Canine Adenovirus Type 2 Vaccination

The canine adenoviruses consist of 2 predominant serotypes, CAV-1 and CAV-2. Canine adenovirus type 2 (CAV-2) is a causative agent of canine infectious respiratory disease (CIRD), a syndrome also called canine infectious tracheobronchitis or kennel cough. Infection is often subclinical but can result in respiratory presentations ranging from mild cough to pneumonia, with rare reports of neurologic and enteric signs.^1,2 While closely related, CAV-2 is genetically distinct from canine adenovirus type 1 (CAV-1), the causative agent of infectious canine hepatitis. Vaccination against CAV-2 is effective at preventing disease caused by both CAV-1 and CAV-2 and renders infection rare in vaccinated populations.³

Pathophysiology of CAV-2

CAV-2 is a double-stranded, nonenveloped DNA virus that belongs to the family Adenoviridae. It displays distinct tissue binding receptors for respiratory epithelium throughout the upper respiratory tract, bronchi, alveoli, and associated lymph nodes, with lesser affinity for stomach and intestinal epithelium;^2,4 in contrast, CAV-1 preferentially targets hepatic, renal, and vascular tissue. Transmission of CAV-2 is oronasal, with rapid replication in the surface cells of the upper respiratory tract, mucous cells of the trachea and bronchi, nonciliated bronchiolar epithelial cells, and type II pneumonocytes. Virus is detectable and tissue damage occurs in the first 3 to 6 days of infection; viral antigen disappears by approximately 9 days after infection. Initial viral tissue injury increases the risk of secondary bacterial infection and continued clinical disease.⁵ The most common bacterial copathogens include Mycoplasma canis, Mycoplasma cynos, Bordetella bronchiseptica, and Streptococcus equi subspecies zooepidemicus.^3,6

Prevalence estimates for CAV-2 vary among studies and countries depending on vaccination and ownership status of the sampled populations. Distribution is worldwide, with lack of owner and lack of previous vaccination noted as the main risk factors for infection.^3,5,7 A study of clinically healthy dogs admitted to animal shelters in regions across the United States found that CAV-2 was the most commonly detected respiratory virus with a 12.5% prevalence.⁸ 

Adenovirus genotypes are generally species specific and cause subclinical infection and a variety of clinical disease presentations across mammalian (including human), reptile, avian, and fish species. Many wild canid species are susceptible to CAV-1 and CAV-2. Although there is evidence of some adenovirus genotypes spreading between humans and nonhuman primates as well as other species, including cats, CAV-1 and CAV-2 are not considered to be zoonotic. Adenoviruses are highlighted as a human health threat to monitor due to their wide species range and mutation potential.^9,10

Diagnosis of CAV-2

Polymerase chain reaction (PCR) analysis of upper respiratory tract swab samples is the standard diagnostic test. Since peak viral replication occurs 3 to 6 days after infection and virus may not be detectable by 9 days after infection, sampling should be performed as soon as possible after onset of clinical illness.¹¹ Reference laboratories provide direction regarding the preferred sampling site. 

A primary limitation of PCR is that recent vaccination can produce a positive result that is not clinically significant. In a research context, puppies tested positive for CAV-2 on PCR testing for up to 21 days after vaccination with a modified live virus (MLV) vaccine despite not showing clinical signs. Therefore, it is important to consider recent vaccination and presence of clinical signs to support management decisions when interpreting PCR results.¹²

Clinical Management of CAV-2

Many CAV-2 infections are subclinical and require no treatment. The primary risk factors for infection and progression to clinical disease are lack of vaccination and co-infection with other viruses. While population density in shelter and kennel environments can increase risk of transmission and co-infection of respiratory pathogens, privately owned dogs are considered to be a reservoir of susceptibility and subclinical carriers.⁷ As a nonenveloped virus, CAV-2 can survive on surfaces for at least 7 days and requires selection of a disinfectant product with appropriate efficacy for facility cleaning.³

When present, clinical signs of uncomplicated infection with CAV-2 are typically indistinguishable from those of other causes of CIRD and include cough due to laryngotracheitis, fever, mucopurulent nasal and ocular discharge, lethargy, and weight loss. Supportive care is the preferred treatment for primary viral infections that last fewer than 10 days without appetite loss or lethargy. Expectorant medications are not recommended. Antitussives can be used for temporary reduction of a dry cough but are contraindicated with a productive cough as they increase risk of secondary bacterial infection.¹³ Antibiotic therapy is indicated after 10 days of clinical illness or if inappetence, lethargy, or fever are noted in addition to mucopurulent discharge. Doxycycline for 7 to 10 days is the most commonly recommended first-line empiric antibiotic choice.⁶

