Vaccinating Dogs Against Lyme Disease: Two Points of View Meryl P. Littman, VMD, Diplomate ACVIM University of Pennsylvania Richard E. Goldstein, DVM, Diplomate ACVIM & ECVIM (Companion Animal) The Animal Medical Center, New York City
First Do No Harm: Lyme Disease Vaccination May Present More Risks than Benefits Meryl P. Littman, VMD, Diplomate ACVIM When veterinary clinicians decide whether to recommend a particular vaccine for a particular patient, risks and benefits are weighed. The “vaccinometer” tool, developed by Larry Glickman, was designed to help practitioners determine whether or not to recommend a vaccine.1 As we investigate Lyme disease vaccination, the questions posed by the vaccinometer help highlight many unanswered questions and potential risks related to this vaccine. With these concerns in mind, I choose “first do no harm.” In other words, if we use proper tick control, vaccination is unnecessary. Question: What is the prevalence and risk of exposure/ infection in your area (eg, infectiousness)? Answer: Risk of Lyme disease exposure/infection is high in my area, but proper tick control lowers the risk greatly. The CDC website2 shows that 95% of human Lyme disease is found in 12 endemic states in the Northeast, MidAtlantic, and Upper Midwest U.S. In some endemic areas, seroprevalence in healthy dogs is as high as 70% to 90%.3 In high-risk areas, risk of exposure can be lowered dramatically with adequate tick control, which also decreases the risk for other tick-borne diseases, such as anaplasmosis, babesiosis, bartonellosis, ehrlichiosis, and Rocky Mountain spotted fever.
espite availability of a consensus statement and up-to-date canine vaccination guidelines (see Lyme Disease Vaccination Guidelines), the decision whether or not to vaccinate dogs against Lyme disease remains an ongoing debate among many veterinary professionals. Today’s Veterinary Practice has gathered 3 experts to discuss this topic—Dr. Meryl Littman and Dr. Richard Goldstein evaluate the benefits and risks of vaccination, while Dr. Richard Ford outlines the current vaccination recommendations.
Today’s Veterinary Practice January/February 2014
Question: How great is the risk of severe disease once the dog is infected (eg, pathogenicity and virulence)? Answer: Risk of Lyme disease becoming severe is low, but possibly somewhat higher in retriever dogs. Less than 5% of seropositive (and seronegative) dogs had signs attributed to Lyme arthritis,3 which generally responds rapidly to antimicrobial therapy. Perhaps 10% to 15% of treated dogs remain non-clinical carriers.3 One study showed that 40% of dogs diagnosed with Lyme disease were misdiagnosed and had another condition instead.4 Adult beagles experimentally infected with Lyme disease via tick exposure became seropositive but remained nonclinical, and exposed puppies showed only self-limiting signs of arthritis, anorexia, and fever, which did not require treatment.3 Perhaps less than 2% of exposed dogs develop the more serious Lyme nephritis,5 an immune-mediated glomerulo-
nephritis, with high Lyme disease-specific antigen–antibody circulating immune complexes (CICs) and deposition in glomeruli, causing protein-losing nephropathy (PLN).6 This entity has not been duplicated in any experimental model, and is seen mostly in Labrador and golden retrievers. However, even in seropositive retrievers, Lyme nephritis is uncommon,7 and we do not understand why some dogs develop it while many do not, despite their high titers and high CICs. It appears that a genetic predisposition exists, and that inflammation from Lyme antigens, and possibly inflammation from other infectious and inflammatory conditions, may be an environmental trigger. A genetic podocytopathy identified in soft-coated wheaten terriers8 may predispose them to further glomerular damage; a similar condition may exist in affected retrievers. In general, coinfections appear to result in more serious illness (eg, anaplasmosis/Lyme disease), which emphasizes the importance of tick control.9 Question: How effective is the vaccine? Answer: Not as effective as other vaccines we use. Lyme vaccines appear to prevent seroconversion or illness in most (60%–86%)3 vaccinates, but not consistently in all dogs, and not for a very long duration of immunity, thus annual (or even every 6 months10) boostering has been recommended. Question: How safe is the vaccine? Answer: These vaccines are not as safe as other vaccines we use. In the Banfield study of 1.2 million vaccinated dogs, the Lyme disease vaccine (monovalent