Feline Infectious THANK YOU! Diseases Thanks to sponsorship from Merial, the makers of PUREVAX® vaccines!

Introduction Introduction

Garret Pachtinger, VMD, DACVECC Justine A. Lee, DVM, DACVECC, DABT COO, VETgirl CEO, VETgirl

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2 Introduction Feline Infectious Diseases • General vaccine immunology • Vaccine Protocols Alice M. Wolf, DVM, • Panleukopenia – Parvovirus DACVIM, DABVP • URI Agents: • Herpesvirus, Calicivirus • Influenza? • Coronavirus (FIP) • FeLV • FIV

General Immunology General Immunology • Serologic “Protective • Should I/Can I use antibody Immunity” titer testing to determine • Relevant for pediatric patients without active the immune status of my immunity patient? • Only Cornell has challenge studies • Mostly irrelevant for actively immunized animals

General Immunology General Immunology • Ab titers don’t always • Ab testing ignores: correlate with protection in • Memory cells that regenerate actively immunized animals: protection within hours • If titer is high: Usually supports • CMI protection • CMI most important for • But Ab makes some diseases some diseases: worse: • Retrovirus (FeLV) • Coronavirus (FIP) • Lentivirus (FIV) • Calicivirus?

3 General Immunology General Immunology • I vaccinated my patient why did it… • Still develop clinical signs of disease? • Become a chronic carrier of the disease? • Sterilizing vs Non- Sterilizing immunity Sterilizing Immunity

General Immunology Feline Vaccination Guidelines • American Association of Feline Practitioners (AAFP) • First guidelines – 1998

Non-sterilizing • Last revision - 2013 Vaccine

Non-Sterilizing Immunity

Feline Vaccination Vaccine-associated Guidelines Sarcoma • World Small Animal VMA • Second revision – 2016 • European Advisory Board on Diseases (ABCD) 8 yo, SF Persian • Vaccines – 2009 • ISS – Prevention/Mgmt - 2015 Photo credit: Dr. Jeff Chalkey

4 Feline Vaccination Feline Vaccination Schedule Guidelines • Kittens Core: • NON-Core Vaccines: • 8-12-16 wks or 6-9-12-16 wks • FeLV – adult • Repeat FVRCP – Year 1 • Intranasal URI (Herpes/Calici) • No more often than q3years • Chlamydia (Chlamydophila) thereafter • Bordetella • RV as labeled • FIP • FeLV – Year 1 then ?

What is a Vaccine VAS – What is it? Adjuvant? • • Chemical additive used to tumor at an enhance the immunologic injection site • Thought to be response to killed antigens caused by • One of the ways that they chronic injection work is by creating chronic site inflammation injection-site inflammation

Role of Inflammation in Oncogenesis VAS • But isn’t it just the genetics of • PubMed search: the cat? • Inflammation Induction Cancer • Doesn’t explain the appearance of this • 2800+ entries problem worldwide at the same time • Other veterinary examples: • Post-traumatic Ocular Sarcoma – Cats • May be some genetic susceptibility to • Spirocerca dog inflammation-induced cancer in cats • Bone plates • BUT we can’t control the genetics of • TPLO (implants) the cat!!

5 VAS VAS • WSAVA (2016) • We can control how much inflammation we create! • “Non-adjuvanted vaccines should be administered to cats wherever possible.” • Use less inflammatory products: • AAFP (2006) • ABCD – European Advisory Board on Cat Diseases (2015) • Vaccination should be performed as necessary but as infrequently as • “Non-adjuvanted, modified live or possible recombinant vaccines should be selected in preference to adjuvanted vaccines.”

Risk Management Risk Management • Wilcock et al: Can Vet J: 2012 • Wilcock et al: Can Vet J: 2012 • “The only proven cause for injection site sarcomas in cats is prior administration of • “… the interval between vaccine a killed, adjuvanted vaccine. Rabies and leukemia vaccines are the only ones with administration and detection of a solid causal associations. Claims implicating other agents such as sarcoma may be as short as 4 lufenuron or microchips are months or as long as 13 to 15 unsubstantiated because previous vaccination in that same location could years.” not be ruled out.”

Feline Parvovirus Risk Management (Panleukopenia) • Srivastav: JAVMA Sep 1, 2012, 595-602 • Do cats become infected or • “…Results consistently showed that case (VAS) cats were significantly LESS likely to ill from Canine Parvovirus? have received recombinant vaccines than inactivated vaccines; ORs from regression • If Yes… analyses equaled 0.1, with 95% confidence • What are the implications for intervals ranging from 0 to 0.4 and 0 to 0.7 my patients? depending on control group and time period of exposure used.” • For my practice?