Pneumonia is the most common and severe complication of CAV-2 infection, caused by increased tissue adhesion with secondary opportunistic bacteria. Clinical indications of progression to pneumonia include crackles or wheezes on thoracic auscultation, fever, and tachypnea. Diagnostics to assess severity of disease and guide treatment may include thoracic radiographs showing alveolar lung disease, complete blood count, and culture and sensitivity testing of transtracheal or bronchoalveolar lavage samples. Doxycycline can be an appropriate empiric antibiotic choice for mild presentations of pneumonia when culture and sensitivity testing is not possible. 

Severe pneumonia with evidence of sepsis, including hypoglycemia and injected mucous membranes, indicates the need for multimodal parenteral therapy, such as a fluroquinolone in combination with an antibiotic with a gram-positive and anaerobic spectrum, until culture and sensitivity results can be obtained.⁶ Neurologic and gastrointestinal signs associated with CAV-2 have been reported but are considered rare.^1,2

Antibody Testing for CAV-2

Antibody testing can be conducted by obtaining titers through virus neutralization at a diagnostic laboratory or by using commercially available enzyme-linked immunosorbent assay (ELISA) point-of-care test kits. Antibody testing is used for verifying response after initial vaccination, evaluating need for revaccination, and assessing risk levels during outbreak management. Limitations of titer testing include interpretation challenges with low quantified titers, since immunological memory cells can replicate at the time of infection; uncertainty regarding cross-protection against different CAV-2 strains; and performance concerns for point-of-care test kits in independent evaluation.¹⁴ While titers can aid in assessing a patient’s risk level for CAV-1 and CAV-2 in dense population settings or for individuals with a problematic vaccine history, caution should be used when attempting to use titers in lieu of vaccination. 

Vaccination for CAV-2

Vaccination is the primary method for prevention of both CAV-2 and CAV-1 disease. The most widely used and effective vaccine for both types of canine adenovirus is an MLV vaccine containing CAV-2. The MLV CAV-2 vaccine provides cross-protection against CAV-1 and therefore also prevents infectious canine hepatitis. Morbidity and mortality are significantly decreased by vaccination, although reduced viral colonization is still possible in vaccinated dogs.⁶ 

The current vaccine protocol recommendation is to administer the MLV CAV-2 vaccine beginning at 6 weeks of age and then at 2- to 4-week intervals until 16 to 20 weeks of age, depending on exposure risk and in consideration of potential interference from maternally derived antibodies. A second vaccine 2 to 4 weeks after the first is recommended for dogs older than 16 weeks at the time of initial vaccination. Another dose should be given within a year after the last vaccine in the initial series and then at 3-year intervals thereafter.¹⁵

Standard commercially available products that contain MLV CAV-2 are labeled for subcutaneous administration and are often formulated with various combinations of canine distemper virus, canine parvovirus, parainfluenza virus, and Leptospira vaccine components. Research evidence has shown strong antibody response to support concurrent administration of these vaccine components as well as the rabies vaccine.¹⁶ The variability in duration of immunity supports the recommendation for complete initial vaccination and triennial revaccination.^14,17 In a high-density setting such as an animal shelter, vaccination at intake to achieve vaccination for 90% of the facility’s population is critical to reducing CIRD clinical signs.¹⁸ 

Serious adverse events are considered uncommon with the MLV CAV-2 vaccine. In one study, mild, self-limiting reactions to the vaccine were noted in 36% of dogs and included lethargy, lymphadenopathy, and gastroenteritis, with local swelling and pain reported in one dog.¹⁴ Hypersensitivity reactions and, rarely, immune-mediated hemolytic anemia are reported as with other vaccines,¹⁷ although the incidence directly related to the CAV-2 component is unclear. Historically, vaccines containing the CAV-1 virus were also effective against both virus types but were associated with more serious adverse reactions, including interstitial nephritis and corneal edema, commonly referred to as “blue eye”; they are no longer widely used.¹⁴ 

Conclusion

CAV-2 is endemic in healthy dog populations worldwide and is a significant viral cause of CIRD, particularly when combined with viral or bacterial co-infections. Vaccination with an MLV vaccine is critical for reduction of clinical signs and to prevent canine infectious hepatitis.