bacterin), when used alone, produced more postvaccinal adverse events within 3 days than any other canine vaccine.11 Adverse events associated with Lyme disease vaccine were described as “moderate” by an AVMA council in 2002.12 All canine Lyme disease vaccines contain outer surface protein A (OspA), which attaches the spirochete to the tick’s midgut and is expressed on Borrelia burgdorferi while in the tick, and induces anti-OspA antibodies. • OspA without adjuvant is a polyclonal B cell mitogen that induces pro-inflammatory cytokines,5 causes arthritis in rats,13 and causes a strong TH1 response in people with HLA-DR4 haplotype, immune-mediated arthritis, and high anti-OspA antibodies after natural infection.14 • Lyme bacterin as well as OspA alone causes arthritis in hamsters15 and sensitization16 so that more severe arthritis is produced with boosters.17 • Lyme bacterins were not developed for humans since various Lyme disease antigens appear to have a role in post Lyme disease immune-mediated diseases.18 • In dogs with suspected Lyme nephritis, immunohistochemistry and elution studies have shown positive staining of glomerular immune complexes for a variety of Lyme antigens, including OspA and others, which are also found in Lyme disease vaccines.5 Remember, inflammation or deposition may be delayed for months after vaccination and not seem temporally related nor recognized as a problem associated with vaccination. Original reports of Lyme nephritis suspect cases19 demonstrated that 30% had received Lyme disease vaccine, from 2 weeks to 15 months prior to illness. There is no experimental model for Lyme nephritis, which makes it impossible to study
whether Lyme disease vaccine prevents, sensitizes, or aggravates it. However, since the most serious forms of Lyme disease are immune-mediated, I choose not to administer Lyme vaccine antigens that may elevate Lyme disease specific CICs (that increase after vaccination, as they should), which would circulate and need to be cleared (or deposited) for weeks to months after vaccination. In addition, should we vaccinate retrievers (some of which are genetically predisposed dogs) that may develop Lyme nephritis or PLN? These patients are most likely the very ones we should NOT vaccinate lest we add more complexes or sensitize them for a more intense immune-mediated reaction when they are boostered or exposed naturally. Question: What is the potential for zoonotic spread to human contacts, and zoonotic spread to other dogs? Answer: Potential for zoonotic transmission of Lyme disease is minimal. B burgdorferi is transmitted via tick bites, and is not contagious from dogs to humans or dogs to dogs via excretions or blood transfusion. The reservoir hosts are wildlife, such as mice, small mammals, and birds. Seropositive dogs are sentinels that their human companions are at risk for exposure— not from dogs, but from ticks in the environment.
In Summary The conclusions we can draw from the questions posed are: • Tick control is important: it prevents pets from acquiring the numerous tick-borne infectious agents, and prevents ticks from feeding on sentinel dogs, thereby acquiring the agent and transmitting it to their next host. • Most dogs exposed to B burgdorferi seroconvert, but are nonclinical and do not need antibiotics.20 While most dogs do not exhibit illness after vaccination against Lyme disease, neither do dogs that are naturally exposed. • Dogs that have Lyme arthritis respond quickly to inexpensive/safe antibiotics. • Lyme disease vaccines have lower efficacy, shorter duration of immunity, and cause more post vaccinal adverse events than other vaccines we use. • Without an animal model for Lyme nephritis, we do not know if the Lyme disease vaccine prevents, sensitizes, or causes more immune complex deposition in kidneys, especially in genetically predisposed dogs. • Accordingly, the subset of dogs that possibly need the most protection (eg, retrievers) from the serious (immunemediated) forms of Lyme disease may be the very ones predisposed to complications. l
What the Future Holds
Since immune-mediated disease triggered by Lyme antigens concerns many physicians, research is now directed at finding future vaccines that may incorporate tick proteins, which can be used to interfere with tick attachment, feeding, and/or transmission of disease.21-23 For instance, the tick salivary protein, SALP15, helps B burgdorferi infect its next host.21 This exciting new paradigm in vaccine development may help prevent tick-borne diseases, including Lyme disease.
