experienced severe adverse reactions to vaccines or have other health issues that would preclude vaccination. These states still require the vaccine in normal circumstances; however, rabiesaware.org provides current rabies vaccination regulations for most states, including if they allow exemption of a rabies vaccine when recommended by a veterinarian. The bottom line is vaccination is safe for the majority of pets and vaccines save many more lives than they harm; however, there are more and more pet owners questioning the need for the number of vaccines their pets receive. There also are many low-cost vaccine clinics that compete for pet owner revenue. The modern practitioner needs to be armed with facts about the real numbers of post-vaccine adverse events, but also remain in tune with their clients’ concerns. AVMA’s vaccination principles contain this statement: “Appropriate decisions concerning individual vaccine selection and vaccination program choices are best made under veterinarian-client-patient relationships” (AVMA 2019). It is important to consider a patient’s lifestyle and health when determining which vaccines are essential. Using lifestyle calculators can help tailor individual vaccine programs for patients and involves the owner. Incorporating titer testing for core diseases can help determine if a patient actually needs a vaccine, or help detect the ones who need a booster. Working with the owner when it comes to vaccinations is not only beneficial for the patient, but the practice as well. Susan M. Moore, PhD, MS, HCLD (ABB), MT (ASCP) SBB, is an assistant clinical professor and rabies laboratory director at Kansas State University. Her research interests are laboratory methods to detect and measure vaccine response, as well as response to infectious diseases with a primary interest in rabies. Dr. Moore can be contacted at smoore@vet.k-state.edu. Susan Nelson, DVM, is a clinical professor in the Pet Health Center at the KSU Veterinary Health Center. She has been a faculty member since 2003 after working the previous 14 years as a companion-animal practitioner in an AAHA-accredited private practice. Dr. Nelson’s interests are in wellness and preventive care. She can be contacted at snelson@vet.k-state.edu. References Aubert, M.F. 1992. “Practical significance of rabies antibodies in cats and dogs.” Rev. Sci. Tech 11 (3):735-760. 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Rigante. 2014. “Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): clues and pitfalls in the pediatric background.” Immunol Res 60 (2-3):366-75. doi: 10.1007/s12026-014-8586-0. Ford, R. B., L. J. Larson, K. D. McClure, R. D. Schultz, and L. V. Welborn. 2017. “2017 AAHA Canine Vaccination Guidelines.” J Am Anim Hosp Assoc 53 (5):243-251. doi: 10.5326/JAAHA-MS-6741. Huang, A. A., G. E. Moore, and J. C. Scott-Moncrieff. 2012. “Idiopathic immune-mediated thrombocytopenia and recent vaccination in dogs.” J Vet Intern Med 26 (1):142-8. doi: 10.1111/j.1939-1676.2011.00850.x. Kennedy, L.J., M. Lunt, A. Barnes, L. McElhinney, A.R. Fooks, D.N. Baxter, and W.E. Ollier. 2007. “Factors influencing the antibody response of dogs vaccinated against rabies.” Vaccine 25 (51):8500-8507. doi: S0264-410X(07)01154-1 [pii];10.1016/j.vaccine.2007.10.015 [doi]. Lawson, K. F., and J. F. Crawley. 1972. “The ERA strain of rabies vaccine.” Can J Comp Med 36 (4):339-44. Ma, X., B. P. Monroe, J. M. 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