6 Feline Parvovirus Feline Parvovirus (Panleukopenia) (Panleukopenia) • CPV- can infect cats: • Practical implications: • Clinical disease - rare • Asymptomatic shedding – PCR • FPV vaccine protects cats feces 2a or 2b (2011) from clinical CPV disease • 32% of healthy cats in Feline-only shelter • Don’t house CPV-dogs in the • 40% of healthy cats in Mixed shelter cat ward? • NO FPV isolated • NO CPV from dogs • Don’t house cats with • NO CPV in environment susceptible puppies? • May shed for 4-6 weeks

URI Agents URI Agents Feline Herpesvirus 1, Feline Calicivirus Feline Herpesvirus 1, Feline Calicivirus • Why do my URI-vaccinated • URI Vaccines only establish patients still show clinical URI Non-sterilizing immunity signs? • Clinical signs reduced, not • How can I prevent early age URI eliminated infection in my patients? • Don’t prevent chronic carriage • Would more frequent vaccination • Don’t prevent shedding provide better protection?

URI Agents URI Agents Feline Herpesvirus 1, Feline Calicivirus Feline Herpesvirus 1, Feline Calicivirus • Protection does wane over time • Early age infection however: • IN vaccines may be helpful in • Number of clinically affected cats high density environments and severity of signs in challenged cats not significantly different weeks • Maternal Ab persistence: to years (3 to 7.5) post-vaccination • Blocking of active immune • Shedding post-challenge is less in response to parenteral vaccines more recently vaccinated cats beyond 12 weeks of age

7 URI Agents URI Agents Feline Herpesvirus 1, Feline Calicivirus Feline Calicivirus • High asymptomatic carriage rates in the population (in spite of • Calicivirus most problematic vaccination): for protection: • HHP: ~20-30% • Plethora of antigenic variants • Cattery cats/Multiple cat environments: • Plasticity of virus • Up to 80% + for either or both • Emergence of new variants • Recrudescence of clinical signs • Arthrotropic, Hypervirulent variants • Stress, etc. • Especially Herpes: Eye, etc.

Feline Calicivirus Feline Calicivirus • Classical URI disease: • Fever • Oral ulcers • Oculo/nasal discharge • Rarely lower URI signs

Feline Calicivirus Feline Calicivirus • Common chronic manifestations: • Common chronic manifestations: • Gingivitis/stomatitis • Super eruption of teeth

8 Calicivirus Calicivirus Uncommon: Skin Lesions

Virulent Calicivirus Feline Calicivirus • It is NOT a new disease • It is NOT a disease of • What about virulent household pets systemic calicivirus? • It IS a very RARE disease of group-housed cats with less • aka: “Killer Calicivirus” than ideal husbandry • Shelters • Catteries • Rescues • Hoarders, etc.

Virulent Calicivirus • Each isolate genetically Virulent Calicivirus unique: • High fever (105 – 106 F) • Spontaneous mutation from circulating calicivirus in the • URI signs population • Edema of face, feet, trunk • No common mutation to • Necrosis of tissue in edematous areas explain virulence • Can be associated with severe • Single virus strain in vaccine will not pneumonia, hepatitis, pancreatitis, protect against other mutants enteritis, DIC, death

9 Virulent Calicivirus

Tissue necrosis

Virulent Calicivirus Virulent Calicivirus

Photo: Dr. Thompson - VIN

Virulent Calicivirus • Bottom line: Feline Herpesvirus 1 • Not a concern for average household pets • Use excellent isolation techniques for ALL hospitalized URI cats • Especially if from high density environments • Or treat all URI cats as outpatients

10 Feline Herpesvirus 1 Feline Herpesvirus 1 Chronic Ocular Complications • Chronic complications: • Ocular lesions • Recurring conjunctivitis, ulcers • Eosinophilic keratitis • Corneal sequestrum

Feline Herpesvirus 1 • Less common: SKIN LESIONS Feline Herpesvirus 1 • Ulcerated areas in the haired skin of: • Major clinical DDX: • Nasal planum • Mosquito Hypersensitivity • Head, face, or ears • Feet • Eosinophilic granuloma • Ventrum complex • Often in areas in contact with • lacrimal or salivary secretions • Allergy

Feline Herpesvirus 1 Feline Herpesvirus 1 • Microscopic: • Special diagnostic tools: • Ulceration and necrosis • Immunohistochemistry • Inflammatory infiltrate • PCR on tissue contains many eosinophils • Intranuclear herpesvirus • Serology or PCR of oral inclusions only on swabs are not diagnostic histopathology • Many cats carry FHV-1