Today’s Veterinary Practice
Vaccinating Dogs Against Lyme Disease: Two Points of View
WITH TICk CoNTRoL & VACCINATIoN IN ENDEMIC AREAs, LYME DIsEAsE Is PREVENTABLE Richard E. Goldstein, DVM, Diplomate ACVIM & ECVIM Lyme disease, its causative tick-borne agent—Borrelia burgdorferi, and Ixodes ticks are all on the rise. in August 2013, the centers for Disease control and Prevention (cDc) increased their estimate of the number of new human cases of Lyme disease from 30,000 to 300,000 annually.1 Tick removal and control is an important part of prevention of Lyme disease, but so is Lyme disease vaccination. No vaccine is completely without risk, but when weighing the risks versus the benefits, i believe the evidence strongly supports the following: 1. In endemic regions, Lyme disease negative dogs should be vaccinated. As part of a Lyme disease prevention protocol, dogs must be vaccinated in addition to tick removal and control. One infected tick that escapes those first 2 barriers can easily cause infection. There is no evidence of any deleterious effects due to vaccinating Lyme disease negative dogs. 2. In endemic regions, Lyme disease positive dogs with no clinical signs of disease should be vaccinated when risk of reinfection is high. There is no natural immunity due to previous infection, which likely results due to bacteria “hiding” themselves from the immune system, mainly in tissue, such as synovial membranes, and down-regulating immunogenic surface proteins.2 in a recent paper on infections in humans with recurrent signs, it appeared that humans can be re-infected over and over again, almost annually, causing severe clinical disease.3 3. In endemic regions, Lyme disease positive dogs with clinical signs should be vaccinated when risk of reinfection is high, and should receive antibiotic therapy, prior to or immediately following vaccination. 4. Lyme disease vaccination should be performed annually, with the currently available vaccines. in addition, tick control, even in vaccinated dogs, must be stressed to owners since very heavy exposure to Lyme disease may override vaccinal protection. FACTs oN HuMAN VACCINATIoN There is a race to bring a “new” human Lyme disease vaccine to market, with some vaccines already in advanced stages of development.4,5 A previous Lyme disease vaccine for humans had been approved for use in the U.s., but was removed from the market. The observation that this vaccine was unsuccessful due to lack of sales is often misused as an argument against canine Lyme disease vaccination. The University of Pennsylvania’s world renowned vaccinologist, stanley Plotkin, described the human vaccine situation in 2011: A vaccine against Lyme disease was licensed in the United States in 1998 but was subsequently removed from the market because of lack of sales. I believe that the poor acceptance of the vaccine was based on tepid recommendations by the CDC, undocumented and probably nonexistent safety issues, and insufficient education of physicians… The fact that there is no vaccine for an infection causing 20,000 annual cases is an egregious failure of public health.6 FouR sAFE & EFFECTIVE VACCINEs compared to humans, dogs are lucky. There are currently 4 extremely safe, effective, and reliable vaccines7-9 (Table) on the market that have all been through the United states Drug Administration licensing requirements for safety, efficacy, purity, and potency. All available canine Lyme disease vaccines produce borreliacidal antibodies in the dog in response to vaccinal outer surface protein A 64
Today’s Veterinary Practice January/February 2014
CuRRENT GuIDELINEs: VACCINATIoN oF DoGs AGAINsT LYME DIsEAsE Although the controversy over whether or not to vaccinate dogs against Lyme disease continues, vaccination guidelines for dogs with known risk for exposure to Borrelia burgdorferi have been published (see Lyme Disease Vaccination Guidelines). Here is a summary of current recommendations: 1. The decision to vaccinate individual dogs is ultimately left to the discretion of the individual veterinarian and must take into consideration reasonable risk for exposure to vector ticks capable of transmitting B burgdorferi. The following protocol is recommended: • Administer 1 dose not earlier than 12 weeks of age; administer second dose 2 to 4 weeks later. • Administer 1 dose annually to dogs with sustained risk for exposure. Because this risk is seasonal (even in endemic areas), it is reasonable to recommend administering annual boosters in the spring. Comment: Two initial doses, 2 to 4 weeks apart, are considered critical to inducing a protective immune response; a single dose will not immunize. if the interval between the initial 2 doses exceeds 6 weeks, recommend administering the initial 2-dose series again. 