[ SHOWGSD-L ] Rabies DOI -- The 1992 French Challenge Study Text(Very Long)
- From: "YCHARRON" <raiseyourpaw4raw@xxxxxxxxxx>
- To: <showgsd-l@xxxxxxxxxxxxx>
- Date: Sat, 26 Feb 2005 19:03:24 -0500
Some very interesting info on Rabies vaccine,for those who belive some vets are
over vaccinating !
Yvette
Greetings!
This document is very important, because rabies is the one vaccine we are
required by law to give our dogs. This study, which I refer to as "The French
Study" demonstrated that, by challenge, vaccinated dogs were immune to rabies 5
years after innoculation. Under separate cover I had e-mailed you an
attachment containing the American Animal Hospital Association's 2003 Canine
Vaccine Guidelines--check out the referenced quote here. Also, check out this
link http://www.rabavert.com/risk.html for the Populations at Risk for Rabies
sheet from Chiron Corporation, manufacturers of the RabAvert rabies vaccines
for humans. Their pre-exposure vaccination recommendation for veterinarians,
who are at greater risk than the general population for contracting rabies
because their profession brings them into physical contact with potentially
rabid animals, is for a "Primary course. No serologic testing or booster
vaccination." In other words, after the initial series of rabies
vaccinations, it is not recommended that veterinarians receive further boosters
or serological testing. Interestingly, the AAHA's 2003 Canine Vaccine
Guidelines state on Page 18 that "There is no indication that the immune system
of canine patients functions in any way different from the human immune system.
In humans, the epidemiological vigilance associated with vaccination is
extremely well-developed and far exceeds similar efforts in animals whether
companion or agricultural. This vigilance in humans indicates that immunity
induced by vaccination in humans is extremely long lasting and, in most cases,
life-long." This strongly suggests that, like the human rabies vaccine, the
canine rabies vaccine may provide life-long immunity as well -- something which
could be determined by long-term challenge studies.
The French rabies challenge study below was published in Scientific
Technical Review (Rev. sci.tech. Off. int. Epiz.) 1992, 11 (3), 735-760.
Anyone wishing to obtain an original copy from the publisher can contact:
Magdalena Banaszak
Publications Department
OIE, 12, rue de Prony, 75017 PARIS
tel. + 33 (0)1 44 15 19 64
fax + 33 (0)1 42 67 09 87
e-mail: m.banaszak@xxxxxxx
Cheers, Kris
PRACTICAL SIGNIFICANCE OF RABIES ANTIBODIES IN CATS AND DOGS*
AND
RESULTS OF A SURVEY ON RABIES VACCINATION AND QUARANTINE
FOR DOMESTIC CARNIVORA IN WESTERN EUROPE
M.F.A. Aubert
Centre national d'études vétérinaires et alimentaires, Laboratoire d'études sur
la rage et la pathologie
des animaux sauvages, B.P. 9, 54220 Malzéville, France
Note : Text figures have been omitted (SG)
Original: French
Summary: Doubt has sometimes been cast upon the protective effect of rabies
antibodies in serum. Animals and humans suffering from fatal rabies often
produce high antibody titres, while rabies cases are also observed in
vaccinated animals. Cellular immunity is also largely involved in protection.
Nevertheless, a large number of laboratory experiments and field observations
clearly demonstrate that cats and dogs which develop antibodies after
vaccination and before challenge have a very high probability of surviving any
challenge, no matter how strong the dose and which virus strain is used.
Rabies antibody titration can, therefore, afford a strong additional guarantee
to the vaccination certificates accompanying domestic carnivores during
transportation between countries. Quarantine rules should also be adapted to
the epidemiological features in the exporting country, e.g. statistics of
vaccination failure in cats and dogs and host-virus adaptation of the rabies
strains circulating in these countries.
1. INTRODUCTION
Cats and dogs can introduce rabies into disease-free countries if they are
incubating the disease and are transported during the pre-symptomatic phase. To
prevent such introduction, vaccination is recommended. The present article
reviews publications dealing with rabies protection afforded to cats and dogs
by vaccination. In addition, the Appendix presents the results of a survey of
the current practices of OIE Member Countries in Western Europe with respect to
rabies vaccination and quarantine of dogs and cats.
Only the parenteral route of vaccination will be considered, as the oral route
is employed only for wandering and non-restrained carnivores; extensive results
for individual cats and dogs are unavailable. Also, since oral vaccination
could mobilise immunity pathways other than those obtained parenterally, the
results with one procedure may not be transposable to the other.
Furthermore, no consideration will be given here to the results of vaccination
after exposure, which does little, if anything, to alter disease (20).
Emphasis will be given to the most common method for measuring rabies
immunisation: assays for rabies virus neutralising antibodies in serum
(henceforth referred to as "neutralising antibodies"). The practical
significance and consequences of rabies virus neutralising antibodies in cats
and dogs are considered; namely, to what extent do neutralising antibody titres
confer protection against subsequent challenge?
No consideration will be given to the question of whether real protection
against challenge is provided by neutralising antibodies and/or other immunity
factors. Titres of neutralising antibodies in serum are simply viewed as the
easiest means of evaluating the likelihood that a cat or dog will not contract
rabies following exposure.
