Rabies
Current Preventive Strategies
Susan M. Moore, PhD, MS, BS, HCLD(ABB), MT(ASCP)SBB
INTRODUCTION
As difficult as it is to imagine, the presence of rabid dogs in cities and the countryside
was of great concern after World War II in the United States.1 The urgency of the problem led to the creation of the National Rabies Program, which began operations in
1947. The program consisted of 3 main pillars: (1) education, (2) dog control, and (3)
vaccination. Relatively quickly, control of urban rabies epizootics was achieved by
the early 1950s.2 This same program was endorsed by the World Health Organization
(WHO)3 and resulted in successful rabies control programs in places such as Taiwan,
Malaya, and Hong Kong. As early as 1983, the idea of a world rabies program was discussed by the WHO, including the cost of such a large endeavor.4 Thirty-two years
later, in 2015, after years of separate efforts by veterinary health and human health organizations, a joint declaration to eliminate human deaths caused by dog-mediated
rabies by the year 2030 was made by WHO, the World Organization for Animal Health
(OIE), the Food and Agriculture Organization of the United Nations, and the Global Alliance for Rabies Control.5 The time to invest in ending human rabies death had arrived:
rabies is a model infectious disease for the One Health approach; several pilot efforts
at dog rabies control have provided proof of concept; and the United Nation’s sustainable development Goal Three targets ending epidemics of neglected tropical diseases
(of which rabies is one) by 2030. Using a blueprint for each country that essentially
The author has nothing to disclose.
Veterinary Diagnostic Laboratory, Kansas State University, Manhattan, KS 66502, USA
E-mail address: smoore@vet.k-state.edu
KEYWORDS
Rabies Serology Diagnostics Disease surveillance Vaccination
KEY POINTS
Rabies control regulations have provided effective protection to humans and pets; however, in some areas the lack of updates in response to evolving risk situations occurs.
Pet owner concerns about vaccination have led to the consideration of alterative vaccine
schedules.
Use of rabies serology in lieu of current recommended booster vaccination, while supported by studies, remains problematic.
Vet Clin Small Anim - (2019) -–-
https://doi.org/10.1016/j.cvsm.2019.02.014 vetsmall.theclinics.com
0195-5616/19/ª 2019 Elsevier Inc. All rights reserved.
mimics the early 3-pillar plan of education, dog control, and vaccination, the effort is in
place.6 In countries and regions that have achieved and sustained rabies control in
dogs, epizootics of rabies involving other animals have become the focus. This
does not mean the National Rabies Program is ended; it expands to include control
of wildlife rabies, constant surveillance, and strict import regulations. Education,
dog control, and vaccination is still needed to protect human from rabies exposure.
The basic components of rabies control are as follows:
Vaccinate pets: 70% vaccine coverage is the minimum required.
Have policies and protocols for treatment of exposed pets and livestock.
Have policies and procedures for animals that bite humans.
Provide rabies diagnostic testing.
Provide preexposure and postexposure vaccination for humans.
Provide education and training for bite prevention, rabies exposure prevention,
and rabies prophylaxis.
Control stray dog and cat populations.
Perform surveillance for rabies and maintain current epidemiology maps and
information.
Control rabies in wildlife.
LEGAL AND REGULATORY CONTROL
As a global model One Health infectious disease, rabies control and prevention is
guided by the WHO and the OIE.7,8 In the United States, the Compendium for Animal
Rabies Control and Prevention, which contains recommendations of the National Association of State Public Health Veterinarians, is updated regularly by consideration of
new/current data on rabies epidemiology, vaccines, and knowledge of the disease.
For example, in 2016 the Compendium was updated to allow postexposure management of dogs, cats, and ferrets that were previously rabies-vaccinated but out of date,
the same as currently vaccinated pets (Table 1).9 This change was in response to a
study that demonstrated there was no significant difference in the antibody response
to booster vaccination in currently vaccinated and out-of-date pets.10
Unfortunately, state and local laws and regulations, for which the Compendium recommendations act as a guide, are not always reviewed and updated in a timely
Table 1
Recommendations of the National Association of State Public Health Veterinarians for rabies
postexposure management of dogs and cats based on their vaccination status from the 2016
of the Compendium for Animals Rabies Control and Prevention guidelines
Vaccination
Status Type of Confinement Vaccinate
Current Observation/Owner’s control for 45 d Booster
Never vaccinated A. None: euthanize NA
B. 4 mo strict quarantine: dogs and
cats 6 mo strict quarantine: ferrets
Vaccinate (<96 2="" 45="" 4="" a.="" a="" analyzed="" and="" are="" as="" b.="" based="" be="" been="" best="" between="" booster="" c.="" can="" cats="" certainly="" control="" current="" d="" da="" data="" date="" differences="" differing="" documented="" dogs="" epidemiology="" euthanize="" evaluation="" expected.="" exposure="" for="" from="" further="" h="" have="" however="" if="" in="" is="" it="" laws="" likely="" manner.="" mo="" moore="" na="" nbsp="" none:="" not="" observation="" obtained.="" of="" on="" other="" out="" outside="" p="" place.="" populations="" practices="" prior="" proof="" provided="" quarantine:="" quarantine="" rabies="" rates="" reasons="" regulations="" resources="" response="" results="" reviewed="" s="" serologic="" states.="" states="" strict="" surveillance="" the="" there="" this="" to="" undocumented="" updated="" updates="" vaccinate="" vaccination="" valid="" variables.="" well="" within="" wner="" years="">ASSESSING THE RISK OF RABIES
Every year the rabies case data are analyzed and reported by the Rabies Section at the
Centers for Disease Control and Prevention in the Journal of the American Veterinary
Medical Association.