2. Vaccination is not considered to be 100% effective in preventing infection or illness. Limiting tick exposure, through treatment of the dog’s environment, direct treatment of the dog, or both, must supplement any vaccination decision. Comment: remind owners that tick control for the pet and its environment helps prevent Lyme disease and other vectorborne diseases (eg, ehrlichiosis, anaplasmosis, spotted-fever group). 3. Vaccination is not recommended for dogs residing outside of endemic states (or regions). Comment: consider vaccinating individual dogs that travel into endemic areas of the U.s. and canada and, subsequently, may be exposed to infected ticks. Administering prophylactic antibiotics during a period of possible exposure is not considered effective infection prevention. Richard B. Ford, DVM, MS, Diplomate ACVIM & ACVPM (Hon), North Carolina State University
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(OspA). These antibodies work in the tick’s gut to bind the bacteria during the blood meal, sterilizing the gut of the tick and preventing transmission of bacteria into the dog. Ospc is the main immunogenic protein exhibited by Borrelia in the tick’s salivary glands and in the dog’s body during natural infection. Three of the current Lyme disease vaccines contain 2 strains of inactivated Borrelia isolates—1 OspA producing strain and 1 unique Ospc producing strain, which perhaps adds an additional layer of protection. EFFICACY oF THE VACCINE These vaccines are extremely safe and, in conjunction with tick removal and control, prevent B burgdorferi infection and clinical Lyme disease, including Lyme nephritis. The anecdotal evidence for this fact is overwhelming, but it has also been shown prospectively in multiple controlled studies in experimental infection and in the field. following are just a few of many examples of such evidence in the field. • Levy showed excellent field efficacy of canine Lyme disease vaccination in 2003.10 • in 2010, Hebert and eschner proved the efficacy of the Lyme disease prevention protocol, including vaccination in a large rhode island practice.11 • in a population of guide dogs in New york, implementation of strict tick control and mandatory Lyme disease vaccination regimen reduced the number of Lyme nephritis cases from approximately 10/year to less than 1/year over 7 years.12 CoMBATING CoNCERNs ABouT VACCINATIoN There are still some who believe that Lyme disease is not a disease “worth” vaccinating against or the vaccine causes more harm than good. This is despite the: • extremely large number of clinical Lyme disease cases and nonclinical Lyme infections seen in small animal practice in endemic areas in the U.s., including the often fatal syndrome of Lyme nephritis • Millions of dogs that receive Lyme disease vaccines annually with no data to suggest any resulting harm from the vaccine.
Lyme Nephritis concerns have also been raised that vaccination can contribute to clinical signs of Lyme disease or the syndrome known as Lyme nephritis.13 However, there is no evidence that Lyme nephritis is a vaccine-induced phenomenon or even commonly aggravated by vaccination.
in addition to the evidence from the case study in guide dogs,12 i have evaluated or been a consultant on over 300 cases of dogs with Lyme nephritis; of these dogs, less than 10% were vaccinated. Moreover, i am not aware of a documented case in which a dog vaccinated against Lyme disease, but not infected with it, contracted Lyme nephritis. Ultimately, if we prevent Lyme disease, we prevent Lyme nephritis.
Adverse Events it has been demonstrated experimentally that, upon vaccination of Lyme disease negative dogs, only a transient, relatively clinically insignificant rise in Lyme disease specific circulating immune complexes (cics) occurs, and this rise lasts 8 weeks of less.14 When Lyme disease positive dogs were vaccinated, cics rose, but this rise was most likely much lower than that seen with new infection, and could likely be mitigated with antibiotic therapy, prior to or immediately following vaccination of Lyme positive dogs.15 The alternative—not vaccinating Lyme disease positive dogs and risking additional Lyme disease infections—is very likely more detrimental than the possible rare negative effects of vaccination. In the next issue of Today’s Veterinary Practice, Dr. Richard Ford will provide an in-depth discussion on Lyme disease vaccination guidelines in the Vital Vaccination column. cDc = centers for Disease control and Prevention; cic = circulating immune complexes; OspA = outer surface protein A; PLN = protein-losing nephritis To view the references for this article, go to todays veterinarypractice.com/resources.asp#resources.
LYME DIsEAsE VACCINATIoN GuIDELINEs 2011 AAHA Canine Vaccination Guidelines Welborn LV, DeVries JG, ford rB, et al. JAAHA 2011; 47(5):1-42. Available at http://www.aahanet.org/ publicdocuments/caninevaccineguidelines.pdf.