2. STUDIES IN DOGS
2.1. Neutralising antibodies after vaccination
General considerations
The kinetics obtained for neutralising antibodies after vaccination have been
thoroughly described in the literature. The curve of neutralising antibodies
after vaccination and boosters follows the pattern generally observed with
other antigens: seroconversion and rapid rise of the level of neutralising
antibodies after first vaccination, followed by a slow decrease, a new rise
after booster to reach a higher level than previously observed, then a new
decrease leading to a stabilised higher level (Fig. 1) (8, 51, 63). The
decrease of neutralising antibody levels has been evaluated in domestic
populations of owned dogs in several countries: in Canada, titres of
neutralising antibodies in the sera of dogs showed a clear division between, on
the one hand, dogs vaccinated or revaccinated one year before and, on the other
hand, dogs revaccinated three weeks before (33). Data from Thailand and Java
show that the neutralising antibody titre decreases very rapidly after 60 to
120 days to levels 5- to 25-fold less than the highest point reached during the
kinetics (Fig. 2) (40, 65). The higher level of neutralising antibodies
obtained when owned dogs are vaccinated several times has been described by
Sasaki and colleagues (55, 56).
Fig. 1
Kinetics of rabies neutralising antibodies in sera of
laboratory dogs vaccinated with a tissue culture vaccine
Variations according to vaccination route and antigenic value of the vaccine as
measured by the NIH test
(63, 64)
Fig. 2
Kinetics of rabies neutralising antibodies in sera of owned dogs of various
ages
in Thailand after one subcutaneous vaccination with a tissue culture vaccine
The number of dogs sampled was 54 at day 0 and 31 at day 360
(65)
With regard to the production of neutralising antibodies and the relationship
of these antibodies to protection against challenge, a clear distinction must
be made between live virus vaccines and inactivated virus vaccines. These two
types of vaccine cannot be directly compared. The best relationship between
antibody production and protection has always been obtained with inactivated
virus vaccines and it is, therefore, the latter which will be considered in
greater detail, especially as they currently represent the only type of vaccine
authorised in a great many countries.
High individual variability
In laboratory dogs bred and kept under the same conditions and in comparable
health, neutralising antibody titres obtained after the same form of
vaccination commonly range from zero to twenty international units per ml (IU)
or more (19, 51, 53).
Influence of vaccine types and potency
The first complete study of live virus vaccines was published by Dean and
colleagues (32). This study established a correlation between antibody
production and resistance to challenge, which was confirmed by later studies
(see below). As far as inactivated virus vaccines are concerned, besides
individual variation, the level of neutralising antibodies in serum correlates
positively with the antigenic value of the vaccine as determined by the
American National Institutes of Health (NIH) test. This observation is common
in the course of vaccine production and control on laboratory dogs (Fig. 1)
(47, 63). The influence of the antigenic value of the vaccine on the level of
neutralising antibodies has also been demonstrated in domestic populations of
owned dogs; in Switzerland, Engels and colleagues (35) showed that in owned
dogs, higher titres were generally obtained with inactivated vaccines than with
live (and less potent) vaccines.
However, when inactivated virus vaccines with an antigenic value (as measured
by the NIH test) equal to or greater than 1.0 IU per dose are employed, no
correlation can be shown between the level of neutralising antibodies in
individual dogs and the titre of the vaccine. This result was first
demonstrated in owned dogs in France by Blancou and colleagues (13). In this
experiment, dogs were sampled randomly from populations living under various
conditions and were vaccinated with a range of commercially available vaccines.
Chappuis and colleagues (30) and Lazarowicz and colleagues (45) used laboratory
dogs to investigate whether the administration of vaccines from the same
producer would entail a correlation between the NIH titre of vaccines and the
level of neutralising antibody response. Even under standardised conditions, no
correlation was found. The same conclusion can be drawn from the results of
Barth and colleagues (7).
In summary, a significant variation of neutralising antibody response can be
shown only under a broad range of vaccine potencies (61). When the potencies of
commercial inactivated virus vaccines are fairly high, the neutralising
antibody response will be related only to the immune responses of individual
dogs.
Influence of the route of vaccination
Since Pasteur, the route of vaccination has been subcutaneous (s.c.).
Fuenzalida in 1967 demonstrated that the intramuscular (i.m.) route resulted in
higher neutralising antibody titres in sera of dogs (37). Apart from Merry
(46), who found no clear advantage for the i.m. over the s.c. route, the
results obtained by Fuenzalida were largely confirmed (22, 25, 63). However,
the advantage of the i.m. route diminishes with high potency vaccines (Fig. 1)
(63) and the use of adjuvanted vaccines renders the i.m. route excessively
painful. Adjuvants confer a longer lasting immunity, which can be obtained with
a smaller quantity of antigen, as first demonstrated on laboratory dogs (52),
then on owned dogs (43, 68, 69). Despite the use of smaller quantities of
antigen and a reduced vaccination schedule (less frequent boosters), the
neutralising antibody levels reached after one, two or three years with
adjuvanted vaccines were equivalent to those reached with non-adjuvanted
vaccines given according to the usual schedule (two injections of vaccine the
first year, with annual boosters).