11 This information has been used to track and illustrate trends in
the spread of rabies variants. Rabies variants are viral strains that circulate in reservoir
species to which the virus has adapted. Vector species are mammals that are susceptible to rabies infection and are able to infect other susceptible individuals. Rabies is an
RNA virus, making it susceptible to mutation and thus adaption into vector species;
surveillance is meant to identify such events. An example of rabies virus crossspecies transmission occurred when positive rabies cases in skunks were reported
in an area of Arizona in which skunk strain of rabies had not previously been identified.12 Viral sequencing of the positive cases determined the variant had passed
from bats in the area and adapted to skunks. This demonstrates that just because
an area is free of terrestrial rabies, it is not absolutely free of the risk of rabies exposure
to pets and domestic animals, and hence humans. Another point to consider when
assessing rabies risk in an area or region, is the “discovery” of rabies in the ferret
badger population in Taiwan. Taiwan was believed to be rabies-free since 1961.13
Further study determined that rabies had been circulating in this population for
years.14 Poor surveillance for rabies can create this peril by not being aware of or controlling rabies exposures from reservoir species. Both examples illustrate the key point
that rabies control measures, including education and surveillance, must be sufficient
and sustainable. In the Americas, all rabies variants are within the classic rabies lyssavirus species. However, companion animals travel with their owners, sometimes to
areas of the world in which other lyssavirus species are present. Rabies vaccine
covers many of the other lyssavirus species in phylogroup I, but those in phylogroups
II and III are not.15
PREVENTING INTRODUCTION INTO RABIES-FREE AREAS
Pet owners have come to view their pets as family members, so much so that pet
travel is a thriving industry. When pets travel from rabies-endemic areas into rabiesfree areas, it is of primary importance that they are not incubating rabies, thereby risking the introduction of rabies into a susceptible population. The incubation period for
rabies in dogs and cats is reported to be approximately 4 months.9 In the past, pets
traveling or moving to rabies-free areas were subjected to long quarantines periods,
established (in consideration of the incubation period) to ensure the pet was not incubating rabies. Starting in the 1990s, rabies-free areas instituted the use of rabies
serology as a surrogate for protection. A defined concentration (level) of rabies virus
neutralizing antibodies (RVNA), typically 0.5 IU/mL, demonstrates proof of adequate
response to rabies vaccination. Once adequate vaccine response is established, a
defined waiting period to account for a prevaccination infection and incubation
must be achieved before the pet can enter the rabies-free area. This procedure was
initiated by Hawaii in 1997 and now many rabies-free areas use similar procedures.16
Rabies 3
POSTVACCINATION SEROLOGY
Studies analyzing rabies antibody level data from pets have provided information about
the immune response to rabies vaccination in dogs and cats, by age, size, and number
of vaccines and timing of vaccination.17–21 The major factors correlated with a robust
rabies vaccine response are vaccination after maternal antibody has declined, small
size, more than 1 vaccination, and time interval between vaccination and blood draw
of 15 to 30 days. Evidence from previous studies has indicated that type of vaccine
(multivalent vs monovalent, and manufacturer) can also play a role.17,18Rabies serology
results from The Kansas State University (KSU) Rabies Laboratory from June 2015 to
July 2017 were used to evaluate factors affecting RVNA levels in dogs. Evaluation of
RVNA levels from 2 groups of pet dogs, that is, dogs being prepared to travel to
rabies-free areas (export group) and dogs whose owners prefer to check rabies titer
rather than revaccinate (core vaccine group), demonstrated that timing of blood sampling influences the probability that the pet was adequately vaccinated (Fig. 1). In the
export group, pet owners and their veterinarians were highly motivated to test at the
expected time interval to coincide with the peak response (15–30 days after vaccination). In this group, only 4.5% of the dogs had a result less than 0.5 IU/mL, compared
with 16.1% of in the core vaccine group. The proportion of dogs with inadequate rabies
antibody levels in the core vaccine group was similar to the proportion of dogs with
nonprotective antibody levels to other core vaccines, at 18%, 13%, and 14% for canine
distemper, canine adenovirus, and canine parvovirus, respectively.