ACVIM small Animal Consensus statement on Lyme Disease in Dogs: Diagnosis, Treatment, and Prevention Littman MP, Goldstein re, Labato MA, et al. J Vet Intern Med 2006; 20:422-434. Available at http://www.cvm. ncsu.edu/vhc/documents/LymeconsstmtACVIM.pdf.
Meryl P. Littman, VMD, Diplomate ACVIM, is a professor of medicine at the University of Pennsylvania School of Veterinary Medicine. Her research includes canine tickborne diseases. She received her VMD from University of Pennsylvania. Richard E. Goldstein, DVM, Diplomate ACVIM & ECVIM (Companion Animal), is chief medical officer at The Animal Medical Center in NYC. His research includes canine Lyme disease and leptospirosis. He received his DVM from Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Israel.
Today’s Veterinary Practice
VAcciNATiNG DOGs AGAiNsT LyMe DiseAse: TWO POiNTs Of VieW
Littman References 1. Fiala J. Researcher creates tool to gauge vaccine needs. DVM360 Magazine 2003; available at http://veterinarynews.dvm360.com/dvm/ article/articleDetail.jsp?id=70130. 2. CDC website; available at http://www.cdc.gov/lyme/. 3. Littman MP, Goldstein RE, Labato MA, et al. ACVIM small animal consensus statement on lyme disease in dogs: diagnosis, treatment, and prevention. J Vet Intern Med 2006; 20(2):422-434. 4. Speck S, Reiner B, Streich WJ, et al. Canine borreliosis: A laboratory diagnostic trial. Vet Microbiol 2007; 120:132-141. 5. Littman MP. State-of-the-art-review: Lyme nephritis. J Vet Emerg Crit Care 2013; 23:163-173. 6. Littman MP. Protein-losing nephropathy in small animals. In Acierno MJ, Labato MA (eds): Kidney disease and renal replacement therapies. Vet Clin N Am Small Animal Pract 2011; 41(1):31-62. 7. Goldstein RE, Cordner AP, Sandler JL, et al. Microalbuminuria and comparison of serologic testing for exposure to Borrelia burgdorferi in nonclinical Labrador and golden retrievers. J Vet Diagn Invest 2007; 19:294-297. 8. Littman MP, Wiley CA, Raducha MG, Henthorn PS. Glomerulopathy and mutations in NPHS1 and KIRREL2 in soft coated wheaten terrier dogs. Mamm Genome 2013; 24:119-126. 9. Beall MJ, Chandrashekar R, Eberts MD, et al. Serological and molecular prevalence of Borrelia burgdorferi, Anaplasma phagocytophilum, and Ehrlichia species in dogs from Minnesota. Vector Borne Zoonotic Dis 2008; 8:455-464. 10. Topfer KH, Straubinger RK. Characterization of the humoral immune response in dogs after vaccination against the Lyme borreliosis agent: a study with five commercial vaccines using two different vaccination schedules. Vaccine 2007; 25:314–326. 11. Moore GE, Guptill LF, Ward MP, et al. Adverse events diagnosed within three days of vaccine administration in dogs. JAVMA 2005; 227(7):1102-1108. 12. Klingborg DJ, Hustead DR, Curry-Galvin EA, et al. AVMA council on biologic and therapeutic agents’ report on cat and dog vaccines. JAVMA 2002; 221:1401-1407. 13. Gondolf KB, Mihatsch M, Curschellas E, et al. Induction of experimental allergic arthritis with outer surface proteins of Borrelia burgdorferi. Arthritis Rheum 1994; 37:1070-1077. 14. Steere AC, Drouin EE, Glickstein LJ. Relationship between immunity to Borrelia burgdorferi outer-surface protein A (OspA) and Lyme arthritis. Clin Inf Dis 2011;52 (Suppl 3):S259-S265. 15. Lim LC, England DM, DuChateau BK, et al. Development of destructive arthritis in vaccinated hamsters challenged with Borrelia burgdorferi. Infect Immun 1994; 62:2825–2833. 16. Croke CL, Munson EL, Lovrich SD, et al. Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi. Infect Immun 2000; 68:658-663. 17. Littman MP. Perspectives in veterinary medicine: Why I don’t use Lyme disease vaccines. Comp Cont Ed Pract Vet 1997; 19(11):1269, 1272, 1274-1275. 18. Littman MP. Immune-mediated reactions against Lyme vaccines. ACVIM Proc 2000; pp 629-630. 19. Dambach DM, Smith CA, Lewis RM, Van Winkle TJ. Morphologic, immunohistochemical, and ultrastructural characterization of a distinctive renal lesion in dogs putatively associated with Borrelia burgdorferi infection: 49 cases (1987–1992). Vet Pathol 1997; 34:8596. 20. Littman MP. A matter of opinion: Should we treat asymptomatic, nonproteinuric Lyme-seropositive dogs with antibiotics? Clin Brief 2011; 9:13-16. 21. Dai J, Wang P, Adusumilli S, et al. Antibodies against a tick protein, Salp15, protect mice from the Lyme disease agent. Cell Host Microbe 2009; 6(5):482-492. 22. Schuijt TJ, Hovius JW, van der Poll T, et al. Lyme borreliosis vaccination: The facts, the challenge, the future. Trends Parasitol 2011; 27:40-47. 23. Embers ME, Narasimhan S. Vaccination against Lyme disease: Past, present, and future. Front Cell Inf Microbio 2013; 3(6):1-15.