The importance of the vaccination route was clearly demonstrated with
intradermal injection of vaccine in dogs (68). Unfortunately, the advantages of
an enhanced response obtained with a minute dose of vaccine (2 x 0.1 ml) were
offset by the fact that intradermal injection must be performed on the inside
of the ear and, hence, this procedure must be conducted dangerously near the
mouth of the animal.
Influence of age
It has been shown that dogs 11-16 weeks of age respond better to Flury low egg
passage (LEP) or high egg passage (HEP) vaccine than dogs 5-10 weeks of age
(81% vs. 38% protection from challenge, respectively) (41). The relationship
between the age of animals and protection from challenge was confirmed in a
laboratory study by Bunn in 3- to 5-month-old pups. Three months after
vaccination with Flury LEP vaccine, ten of forty pups had antibody titres below
1/5 (24, 25).
A survey on owned dogs in France showed that even beyond three months of age,
older dogs produced higher titres (Fig. 3) (13).
Fig. 3
Correlation between rabies antibody level reached
after one vaccine injection and age of dogs
Study conducted on 66 owned dogs in France
(13)
The influence of age on the neutralising antibody response in dogs was also
clearly demonstrated on owned dogs in Thailand by Teepsumethanon and colleagues
(65). These authors described the kinetics of neutralising antibodies in three
age groups: 3 weeks to 3 months, 6 to 12 months, and more than 12 months.
Whenever the mean level of neutralising antibodies was evaluated after
vaccination, the older dogs had the highest levels of response. Given the
difficult conditions prevailing in Thailand, the superior response of older
dogs could also be related to the increased life expectancy of dogs with a more
powerful immune system (Fig. 2).
The presence of specific neutralising antibodies transmitted to puppies via
colostrum impedes development of active immunity. The interference between
passive neutralising antibodies of maternal origin and active immunisation has
been studied by Précausta (52, 53). Puppies of non-immune bitches vaccinated at
the age of one month respond with the same neutralising antibody level as
puppies vaccinated at seven months of age. Puppies of immune bitches vaccinated
at one month of age show neutralising antibody levels which decrease according
to the same kinetics as unvaccinated members of the same litter.
After ten weeks (44) to twelve weeks (52), no traces of maternal neutralising
antibodies remain. Surveys in pet dog populations where systematic vaccination
of adult dogs is practised (in France and elsewhere) have confirmed that no
further interference between active and passive immunity occurs beyond this age
(53).
Influence of the health and breeding status of dogs
Blancou and colleagues (19) compared the proportion of individuals developing
neutralising antibodies in 64 dogs after the administration of adjuvanted or
non-adjuvanted vaccines. This rate may vary considerably depending on the
category of dog (bred for laboratories, belonging to individuals in France or
uncontrolled in Tunisia). The rate drops from 100% to 59% in the case of
semi-stray dogs as compared to laboratory dogs (Fig. 4). Urban dogs in Lima
(Peru) exhibited better rates than in Tunisia, but the rates were still lower
than in dogs kept under laboratory conditions (31). Although the health status
of these populations had not been measured in the previous studies, this status
is probably responsible for the differences observed by Teepsumethanon and
colleagues (65) in Thailand: Thai pet dogs which had received one s.c. dose of
rabies vaccine exhibited a better neutralising antibody response when they did
not suffer from anaemia (Fig. 5). In 440 pets under quarantine in Hawaii,
Sasaki and colleagues (56) demonstrated that those with internal parasites had
significantly lower levels of neutralising antibodies than those without
parasites.
Fig. 4
Influence of the breeding standards of dogs on the level
of rabies antibody reached one year after vaccination
Comparison of laboratory dogs, pet dogs in France and stray dogs in Tunisia
(19)
Fig. 5
Influence of the health status of Thai dogs on the level
of rabies antibody reached after one vaccination
Comparison of dogs with or without anaemia
(65)
2.2. Level of neutralising antibodies in sera and results of challenge
Challenge under laboratory conditions
In view of the serious problem posed by rabies, challenge of previously
vaccinated dogs has often been performed even when a large proportion of the
dogs under experiment exhibited a seroconversion. Moreover, such challenges are
performed in response to doubts which have sometimes been cast on the
significance of neutralising antibodies to rabies, due to the fact that high
titres have been measured in human beings and animals dying of rabies. In fact,
very few diseases show so clear a correlation as in rabies between
seroconversion before challenge and protection from challenge.
In the context of movement of dogs between countries, it is possible to check
the efficiency of previous vaccinations. A large number of reports can be
summarised by the simple comparison of the proportion of dogs surviving
challenge vs. the proportion of dogs with detectable neutralising antibodies in
serum just before challenge (i.e. theoretically when the neutralising antibody
level is lowest). These summaries are given in Tables 1 to 8.