11 Feline Herpesvirus 1 Feline Herpesvirus 1

Herpesvirus Herpesvirus dermatitis Mosquito Hypersensitivity SCC

Feline Herpesvirus 1 Feline Herpesvirus 1

Cryptococcus Herpesvirus or EGC? Photo credit - Dr. Abramo - VIN

FHV-1 Feline Herpesvirus 1

Dr. McElroy - VIN Dr. Gotthelf - VIN Dr. Lindquist - VIN

12 Feline Herpesvirus 1 Feline Herpesvirus 1

Confirmed Herpes by BX DDX from “Dirty Faced Persian” Dr. Zimmerman - VIN Dr. Wilkie - VIN Dr. Ortunez - VIN Dr. Povar - VIN

Feline Herpesvirus 1 Feline Herpesvirus 1 • Diagnosis: • Treatment: • L-lysine • Immunohistochemistry • Not harmful but questionably • PCR on tissue useful • Confirmed DX is important • IFNα ? because steroids will worsen • 30 – 30,000 U PO q24h the condition • 250-500K U SQ 3X/week for 6 weeks

Feline Herpesvirus 1 Do Cats get Influenza? • Treatment: • Acyclovir • Not Canine (H3N2, H3N8) • Not effective against FHV-1 • Famciclovir • Not Equine • 90 mg/kg PO q8-12h (125 mg tabs) • Not approved for cats • Active metabolite penciclovir in tears • Imiquimod (Aldara®) 5% Cream • Topical immunomodulatory - Herpes • Apply topically to lesions q48-72h

13 Do Cats get Influenza? Do Cats get Influenza?

• Outbreak of Avian • Source of the Influenza H7N2 outbreak/infection unknown • Shelter in NYC • No further cases reported • Dec 2016 – Jan 2017 since this outbreak • One human infected

Feline Coronavirus Feline Coronavirus Feline Infectious Peritonitis (FIP) Feline Infectious Peritonitis (FIP) • Ubiquity of FECV carriage: • Why do I see FIP in an • ~30% of HHP isolated household cat? • 80-90% of Cattery, Shelter cats • Spontaneous pathogenic • Why don’t we have an mutations in carrier cats effective “FIP” vaccine? • Replication and emergence of pathogenic mutants is enhanced • What’s new in FIP by high carriage rates, stress, crowding, poor husbandry, poor treatment? nutrition, etc.

Feline Coronavirus Feline Coronavirus Feline Infectious Peritonitis (FIP) Feline Infectious Peritonitis (FIP) • Other influences: • Genetic predisposition • Macrophage receptors for coronavirus • Concurrent diseases • FeLV • FIV • Age

14 Feline Coronavirus Feline Coronavirus Feline Infectious Peritonitis (FIP) Feline Infectious Peritonitis (FIP)

• High Ab, little CMI • No common mutation • Effusive disease accounts for virulence • Ab, Partial CMI • No FIP-specific test • Non-effusive disease • At this time, no “target” has been identified that can • Ab?, Strong CMI specifically ID “FIP” • No disease? coronavirus

Feline Coronavirus Feline Coronavirus Feline Infectious Peritonitis (FIP) Feline Infectious Peritonitis (FIP)

• FIP Vaccine • Best preventative strategies • Conventional vaccine strategies • Prevent intestinal are ineffective colonization by coronavirus • Current FIP vaccine not effective • Vaccine that stimulates • Shelter study in Germany • May sensitize to infection (Cornell strong CMI with little to no studies – Fred Scott) humoral response • Not recommended • Recombinants and other genetically engineered vaccines?

Feline Coronavirus Feline Coronavirus Feline Infectious Peritonitis (FIP) Feline Infectious Peritonitis (FIP)

• New frontiers in • PPI treatment: • Commercially available • PPI • Approved to treat FVR • Polyprenyl immunostimulant • NOT a cure • 3CL protease inhibitor • May > survival time and QOL GC376

15 Feline Coronavirus Feline Coronavirus Feline Infectious Peritonitis (FIP) Feline Infectious Peritonitis (FIP)

• 3CL protease inhibitor • 3CL protease inhibitor GC376 GC376 • Drs. Pedersen, Kim, and Chang • Experimental studies • Inhibits protease enzyme • Clinical trials • Blocks virus from infecting • Not commercially available more cells and replicating • Looking for manufacturer

Feline Leukemia Virus (FeLV) FeLV § Type C oncornavirus in the retrovirus group. § Horizontal and vertical transmisison. § A disease of friendly cats, close, intimate contact needed for transmission.

Feline Leukemia Virus Feline Leukemia Virus (FeLV) (FeLV) § Testing conundrums: § Which cats to test? • Which cats should be tested and • AAFP: “The retrovirus status of when? all cats should be known.” • Which test should be used for • Pre-vaccination of kittens/cats screening? • Sick cats • Which test should be used for • Routine health screening? confirmation?