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Goldstein References 1. Kuehn BM. CDC estimates 300,000 US cases of Lyme disease annually. JAMA 2013; 310(11):1110. 2. Grimm D, Tilly K, Byram R, et al. Outer-surface protein C of the Lyme disease spirochete: A protein induced in ticks for infection of mammals. Proc Natl Acad Sci USA 2004; 101(9):3142-3147. 3. Nadelman RB, Hanincová K, Priyanka Mukherjee P, et al. Differentiation of reinfection from relapse in recurrent lyme disease. N Engl J Med 2012; 367:1883-1888. 4. Embers ME, Narasimhan S. Vaccination against Lyme disease: Past, present, and future. Front Cell Infect Microbiol 2013; 3:6. 5. Barrett PN, Portsmouth D. A novel multivalent OspA vaccine against Lyme borreliosis shows promise in Phase I/II studies. Expert Rev Vaccines 2013; 12(9):973-975. 6. Plotkin SA. Correcting a public health fiasco: The need for a new vaccine against Lyme disease. Clin Infect Dis 2011; 52(3):S271-S275. 7. LaFleur RL, Callister SM, Dant JC, et al. One-year duration of immunity induced by vaccination with a canine Lyme disease bacterin. Clin Vaccine Immunol 2010; 17(5):870-874. 8. LaFleur RL, Dant JC, Wasmoen TL, et al. Bacterin that induces antiOspA and anti-OspC borreliacidal antibodies provides a high level of protection against canine Lyme disease. Clin Vaccine Immunol 2009; 16(2):253-259. 9. Conlon JA, Mather TN, Tanner P, et al. Efficacy of a nonadjuvanted, outer surface protein A, recombinant vaccine in dogs after challenge by ticks naturally infected with Borrelia burgdorferi. Vet Ther 2000; 1(2):96107. 10. Levy SA, Lissman BA, Ficke CM. Performance of a Borrelia burgdorferi bacterin in borreliosis-endemic areas. JAVMA 1993; 202(11):18341838. 11. Hebert D, Eschner A. Seroprevalence of Borrelia burgdorferispecific C6 antibody in dogs before and after implementation of a nonadjuvanted recombinant outer surface protein A vaccine in a Rhode Island small animal clinic. Vet Ther 2010; 11(3). 12. Personal communication with Jody Sandler, DVM, Director of Veterinary Services, Guiding Eyes for the Blind, Yorktown, New York. 13. Littman MP, Goldstein RE, Labato MA, et al. ACVIM small animal consensus statement on Lyme disease in dogs: Diagnosis, treatment, and prevention. J Vet Intern Med 2006; 20(2):422-434. 14. Goldstein RE, Atwater DZ. Serologic and circulating immune complex analysis in dogs naturally infected with Borrelia burgdorferi (abstract). ACVIM Forum Proc 2006. 15. Goldstein RE, Atwater DZ. Serology and circulating immune complexes in dogs naturally infected with Borrelia burgdorferi before and after doxycycline therapy (abstract). ACVIM Forum Proc 2006.