Table 1
Laboratory dogs: one intramuscular vaccination with various vaccines,
challenge with rabies virus NYC-Ga strain, one year after vaccination
(61)
--------------------------------------------------------------------------------
Vaccine Dogs with antibodies Dogs surviving
challenge
just before challenge
(%)
Experiment 1
LEP tissue culture 88 9/10
LEP tissue culture 73 10/10
ERA tissue culture 73 10/10
LEP chicken embryo 70 10/10
HEP tissue culture 63 10/10
CVS adjuvanted 13 7/10
None 0 0/10
Experiment 2
Suckling mouse brain 95 10/10
Suckling mouse brain 67 10/10
None 0 0/10
--------------------------------------------------------------------------------
LEP: low egg passage
HEP: high egg passage
ERA: Elizabeth (Gaynor) Rokitniki Abelseth
CVS: challenge virus strain
Table 2
Laboratory dogs: one intramuscular vaccination with various vaccines,
challenge with rabies virus NYC-Ga strain, three years after vaccination
(61)
--------------------------------------------------------------------------------
Vaccine Dogs with antibodies Dogs surviving
challenge
just before challenge
(%)
LEP tissue culture 87 29/30
LEP tissue culture 69 26/29
ERA tissue culture 57 27/30
LEP chicken embryo 54 28/30
Suckling mouse brain 48 27/27
HEP tissue culture 42 27/29
Suckling mouse brain 28 23/29
CVS adjuvanted 0 17/29
None 0 3/30
Results of challenge Antibodies before challenge
yes no
Rabid 3* 26
Surviving 157 47
--------------------------------------------------------------------------------
* titres of 1/2, 1/3 and 1/5 (end point neutralising dilution of the serum)
Table 3
Laboratory dogs: one vaccination with HEP vaccine, challenge with rabies virus
NYC-Ga strain
three years after vaccination
(22)
--------------------------------------------------------------------------------
Vaccination Dogs with detectable Dogs surviving
antibodies challenge
just before challenge
Intramuscular injection
Undiluted 29/30 30/30
Diluted 1/10 6/10 10/10
Diluted 1/100 4/10 9/10
Subcutaneous injection
Undiluted 4/29 17/29
Diluted 1/10 0/9 2/9
Diluted 1/100 0/8 2/8
None 0/30 0/30
--------------------------------------------------------------------------------
Table 4
Laboratory dogs: subcutaneous vaccination with tissue culture vaccine,
challenge with rabies virus NYC-Ga strain, twenty-seven months after vaccine
(8)
--------------------------------------------------------------------------------
Antigenic value Dogs with detectable antibodies Dogs surviving challenge
of vaccine 12 months after vaccination
Vaccinated
Controls
0.6 8/8 8/8
0/7
1.7 19/20 17/18**
3/12
2.3 6/9 8/9***
4/12
4.6 10/10 9/9 -
--------------------------------------------------------------------------------
* measured by the NIH test, expressed in IU/dose
** The dog which died of rabies had always had the lowest antibody titre in the
group
*** The dog which died of rabies had never seroconverted
Table 5
Laboratory dogs: subcutaneous vaccination with tissue culture vaccine,
challenge with rabies virus NYC-Ga strain, three years after vaccination
(52)
--------------------------------------------------------------------------------
Vaccination Dogs with serum antibodies Dogs surviving
challenge
> 0.5IU/ml just before challenge
Vaccinated
Controls
One injection of 29/30 29/30 0/20
adjuvanted
vaccine
--------------------------------------------------------------------------------
Table 6
Laboratory dogs: intramuscular vaccination with tissue culture adjuvanted
vaccine,
challenge with rabies virus NYC-Ga strain, three years after vaccination
(59)
--------------------------------------------------------------------------------
Vaccination Dogs with detectable antibodies Dogs surviving
just before challenge challenge
Yes 14/25 23/25*
No 0/10 2/10
--------------------------------------------------------------------------------
* One of the two dogs which died following challenge was seronegative, the
other had a titre of 1/4 (endpoint neutralising dilution of the serum)
Table 7
Laboratory dogs: intramuscular vaccination with ERA vaccine,
challenge with rabies virus fox strain four or five years after vaccination
(44)
--------------------------------------------------------------------------------
Vaccination Dogs with detectable Dogs surviving
challenge
antibodies just before challenge
Four years before
challenge
Yes 5/10 7/10
No 0/9 0/9
Five years before
challenge
Yes 7/14 13/14
No 0/14 5/14
--------------------------------------------------------------------------------
Table 8
Laboratory dogs: subcutaneous vaccination with adjuvanted tissue culture
vaccine,
challenge with rabies virus fox strain, two years after booster vaccination
(38)
--------------------------------------------------------------------------------
Antigenic value Dogs with detectable Dogs surviving challenge
of vaccine* antibodies just before challenge
Vaccinated
Controls
4.2 9/10** 10/10 0/5
--------------------------------------------------------------------------------
* measured by the NIH test, expressed in IU/dose
** two dogs with an antibody titre <0.5 IU/ml
Sikes and colleagues (62) employed several types of vaccine on dogs and
challenged them one or three years after vaccination (Tables 1 and 2). Sikes
(61) commented on the three-year experiment as follows: "In this study, as in
many others, presence of neutralising antibodies to rabies at the time of
challenge did not indicate protection for all of the animals. Likewise, absence
of neutralising antibodies in serum at the time of challenge did not mean the
animals were unprotected. However, there was strong statistical significance (P
< 0.1) that animals with neutralising antibodies at the time of challenge were
better protected than those with no detectable neutralising antibodies."