A repeated observation in these studies is the higher probability of failure to mount
or sustain a robust RVNA response in young animals. The presence of maternal antibodies has been identified as one reason for this finding, due to interference by maternally derived rabies with vaccine antigen presentation to the immune system.22,23
However, the decline of the primary humoral immune response to below detectable
levels before 6 months of age is also a factor. Both duration and magnitude of
response is affected by the number of vaccinations administered.20 The influence of
age on the probability of inadequate response to rabies vaccination is consistent,
even when data are stratified by dog size. Results of rabies serology testing of
20,447 dogs being prepared for travel to rabies-free areas, performed at KSU Rabies
Laboratory from July 2016 to April 2017, demonstrated the influence of age by breed
size (Fig. 2). Breed size was defined by American Kennel Club standards. The largest
group that failed to respond to vaccination was younger than 2 years (48.5% <2 1.="" 19.5="" 1="" 2015="" 2017.="" 29.0="" 4="" 6="" a="" age="" an="" and="" antibody="" are="" areas.="" at="" be="" because="" being="" between="" booster="" brought="" challenge="" check="" combined="" compared="" considered="" core="" correlation="" could="" dogs="" export="" exposure.="" fig.="" findings="" first="" for="" from="" give="" has="" having="" in="" inadequate="" increase="" increased="" into="" july="" june="" know="" ksu="" level="" months="" moore="" nbsp="" of="" p="" performed="" pets="" positive="" practice="" prepared="" probability="" proportion="" providing="" question="" rabies-free="" rabies="" response="" risk="" rvna="" serology="" studies="" survival="" than="" that="" the="" these="" titer="" to="" until="" vaccination.="" vaccination="" vaccine="" waiting="" we="" with="" year="" years="" younger="">VACCINATION CONCERNS BY PET OWNERS AND VETERINARIANS
Rabies control in the United States has been so effective that the canine variant was
eliminated from the United States in 2007.25 This achievement is also a challenge for
maintaining a sufficient level of awareness of the continued risk of rabies exposure,
particularly lowering awareness of the importance of rabies vaccination by pet
owners. In addition, an increasing focus on the human-animal bond has changed
how pet vaccination is evaluated and consequently, is either valued or questioned.
Concerns regarding adverse reactions and immune modulation caused by vaccination
have increased among pet owners and some veterinarians, who have suggested the
use of smaller doses of rabies vaccine to potentially reduce reaction rates, and using
rabies serology to provide proof of immunity and thus waive routine booster vaccinations. The frequency of reactions to rabies vaccines has been evaluated by industry
groups and organizations. The following are potential vaccine adverse reactions in
dogs and cats according to the American Animal Hospital Association Canine Vaccine
Guidelines, 201726 and the American Association of Feline Practitioners, Feline Vaccination Advisory Panel Report, 2013,27 respectively:
Injection-site reactions
Allergic or immune-mediated reactions
Tumorigenesis
Vaccine-induced immunosuppression
Anaphylaxis
Injection-site sarcomas
A 2007 study of approximately 1.2 million dogs whose medical records were in a
large veterinary database reported that the rate of vaccine-associated adverse events
Fig. 2. Percentage of dogs with inadequate rabies vaccine response by age (in years) and
breed size group, from a data set of 20,447 dogs tested for rabies antibody at KSU from
July 2016 to April 2017.