16 Feline Leukemia Virus Feline Leukemia Virus (FeLV) (FeLV) § ELISA (enzyme-linked § IFA test immunosorbent assay) • Looks for viral antigen in cells • Best for screening due to speed, • Cannot be performed in-house ease of use in-house, and • Delay in results sensitivity. • Substrates – submit air dried slides: • Of the in-house tests, the IDEXX o Peripheral blood (WBC, ) SNAP® appears to have the highest o sensitivity and specificity (2016)

Feline Leukemia Virus Feline Leukemia Virus (FeLV) (FeLV) § PCR test § Incidence in the population • Detects minute amounts of viral protein must be taken into account o Excellent correlation with ELISA results when interpreting FeLV test • Cannot be performed in-house results • Delay in results • Substrates § Healthy cats: 1-3% o Peripheral blood § Sick cats: up to 30% o Bone marrow

SPINS and SNOUTS Test Reliability § SPecificity: Positive test rules in § If the incidence in the DX population is 1%: • Specificity of 98% • You will get 3 positives/100 cats • Test 100 positives cats, 98 will test tested positive o ONE true positive § SeNsitivity: Neg test rules out DX o TWO false positives • Sensitivity of 98% • RELIABILITY: 33% • Test 100 negative cats, 98 will test § Recheck positive results in negative low risk animals!

17 Feline Leukemia Virus Feline Leukemia Virus (FeLV) Vaccination § False positive tests? § Which FeLV vaccine is the best? • “Weak positives” often false § Field efficacy is impossible to positives determine: o Retest with serum, not whole blood • Incidence of FeLV in population is • ELISA positives should be low confirmed with an IFA or PCR • Effect of age-related resistance testing • Difficulty in collecting data

Feline Leukemia Virus Feline Leukemia Virus (FeLV) Vaccination § Age-related resistance § Difficulty comparing studies • < 6 weeks of age ~ 100% susceptible • Apples and Oranges • > 1 year of age <10% susceptible § Read materials/methods of each publication • Age of cats • Challenge model • Artificial immunosuppression

Feline Leukemia Virus Feline Leukemia Virus Vaccination Vaccination § Newest comparative FeLV vaccine § Newest comparative FeLV vaccine study (Biologicals: In press: 2017): study (2017): • Recombinant FeLV (non-adjuvanted) • No statistically significant • Two inactivated, adjuvanted FeLV differences among the vaccines’ o Subjects: Kittens 9-10 weeks of age ability to protect against persistent viremia. o Identical laboratory conditions and mimicking natural challenge • I recommend using the least reactive (non-adjuvanted) vaccine

18 Feline Leukemia Virus Feline Leukemia Virus Vaccination Vaccination § Which cats should be § Because of high kitten vaccinated against FeLV? susceptibility: • Kittens are the most susceptible • All feline vaccination guidelines recommend universal kittenhood group vaccination • In nature most are infected from § Vaccination of adults after 1 the dam in-utero or during the year of age depends on risk nursing period assessment.

Feline Immunodeficiency Feline Immunodeficiency Virus Virus • FIV is a relatively benign disease in most cats • Only 3 viral isolates (of all those isolated) consistently cause fatal immunodeficiency disease under experimental conditions • Two clade A (one of which is Petaluma), one clade C

Feline Immunodeficiency Virus Feline Immunodeficiency Virus • Transmission in stable • FIV testing households is rare • Screening test: ELISA • FIV is a disease of unfriendly • Detects antibody against p24 cats • Confirmatory test: Western • Bite wound Blot transmission • Positive result requires at least 3 bands of antibody identity to different FIV antigens

19 Feline Immunodeficiency Virus Feline Immunodeficiency Virus • How do I differentiate truly • FIV vaccine? FIV-infected cats from those that may have been • No longer a question… • FIV vaccine is no longer FIV vaccinated? manufactured or distributed in • Witness® FeLV/FIV North America • Anigen Rapid FeLV/FIV • Ineffective (UK study) • Do not detect vaccine-Ab • Sensitized cats to infection when positive cats challenged

Feline Immunodeficiency Virus FIV Vaccine Challenges • If it was easy to protect • Genetic diversity of FIVs against FIV, we would have • Present and increasing had an effective HIV • Among/between clades vaccine long before now! • Viral envelope proteins • FIV used as model in HIV • Target for virus neutralization studies • Highly variable and changing • Billions of $$ in research to date

Feline Immunodeficiency Virus Questions?

20 THANK YOU! VETgirl Thanks to sponsorship from Merial, the makers of PUREVAX® vaccines!

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