Sikes employed the NYC-Ga (New York City-Georgia) dog salivary gland strain of
rabies virus. The same strain has also been used for challenge in other
experiments (Tables 3 to 6) and the results confirm each point of the
statements made by Sikes (60) regarding vaccination of dogs:
a) generally, groups of dogs with a high percentage of seroconversion will have
the highest probability of surviving challenge;
b) on an individual basis:
- a dog with neutralising antibodies just before challenge will have the best
chance of surviving a severe challenge;
- a dog with no detectable neutralising antibodies just before challenge will
have a high chance of surviving a severe challenge if it seroconverted after
vaccination;
- some dogs will not survive a severe challenge even if they have detectable
neutralising antibody titres before challenge; generally these titres are the
lowest of the group.
In studies of fox strains of rabies virus (Tables 7 and 8), the possibility of
procuring a strong immunity as long as four to five years after vaccination,
and of enhancing protection by the use of adjuvanted vaccines, has been
demonstrated. These studies also confirmed the correlation between neutralising
antibodies and protection against a fox strain.
Bunn and colleagues (28, 29) gathered pre-challenge neutralising antibody
titres and challenge results obtained on dogs by the United States National
Veterinary Services Laboratories and by vaccine manufacturers. Most of the dogs
were challenged with the NYC-Ga strain, but results obtained with fox or skunk
strains were also added. Sera were titrated either by the virus neutralisation
test in mice (MNT) (5) or the rapid fluorescent focus inhibition test (RFFIT)
(62). Data on neutralising antibodies originally expressed in arithmetical
dilutions by Bunn (26, 27) have been converted into IU in Figure 6. Beyond 0.03
IU/ml with the MNT or 0.05 IU/ml with the RFFIT, the expected survival to
challenge by a dog strain reaches 95%. With 288 dogs having RFFIT titres above
0.1 IU/ml, a 100% survival rate was obtained. The maximum survival rate
observed among animals with the highest neutralising antibody titres measured
by MNT was 99.5%.
Fig. 6
Survival rate after challenge of laboratory dogs correlated
with the level of rabies antibody reached before challenge
Dogs were vaccinated with various vaccines and challenged one year after
vaccination with NYC-Ga,
fox or skunk strains; the number of dogs in each class is written at the top of
the bars
(65)
Given the higher susceptibility of dogs to dog strains (e.g. NYC-Ga), which was
proven by cross challenge of dogs with homologous and heterologous (fox)
strains (15, 17), the challenge with fox strains could be expected to be less
severe. Unfortunately, the data are too scarce to permit a definitive
conclusion.
Natural infection of vaccinated dogs
The number of vaccinated dogs which become naturally infected is related to
several factors other than vaccine potency, such as probability of encountering
an infected animal, severity of bites, health status and immune efficiency of
the vaccinated dogs, and host-virus adaptation. Such considerations could
explain why vaccinated dogs suffer rabies more often in the course of dog
rabies enzootics than during fox rabies enzootics. In Thailand, 9% of the dogs
found positive upon laboratory diagnosis had been vaccinated within the
previous two years (39). In Nigeria, a survey of 2,500 dogs vaccinated over two
years, showed that at least four died of rabies three to eight months after
vaccination (1, 2).
The following reasons (16) for the failure of immunity may be suggested:
- inappropriate vaccination with inadequately stored or improperly injected
vaccine
- vaccination during the incubation of rabies or before the onset of an
immunological response
- a heavy challenge overwhelming host defences
- intrinsic incapacity in the host.
Whatever the origins of rabies cases recorded in vaccinated dogs, their number
seems relatively low in areas contaminated with fox rabies (e.g. in Europe)
(20). In France, only ten cases of so-called vaccination failures in dogs (and
four among cats) have been registered over a period of twenty-three years (6).
This number should be compared with the 4,250,000 cats and dogs vaccinated
annually in France (this figure is based on the annual number of vaccine doses
sold for domestic carnivores). The probability of a cat or dog becoming rabid
if vaccinated can be estimated as 14/(23 x 4,250,000), which is less than
1/6,980,000. In France, dogs in contact with a rabid animal in an enzootic area
are not sacrificed and can be kept alive if, prior to contamination, they have
been properly vaccinated (with certificate and identification). In such cases,
the animals are immediately revaccinated. A study of more than 3,500 dogs which
had close contacts (bites in 36% of cases) with foxes (mainly) or other
carnivores which were diagnosed as rabid by laboratory examination, revealed
that only three dogs developed rabies (50). The failure rate in animals which
were definitely contaminated can be estimated as 3/3,500, given that injection
of vaccine after contamination has been shown to provide no protection (20). It
must be emphasised that these failures were recorded before 1984 and that
failure is now less probable, given the generalisation of adjuvanted vaccines
for dogs. In the United States of America, four rabies vaccine failures were
recorded in cats and dogs in 1988 with 33,182,575 vaccinated domestic
carnivores the same year (rate = 1/8,296,000) (34).