Rabies 5
(VAAE) within 3 days of vaccination in d ogs was 38.2 of 10,000 dogs vaccinated.28 A
study of VAAE within 30 days of vaccination in almost 500,000 cats in the same database and performed by the same group reported a VAAE rate of 51.6 of 10,000 cats
vaccinated; 92.0% were diagnosed within 3 days after vaccination. Anaphylaxis
comprised 17 of 2560 total cases of feline VAAE (0.7%).29 These organizations recognize that adverse reactions are likely to be underreported by both veterinarians and pet
owners27 and that in veterinary medicine there is no requirement to report VAAE, either
known or suspected.26
RABIES VACCINE REGIMENS
Fear of vaccine adverse reaction/immune modulation or questioning the need for
vaccination among pet owners parallels the similar concerns for human vaccination
that has existed for many decades. It may be useful to compare rabies vaccines
and vaccine regimens for humans and pets for perspective. For humans who are at
increased risk of rabies exposure and thus rabies preexposure vaccinated with a series of 3 vaccinations,30 2 booster vaccines are given at day 0 and day 3 on exposure,
regardless of titer. Titer does not affect the recommendations for people because it is
absolutely necessary to stimulate an anamnestic response. This is to ensure (1) the
highest level of RVNA is present to neutralize the virus; and (2) that other immune system components are stimulated (T memory cells), to help with B-cell antibody production and cytokine responses, which alert immune effectors to the threat. For animals
that are preexposure vaccinated, after a known or suspected rabies exposure, regardless of titer, a single booster vaccine is given on day 0 (or as soon as seen by a veterinarian), for the same reasons as stated previously. One vaccine booster is
administered rather than 2, because to ensure effective prevention in humans for a
fatal disease such as rabies, no risk of understimulating the anamnestic response is
tolerated. However, for animals, protection from rabies is intended to prevent rabies
exposure to humans; thus, different standards, different regimens/policies are
applied. Humans who have had preexposure vaccination and continue to be at risk
of rabies exposure due to occupation or travel are recommended by the Advisory
Committee on Immunization Practices (ACIP) and WHO to have routine titer checks
to ensure an adequate level exists to ensure a fast, robust rise in immune defenses
on postexposure vaccinations, and to protect from unrecognized exposures.7,31 In
addition, humans who have been preexposure vaccinated are informed to recognize
rabies exposure and to seek postexposure treatment, including wound care, which
alone can reduce the chance of infection by up to 60%,32,33 whereas pets cannot.
Although rare, vaccinated pets have succumbed to rabies after exposure to rabid
animals.34,35
The dose of human rabies vaccine used is related to the antigenic content and the
route. Human rabies vaccines must provide 2.5 IU antigen by intramuscular (IM) injection, whether in 1 mL or in 0.5 mL of diluent. An intradermal (ID) dose uses a tenth of the
antigen in an IM dose and can be given for preexposure and postexposure rabies
vaccination. Although ID rabies vaccination is not approved in the United States, it
is recognized by the WHO. Some rabies ID regimens require multiple ID injections
per day at different sites on the body.7 Horses, cows, and pigs typically receive a
2-mL dose, and dogs and cats, 1 mL; the entire list of US-approved veterinary vaccines are listed in Compendium for Animals Rabies Control and Prevention.9 As
with human vaccines, all rabies vaccines must meet minimum standards for safety, efficacy, and immunogenicity. The Code of Federal Regulations (CFR) defines standard
requirements for both human and animal vaccines.36
6 Moore THE IMMUNE RESPONSE TO RABIES VACCINATION
Vaccines must contain sufficient antigen to induce an adequate immune response in
the target species that affords protection from infection, disease, or in some cases,
reduction in severity of disease. Vaccines induce immune responses based on amount
of antigen and the corresponding immune cell receptor availability and degree of
specificity (including avidity and affinity). Receptor specificity is controlled by the major histocompatibility complex (MHC), which is polygenic, meaning there is a great diversity of MHC genes and hence molecules within a species. MHC molecules on the
surface of immune cells take up, process, and present antigen to immune cells for the
induction immune response. Alongside the diversity of immunity induced by MHC
molecules, there is variation between animals in a population in terms of protective
response. A vaccine must show the ability to produce a robust and protective immune
response among representative animals of the intended species. The notion that size
of animal is the major factor in vaccine response, with larger animals mounting a lower
response than smaller animals for a defined antigenic dose, or that smaller animals
require a smaller dose is prevalent among those who fear the effects of vaccination.
The role of immune genetics and mechanisms of the immune response, as described
previously, argues against this. Moreover, further analysis of the KSU study of the
canine RVNA response (see Fig. 2), by breed and by size, indicated that breed also
influences the probability of mounting an adequate RVNA response to vaccination
(Fig. 3). In both the 10 breeds with the highest percentage of dogs with inadequate
RVNA (<0 .5="" 10="" 1="" 2016="" 2017.="" 20="" 3.="" 3="" 7="" a="" adults="" all="" alone.="" also="" although="" and="" antibody="" april="" are="" as="" associated="" associations="" at="" average="" bar="" based="" be="" been="" breed="" breeds="" by="" case.="" cats="" chart="" children="" colleagues="" data="" demonstrated="" difficult="" diluted="" displaying="" distribution="" dog="" dogs.="" dogs="" dose="" doses="" dosing="" each="" entire="" factor.="" fig.="" findings="" for="" from="" gene="" giant="" group="" groups="" has="" highest="" however="" human="" in="" inadequate="" indicating="" infants="" into="" is="" it="" iu="" july="" kennedy="" ksu="" large="" level="" levels.37="" lowest="" medium="" mhc="" ml="" moreover="" nbsp="" no="" not="" of="" on="" other="" p="" percentage.="" percentage="" pie="" rabies="" ranking="" receive="" recommend="" reduced="" represented.="" represented="" response.="" response="" result="" rvna="" same="" set="" shown="" size="" small="" some="" study.="" study="" supported="" tested="" that="" the="" there="" these="" this="" to="" toy="" vaccine.="" vaccine="" vaccines="" was="" were="" who="" with="" within="" would="">
TITER TESTING TO INFORM VACCINATION DECISIONS
One way to address concerns over vaccine adverse reactions/immune modulation is
allowance of RVNA titer checks in lieu of routine vaccination. Indeed, in general, revaccination of an animal already protected does not result in enhanced disease resistance. However, the main challenge for a particular disease or infection for which
vaccination is available is to provide proof of “already protected.” Peer-reviewed
data regarding proof of rabies protection afforded by vaccination, as well as the predictive ability of rabies serology results, is primarily obtained from published rabies
challenge studies. Per the CFR, studies for vaccine approval must demonstrate protection by survival of the challenged animals; included in the requirement is proof of
immunogenicity by the measurement of rabies antibody levels.36 The following list includes information from challenge studies publications,24,38,39 the 9 CFR 113.209,36
and the Compendium,9 regarding rabies vaccines:
Vaccines for dogs and cats: At least 86% to 87% of animals must survive challenge and at least 80% of unvaccinated controls must succumb to challenge.
Current rabies vaccines are licensed for 1 to 3 years.
Dogs and cats with rabies serology results greater than 0.5 IU/mL survive more
frequently than dogs and cats with results less than 0.5 IU/mL; there are almost
100% survival rates in animals with RVNA greater than 0.5 IU/mL.
There are a few reported animals with an RVNA result greater than 0.5 IU/mL that
succumbed to challenge.
Challenge studies require experimental challenge through the intracerebral route,
which is considered an extreme challenge route of exposure for pets.
Rabies serology methods have a precision (CV%) of 50% (or less), meaning an
RVNA level of 0.5 IU/mL could actually be 0.25 to 1.0 IU/mL in any given assay
run. Greater or lesser variability may occur between laboratories and assay
types.
The 0.5 IU/mL “adequate level” was identified as robust based on this knowledge. In
the conclusions made by Aubert38 in a 1992 publication presenting a comprehensive
review of challenge studies in dogs and cats, it was stated “The security of the protection constituted by this threshold [RVNA level] would be increased by the extent to
which it exceeds the level recognized as effective against experimental challenge in
cats and dogs 0.1 IU/mL and 0.2 IU/mL, respectively, measured by the RFFIT” (rapid
fluorescent focus inhibition test). Even before this study was published, a study by
Bunn and Ridpath24 (1984) analyzed the probability of survival by RFFIT level using
challenge study data and concluded that survival rate increased as RVNA level
increased up to approximately 1.0 IU/mL, with a survival probability of approximately
99% at level of 0.5 IU/mL. Whether these findings can be extrapolated to pets without
current vaccination status is the question at hand.
8 Moore
IMMUNOLOGIC PROTECTION IN THE FACE OF EXPOSURE
Currently, limited published studies provide rabies serology to correlate with survival
data in dogs and cats. A study by Lawson and Crawley40 provides some information.
The investigators challenged vaccinated dogs and cats at 5 and 4 years, respectively,
after vaccination and reported that 92% of dogs and 100% of cats survived; 54% of
dogs and 87% of cats had detectable RVNA before challenge. Assuming that immune
protection extends for an indeterminate period beyond the due date for a booster is
reasonable, based on immunologic principles. An argument supporting this idea is
that for human postexposure prophylaxis (PEP), a single dose (40 IU/kg bodyweight)
of heterologous antirabies serum was protective in combination with vaccination.41 In
the case of an unrecognized rabies exposure in a pet, it is assumed that stimulation of
memory immune cells to become effector cells would provide protection, rather than
vaccination. There is evidence of this kind of response in a report of a human organ
recipient of a rabies-infected liver, who survived even though their last rabies vaccination was many years previously,42 due to a robust protective anamnestic response.
However, this was a single case, and the outcome cannot be reliably generalized to
larger groups, as exposures and the probability of infection can vary considerably.32
PEPs and other protocols are based on the level of risk regulatory authorities and policy makers consider acceptable.
SEROLOGIC DATA TO DEMONSTRATE PROTECTION AGAINST RABIES
Based on the data from challenge studies, there is a valid argument for use of rabies
serology to estimate rabies protection. However, several critical parameters need to
be defined before confidently using rabies serology as a correlate of protection:
Definition of an adequate antibody response (correlation of protection level)
Significance of a rise or fall in antibody level
Method (assay used) of measurement (correlate with protection, with ample data)
Reported value: IU/mL or titer
Timing of blood sampling and how often is the level assessed
4 weeks after vaccination? Yearly? After exposure to rabies?