Such evaluations could be useful in comparing the risks of vaccination with
those of quarantine. For even when they are strictly managed, quarantines still
entail a risk. For instance, in many countries, the quarantine period is six
months. However, longer incubation periods have been reported in dogs (8.5
months after challenge) (67) and in other carnivores (12 months or more for
foxes) (57). According to Sasaki and colleagues (55), Beynon determined that a
quarantine period of nine months would be necessary to detect all cases of
incubating rabies with a 95% degree of confidence.
3. STUDIES IN CATS
3.1. Neutralising antibodies after vaccination
Although fewer studies have been conducted on vaccination of cats against
rabies, several of the characteristics observed in dogs were also observed in
cats:
- the kinetics of neutralising antibodies follow the same profile in the two
species (8, 23, 64)
- the relationship between the potency of vaccines and the level of
neutralising antibodies: Lawson and colleagues (44) have shown that the less
diluted modified live vaccines induced the highest rate of seroconversion in
vaccinated cats (Table 9), but Lazarowicz and colleagues (45) obtained no
correlation of the antigenic value of inactivated virus vaccines as determined
by the NIH test and mean neutralising antibody titres in vaccinated cats.
However, as for dogs, it is necessary to take account of the fact that the
production of antibodies (and protection against challenge) obtained after
administration of live virus vaccine (44) and inactivated virus vaccine (45)
can show great divergence and are not readily comparable.
- intramuscular vaccination provides longer lasting protection than
subcutaneous vaccination (Table 10) (59).
Table 9
Laboratory cats: intramuscular vaccination with various vaccines,
challenge with rabies virus fox strain five weeks and four years after
vaccination
(44)
--------------------------------------------------------------------------------
Vaccination Cats with detectable antibodies Cats
surviving
just before challenge challenge
Five weeks before challenge
ERA undiluted or diluted 1/10 19/19 19/19
Inactivated virus vaccine 20/20 20/20
undiluted or diluted 1/10
ERA diluted 1/100 or 1/1000 5/20 12/20
HEP diluted 1/1000 1/40 11/40
Inactivated virus vaccine
diluted 1/1000 0/5 2/5
None 0/11 3/11
Four years before challenge
ERA 7/8 8/8
None 0/8 1/10
--------------------------------------------------------------------------------
ERA: Elizabeth (Gaynor) Rokitniki Abelseth
HEP: high egg passage
Concerning the influence of age, Précausta and colleagues (53) described the
good neutralising antibody response achieved by three-month-old kittens, even
those born of immune queens.
To our knowledge, Blancou and colleagues (18, 19) are the only authors who have
tested vaccination results on owned cat populations. Pet cats appeared to
respond well to the administration of an adjuvanted vaccine. In contrast, the
same authors obtained mild or zero neutralising antibody responses when
vaccinating cats sampled from stray populations in France. With stray cats, the
worst result was obtained with non-adjuvanted vaccines: 5 of 9 individuals did
not respond (Fig. 7).
Fig. 7
Influence of the breeding standards of cats on the level of
rabies antibody reached one year after vaccination
Comparison of laboratory cats, pet cats in France and stray cats in Tunisia
(19)
3.2. Level of neutralising antibodies and result of challenge
Challenge under laboratory conditions
Although there are few field studies on the immunity of pet or stray cat
populations, there are numerous laboratory studies on challenge of vaccinated
cats (Tables 10 to 12).
Table 10
Laboratory cats: intramuscular vaccination with tissue culture adjuvanted
vaccine,
challenge with rabies virus NYC-Ga strain, one to three years after vaccination
(59)
--------------------------------------------------------------------------------
Vaccination Cats with detectable Cats surviving
antibodies just before challenge challenge
One year before
challenge
Yes (subcutaneous) 5/5 5/5
No 0/4 0/4
Three years before
challenge
Yes (intramuscular) 25/25 24/25*
No 0/10 1/10
--------------------------------------------------------------------------------
* Prior to challenge the cat which died of rabies had an antibody titre of 1/2
(endpoint neutralising dilution)
Table 11
Laboratory cats: subcutaneous vaccination with tissue culture vaccine,
challenge with rabies virus NYC-Ga strain, 3.4 to 3.7 years after vaccination
(64)
--------------------------------------------------------------------------------
Vaccination Cats with antibodies >0.5 IU/ml Cats surviving
challenge
0-6 months before challenge
Vaccinated
Controls
Non-adjuvanted 8/8 8/8 0/5
vaccine
Adjuvanted vaccine 5/5 5/5 0/5
Adjuvanted vaccine 8/11 10/10 1/10
--------------------------------------------------------------------------------
Table 12
Laboratory cats: challenged with rabies virus NYC-Ga strain
four to six-and-a-half months after vaccination
(42)
--------------------------------------------------------------------------------
Vaccination Cats with antibodies >0.5 Cats surviving challenge
IU/ml just before challenge
Vaccinated
Controls
Inactivated virus in cell
culture:
antigenic value: 0.9* 8/8 7/8**
antigenic value: 1.8 5/8 8/8 0/16
Modified live virus:
ERA 2/8 3/8***
--------------------------------------------------------------------------------
* Measured by the NIH test, expressed in IU/dose
** The cat which died of rabies had a pre-challenge titre of 5.34 IU/ml
*** The cats which died of rabies had the lowest antibody titres
ERA: Elizabeth (Gaynor) Rokitniki Abelseth
Challenge was performed with a dog strain (NYC-Ga) mimicking the situation of
canine street rabies (42, 61, 64) or, in other experiments, a fox strain
mimicking the situation of sylvatic fox rabies in continental Europe (38, 44).