Will there be different acceptance levels based on timing of blood draws?
Approval for laboratories providing testing; routine proficiency testing required
for approval (as for rabies serology for pet travel and equine infectious anemia/
Coggins for horses).
In an article that attempted to define rabies antibody level as proof of protection in
different wildlife species using rabies serology results, few conclusions could be
drawn from a systematic review of published studies, due to the highly variable study
designs and results.39 Also, in this article, sets of serum samples from challenge
studies in dogs, foxes, skunks, raccoons, raccoon dogs, and mongooses were tested
using 2 types of assay: serum neutralization (RFFIT) and a blocking enzyme-linked
immunosorbent assay (ELISA). it was concluded that a level of 0.25 IU/mL and 40%
inhibition by RFFIT and ELISA, respectively, were reasonably associated with survival;
however, species differences were noted. Similarly, a study comparing RFFIT results
with indirect ELISA results for a human rabies vaccine trial demonstrated that results
from the assays were variously correlated by time since vaccination; results at day 14
were very poorly correlated, whereas results at day 90 had good correlation.43
Although there are studies that have demonstrated good correlation between serum
neutralization and ELISA techniques for rabies antibody measurement,44–46 it is
necessary to establish requirements by method validation, including diagnostic
Rabies 9
specificity and sensitivity, before approval of an assay for a specific use, such a proof
of adequate vaccine response in lieu of booster vaccination.47 PRACTICAL USE OF TITER TESTING
The use of serology for verification of rabies immunity should be reserved for wellvaccinated pets (dogs and cats that have received a primary vaccination, followed
by 1 or 2 boosters). Rabies titer checks in animals could also be used for prospective
serologic monitoring to help determine whether an animal has been previously vaccinated.9 In addition, they can be used if public health officials need to determine the risk
of an exposed pet becoming infected after a nonstandard postexposure treatment or
other unusual circumstances (eg, vaccinated animal for which no licensed vaccine is
approved, such as an alpaca or monkey), or in pets for which routine vaccinations are
contraindicated because of health concerns.48 In a perfect world, defining pet risk
would also be part of the decision to perform titer testing.
ADVANTAGES AND DISADVANTAGES OF USING SEROLOGY IN LIEU OF
REVACCINATION
Advantages
Reduces the number of vaccinations, hence reduces the risk of VAAEs.
If required yearly for pet licensing, would identify pets that fail to respond to
vaccination or have low titers, making them at higher risk of vaccine failure on
rabies exposure.
Disadvantages
The accuracy of the RVNA level to predict protection in pets for which vaccination is out of date is unknown because there have not been any studies to determine this.
Routine vaccination stimulates/activates both humoral and cellular immune
effectors.
Enhanced assurance of human protection to humans is achieved by routine
vaccination of pets, based on current knowledge.
SUMMARY
Current measures to prevent and control rabies in animals work very well, but there are
challenges, such as decreased awareness of rabies risks, given the shift of rabies
cases from primarily dogs before the establishment of the National Rabies Program
in the 1940s, to wildlife. The threat of rabies virus variants adapting to new wildlife species is real, requiring continuous surveillance and prevention procedures. Viewpoints
and opinions toward vaccination of pets and the compilation of robust data correlating
rabies serology with adequate protection will drive changes in rabies control policies.
An RVNA level of 0.5 IU/mL in a dog or cat demonstrates a continuing robust response
to rabies vaccination and there is an expectation of sufficient immunologic memory to
produce a protective response following exposure. Ideally, the animal would also
receive postexposure treatment (wound care/cleaning and booster vaccination).
Without postexposure treatment, complete protection is somewhere between expected and probable, but is unknown at this time, given lack of published data and
variability in immune status at the time of exposure and exposure type. No vaccine
can be 100% effective in every animal because of these variables. Given the importance of rabies protection in pets to human protection, an abundance of caution
regarding defining the protective level and how it is measured in pets is warranted.
10 Moore
Rabies serology testing is not regulated, except for the recommendation of the ACIP
to measure RVNA by the RFFIT. Experts in public health administration are responsible for weighing the risks of recognizing RVNA levels in animals solely as proof of
rabies protection. Science is just one part of the equation; public health decisions in
light of scientific data is another, and a multitude of factors, including the enforcement
of laws both technically and politically, must be considered.
REFERENCES
1. Blanton JD, Palmer D, Christian KA, et al. Rabies surveillance in the United States
during 2007. J Am Vet Med Assoc 2008;233(6):884–97.
2. Steele JH, Tierkel ES. Rabies problems and control. Public Health Rep 1949;
64(25):785–96.
3. World Health Organization. WHO Expert Committee on Rabies & World Health Organization. In: WHO expert committee on rabies: sixth report. 1973. Geneva
(Switzerland). p. 1–54.
4. World Health Organization. Guideline for rabies control. 1983. Geneva
(Switzerland). p. 1–92.
5. Zero by 30: the global strategic plan to prevent human deaths from dogtransmitted rabies by 2030. 2015. Available at: http://www.who.int/rabies/
Executive_summary_draft_V3_wlogo.pdf?ua51. Accessed October 14, 2018.
6. World Health Organization WOfAH. Global elimination of dog-mediated human
rabies report of the Rabies Global Conference, Geneva, Switzerland, December
10–11, 2015. Geneva, Switzerland, June 2016. p. 1–33.
7. World Health Organization. WHO expert consultation on rabies third report.
Geneva (Switzerland): WHO; 2018.
8. Fooks A. Rabies (infection with rabies virus and other lyssaviruses). In: (OIE) WOfAH, editor. Manual of diagnostic tests and vaccines for terrestrial animals 2018.
2018. p. 1–35. Available at: http://www.oie.int/fileadmin/Home/eng/Health_
standards/tahm/3.01.17_RABIES.pdf. Accessed March 21, 2019.
9. Brown CM, Slavinski S, Ettestad P, et al. Compendium of Animal Rabies Prevention and Control, 2016. J Am Vet Med Assoc 2016;248(5):505–17.
10. Moore MC, Davis RD, Kang Q, et al. Comparison of anamnestic responses to
rabies vaccination in dogs and cats with current and out-of-date vaccination status. J Am Vet Med Assoc 2015;246(2):205–11.
11. Birhane MG, Cleaton JM, Monroe BP, et al. Rabies surveillance in the United
States during 2015. J Am Vet Med Assoc 2017;250(10):1117–30.
12. Leslie MJ, Messenger S, Rohde RE, et al. Bat-associated rabies virus in skunks.
Emerg Infect Dis 2006;12(8):1274–7.
13. Wu H, Chang SS, Tsai HJ, et al. Notes from the field: wildlife rabies on an island
free from canine rabies for 52 years—Taiwan, 2013. MMWR Morb Mortal Wkly
Rep 2014;63(8):178.
14. Lin YC, Chu PY, Chang MY, et al. Spatial temporal dynamics and molecular evolution of re-emerging rabies virus in Taiwan. Int J Mol Sci 2016;17(3):392.
15. Evans JS, Wu G, Selden D, et al. Utilisation of chimeric lyssaviruses to assess
vaccine protection against highly divergent lyssaviruses. Viruses 2018;10(3)
[pii:E130].
16. Lopez T. Quarantine changes take effect in Hawaii. J Am Vet Med Assoc 1997;
211(7):817, 819.
17. Cliquet F, Verdier Y, Sagne L, et al. Neutralising antibody titration in 25,000 sera of
dogs and cats vaccinated against rabies in France, in the framework of the new
Rabies 11
regulations that offer an alternative to quarantine. Rev Sci Tech 2003;22(3):
857–66.
18. Mansfield KL, Burr PD, Snodgrass DR, et al. Factors affecting the serological
response of dogs and cats to rabies vaccination. Vet Rec 2004;154(14):423–6.
19. Jakel V, Konig M, Cussler K, et al. Factors influencing the antibody response to
vaccination against rabies. Dev Biol (Basel) 2008;131:431–7.
20. Kennedy LJ, Lunt M, Barnes A, et al. Factors influencing the antibody response of
dogs vaccinated against rabies. Vaccine 2007;25(51):8500–7.
21. Wallace RM, Pees A, Blanton JB, et al. Risk factors for inadequate antibody
response to primary rabies vaccination in dogs under one year of age. PLoS
Negl Trop Dis 2017;11(7):e0005761.
22. Morters MK, McNabb S, Horton DL, et al. Effective vaccination against rabies in
puppies in rabies endemic regions. Vet Rec 2015;177(6):150.
23. Muller TF, Schuster P, Vos AC, et al. Effect of maternal immunity on the immune
response to oral vaccination against rabies in young foxes. Am J Vet Res
2001;62(7):1154–8.
24. Bunn TO, Ridpath HD. The relationship between rabies antibody titers in dogs
and cats and protection from challenge, vol.11. Lawrenceville (GA): U S Department of Health, Education and Welfare, Public Health; 1984. p. 43–5.
25. Velasco-Villa A, Reeder SA, Orciari LA, et al. Enzootic rabies elimination from
dogs and reemergence in wild terrestrial carnivores, United States. Emerg Infect
Dis 2008;14(12):1849–54.