With both strains, the general conclusion was the same as for dogs: the
probability of a cat surviving challenge can be predicted by the level of
neutralising antibodies. Of course, unexpected deaths can occur: Kihm and
colleagues (42) reported a rabies death in a cat which had a pre-challenge
titre of 5.34 IU, and Blancou and colleagues (18) in another cat with a
pre-challenge titre of 0.87 IU/ml.
The cumulative challenge results on cats reported by Bunn (26, 27) are
described in Figure 8 and Tables 13 and 14. With a neutralising antibody level
of more than 0.1 IU (measured by MNT) or more than 0.2 IU (measured by RFFIT),
all of the cats survived challenge.
Fig. 8
Survival rate after challenge of laboratory cats correlated with
the level of rabies antibody reached before challenge
Cats were vaccinated with various vaccines and challenged one year after
vaccination with NYC-Ga,
fox or skunk strains; the number of cats in each class is written at the top of
the bars
(27)
Table 13
Challenge results from rabies immonogenicity tests conducted in dogs and cats
with vaccines approved for use in the United States of America
(27)
--------------------------------------------------------------------------------
Vaccine Antibody titre*
<5 5-9 10-19 20-39
>40
Flury modified live 1/50** 0/16 0/26 0/15
0/40
vaccine
SAD modified live 5/55 3/36 1/41 0/35
1/188
vaccine
SAD inactivated virus, 21/156 2/63 1/116 0/79
0/150
tissue culture origin
Pasteur inactivated 5/44 1/45 0/38 0/32
0/76
virus, tissue culture
origin
Pasteur inactivated 13/133 2/62 5/73 1/34
0/164
virus, nervous tissue
origin
--------------------------------------------------------------------------------
* antibody titres expressed as 50% endpoint neutralising dilutions established
by either the MNT or RFFIT
** challenge results are expressed as number of animals which died/number of
animals challenged
SAD: Street Alabama Dufferin strain
Table 14
Neutralising antibody titres in dogs and cats and protection from challenge
with rabies virus
(26)
--------------------------------------------------------------------------------
Animals Antibody test Antibody titre*
<5 5-9 10-19 20-39
>40
Dogs MNT 56/251** 9/100 9/92 1/63
0/171
RFFIT 84/241 13/112 9/119 0/87
0/201
Total 140/492 22/212 18/211 1/150
0/372
Cats MNT 25/155 5/57 5/94 0/33
0/144
RFFIT 17/87 3/59 1/62 1/49
1/187
Total 42/242 8/116 6/156 1/82
1/331
--------------------------------------------------------------------------------
* antibody titres expressed as 50% endpoint dilutions established by either the
virus neutralisation test in mice (MNT) or the rapid fluorescent focus
inhibition test (RFFIT)
** challenge results are expressed as number of animals which died/number of
animals challenged
Natural infection of vaccinated cats
The safety problem associated with the receptivity of cats to live virus
vaccines such as Flury LEP and HEP or Street Alabama Dufferin (SAD) strain
vaccines will not be reviewed here (11). But it should be remembered that while
cats are the species with the largest number of rabies cases directly induced
by the inoculation of live modified virus strains, other species such as dogs
and foxes are also receptive (72).
Inactivated virus vaccines are employed on cats as they are more efficient in
protecting the species against natural challenge. However, considering the
results of challenge experiments on vaccinated cats, natural infection among
vaccinated pet cats is suspected to be as frequent as for vaccinated dogs. But
investigations on rabies cases in vaccinated cats are scarce: apart from the
four cases reported in France (6) there appear to be no other reports. This
discrepancy is due to the fact that dogs have been studied considerably more
than cats.
4. THE SIGNIFICANCE OF NEUTRALISING ANTIBODIES
IN NON-VACCINATED CARNIVORES
4.1. Non-specific and specific neutralising factors
Sekine and colleagues (58) found that sera of normal rabbits and guinea-pigs
contained non-specific inhibitors capable of neutralising the virus in the
presence of complement. In a well-conducted seroneutralisation on mice,
therefore, inactivation of sera is performed for 30 minutes at 56°C. Virus
inhibition by other substances was described in infected skunks and foxes (74).
Infection by mycobacteria, e.g. Bacillus Calmette-Guérin (BCG), can also induce
the production of rabies neutralising antibodies in mice and provide protection
against rabies in a number of animals (70). Since more specific immunological
tests (such as enzyme-linked immunorescent assay: ELISA) have become
widespread, non-specific neutralising factors have not generated further
scientific reports.