26. Ford RB, Larson LJ, McClure KD, et al. 2017 AAHA Canine Vaccination Guidelines. J Am Anim Hosp Assoc 2017;53(5):243–51.
27. Scherk MA, Ford RB, Gaskell RM, et al. 2013 AAFP Feline Vaccination Advisory
Panel Report. J Feline Med Surg 2013;15(9):785–808.
28. Moore GE, Guptill LF, Ward MP, et al. Adverse events diagnosed within three days
of vaccine administration in dogs. J Am Vet Med Assoc 2005;227(7):1102–8.
29. Moore GE, DeSantis-Kerr AC, Guptill LF, et al. Adverse events after vaccine
administration in cats: 2,560 cases (2002-2005). J Am Vet Med Assoc 2007;
231(1):94–100.
30. Centers for Disease Control. Vaccine recommendations and guidelines of the
ACIP. 2015. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vaccspecific/rabies.html. Accessed October 23, 2018.
31. Manning SE, Rupprecht CE, Fishbein D, et al, Advisory Committee on Immunization Practices Centers for Disease Control and Prevention (CDC). Human rabies
prevention - United States, 2008 recommendations of the Advisory Committee on
Immunization Practices. MMWR Recomm Rep 2008;57(RR-3):1–28. Atlanta, GA.
32. Fishbein DB, Robinson LE. Rabies. N Engl J Med 1993;329(22):1632–8.
33. Dean DJ, Baer GM, Thompson WR. Studies on the local treatment of rabiesinfected wounds. Bull World Health Organ 1963;28(4):477–86.
34. Murray KO, Holmes KC, Hanlon CA. Rabies in vaccinated dogs and cats in the
United States, 1997-2001. J Am Vet Med Assoc 2009;235(6):691–5.
35. Eng TR, Hamaker TA, Dobbins JG, et al. Rabies surveillance, United States,
1988. MMWR CDC Surveill Summ 1989;38(1):1–21.
36. Rabies vaccine, killed. In: Regulations CoF, vol. 9. U.S. National Archives and records Administration; 2007. Available at: https://www.govregs.com/regulations/9/
113.209. Accessed March 21, 2019.
37. Beran J, Honegr K, Banzhoff A, et al. How far can the antigen content of tissue
culture rabies vaccine be reduced safely? Vaccine 2006;24(13):2223–4.
12 Moore
38. Aubert MF. Practical significance of rabies antibodies in cats and dogs. Rev Sci
Tech 1992;11(3):735–60.
39. Moore SM, Gilbert A, Vos A, et al. Rabies virus antibodies from oral vaccination as
a correlate of protection against lethal infection in wildlife. Trop Med Infect Dis
2017;2(3) [pii:E31].
40. Lawson KF, Crawley JF. The ERA strain of rabies vaccine. Can J Comp Med 1972;
36(4):339–44.
41. Bahmanyar M, Fayaz A, Nour-Salehi S, et al. Successful protection of humans
exposed to rabies infection. Postexposure treatment with the new human diploid
cell rabies vaccine and antirabies serum. JAMA 1976;236(24):2751–4.
42. Lu XX, Zhu WY, Wu GZ. Rabies virus transmission via solid organs or tissue allotransplantation. Infect Dis Poverty 2018;7(1):82.
43. Moore SM, Pralle S, Engelman L, et al. Rabies vaccine response measurement is
assay dependent. Biologicals 2016;44(6):481–6.
44. Feyssaguet M, Dacheux L, Audry L, et al. Multicenter comparative study of a new
ELISA, PLATELIA RABIES II, for the detection and titration of anti-rabies glycoprotein antibodies and comparison with the rapid fluorescent focus inhibition test
(RFFIT) on human samples from vaccinated and non-vaccinated people. Vaccine
2007;25(12):2244–51.
45. Servat A, Feyssaguet M, Blanchard I, et al. A quantitative indirect ELISA to
monitor the effectiveness of rabies vaccination in domestic and wild carnivores.
J Immunol Methods 2007;318(1–2):1–10.
46. Wasniewski M, Guiot AL, Schereffer JL, et al. Evaluation of an ELISA to detect
rabies antibodies in orally vaccinated foxes and raccoon dogs sampled in the
field. J Virol Methods 2013;187(2):264–70.
47. Moore SM, Hanlon CA. Rabies-specific antibodies: measuring surrogates of protection against a fatal disease. PLoS Negl Trop Dis 2010;4(3):e595.
48. Wallace RM, Niezgoda M, Waggoner EA, et al. Serologic response in eight alpacas vaccinated by extralabel use of a large animal rabies vaccine during a
public health response to a rabid alpaca in South Carolina. J Am Vet Med Assoc
2016;249(6):678–81.0>2>96>
No hay comentarios:
Publicar un comentario