In endemic areas, serosurveys in wild carnivores demonstrated a high proportion
of apparently healthy individuals with neutralising antibodies in serum (54,
71) and it has been suggested that these antibodies may have been produced
following contact with virus from other species, which was therefore immunising
but rarely fatal (12). However, the same observations have also been reported
for dog populations in areas where dog rabies is endemic: in Thailand, in areas
where no canine vaccination programme has ever been conducted, 15-20% of dogs
had neutralising antibodies, yet remained perfectly normal when observed for
prolonged periods (75); similar results had also been reported previously in
other countries of Asia and in Africa (3, 36). These observations correlate
with the high probability of inter-individual contamination within the
reservoir species, which is not the case for pet populations in areas where
rabies is endemic. The possibility of non-fatal contamination of dogs by
non-canine strains (e.g. those from wild animals living in the region) has also
been proposed (20). Several questions thus arise regarding:
a) the specificity of serum titrations and the threshold level for protection
against rabies;
b) the possibility of rabies outbreaks in naturally seroconverted dogs, and the
interval between seroconversion and the onset of clinical symptoms.
4.2. Rabies infections
The viral infection triggers the production of neutralising antibodies. When a
high dose of rabies virus reaches the central nervous system, neutralising
antibodies are not detectable before or at the onset of clinical signs; they
are usually induced by longer incubation periods. This phenomenon has been
studied mainly in laboratory rodents, which supply the chief model of rabies
immunopathology (49, 73). Unfortunately (but not surprisingly, considering the
difficulty of handling rabid carnivores), there appears to be no literature on
the frequency and intensity of neutralising antibody production in
non-vaccinated infected cats and dogs. Some data can be found in articles by
Artois and colleagues (4), Blancou and colleagues (17) and Fekadu (36)
regarding latent or abortive rabies.
Bell and colleagues (10) proved that dogs which recovered from rabies after
intracerebral inoculation of homologous strains, had high titres of
neutralising antibody in the cerebrospinal fluid as well as in serum and
retained these titres for several months, whereas vaccinated dogs did not have
high cerebrospinal fluid titres. Murphy and colleagues (48) demonstrated the
same phenomenon in cats.
Bell and colleagues (9) were the first to apply cerebrospinal fluid titration
for an epidemiological survey. Of 120 dogs sampled in an area where rabies was
enzootic (Buenos Aires), none was found to be positive; thus, it cannot be
concluded that non-fatal rabies is common.
Blenden and colleagues (21) have suggested that the kinetics of antibody levels
in blood and cerebrospinal fluid should be compared, to determine whether
specific antibodies have been produced by infection or by immunisation. Without
a booster after a first blood and cerebrospinal sampling, the antibody level
should remain stable in cases of immunisation, or increase in cases of
infection. In fact, such procedures have never been routinely used anywhere.
Indeed, given the variability of the titration test, the constancy of an
antibody titre over time is difficult to verify even in a vaccinated animal.
Given the lack of easily-performed experimental methods, the only basis for
considering that an individual dog or cat possessing rabies neutralising
antibodies has been vaccinated is good individual identification and
certification.
5. DISCUSSION
Laboratory conditions described in the challenge of vaccinated cats and dogs
generally appear more severe than natural conditions of challenge in the field.
In normal practice, experimenters use extremely long intervals between
vaccination and challenge (three to five years) and high virus doses involving
100% mortality in controls. In areas contaminated by fox rabies, natural
challenge is not as severe for dogs and this could compensate for the fact that
the health status of pets may be lower than that of dogs bred in the
laboratory. Epidemiological observation is by far the more important evidence;
in continental Europe, rabies vaccination of cats and dogs is so efficient that
where the annual risk of a fatal case of rabies has been evaluated for a
vaccinated pet, this risk is minute (1/6,980,000). It is also noteworthy that
in continental Europe, fox rabies has never been propagated by domestic animals
from an enzootic area to a free one - even if administrative rules concerning
compulsory confinment, leashing or vaccination have sometimes been broken
either deliberately or by the simple fact that rabid pets have escaped from
their owners.
If a neutralising antibody titration were required for certifying the
immunological capacity of vaccinated animals, two questions would arise
regarding:
a) the choice of techniques for antibody titration
b) the definition and acceptance of a minimum antibody titre considered as
providing protection against rabies.
A general analysis of challenge experiments leads to the conclusion that
neutralising antibody titres enable prediction of survival more often on a
qualitative basis (i.e. Do the animals have detectable neutralising antibodies
or not?) than on a quantitative basis. This fact becomes apparent when one
tries to determine a "protective" threshold. For this purpose, either method of
seroneutralisation (RFFIT or MNT) can be employed, provided a correlation
between the two methods has been demonstrated in the same laboratory (14, 66).
Agreements on the international transfer of dogs and cats could be formulated,
therefore, based on a designated minimum level of neutralising antibodies, and
could be proposed as an alternative to quarantine measures. The designated
threshold could be based on the results presented in this study. The security
of the protection constituted by this threshold would be increased by the
extent to which it excedes the level recognised as effective against
experimental challenge in cats and dogs (0.1 IU/ml and 0.2 IU/ml, respectively,
measured by RFFIT).
6. ACKNOWLEDGEMENT
The author wishes to express his gratitude to Dr J. Blancou for kindly revising
the manuscript of this paper.
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