REVIEW ARTICLE
RABIESPROPHYLAXISIN MAN
By Karl Habel, M.D.
Natiotwi institutes of Health, U. S. Department of Health, Education and Welfare,
Public Health Sercice
I N SPITE of the fact that rabies has long beemi recognized as a virus disease, that
more experimental work has been carried
out on this disease than on any other human illness of virus etiology, and in spite of the
existence of a prophylactic vaccine for the past 70 years, nevertheless there continues
to be a rabies problem in most parts of the
world imicluding the United States. Although the number of animals reported annually as rabid in this country varies
l)etweeii 6,000 and 10,000 it is estimated
that those reported represent only a small
proportion—perhaps only a third—of the actual numnber. However, with only 10 to 20 hullian deaths each year due to rabies it would appear that this disease is of minor importance among the health problems of
our human population, yet as many as
50,000 individuals receive antirabies pro phylaxis each year.
A long range program aimed at the elimination of rabies as a public health
problem in any area is actually a veterinary alid wildlife rather than a medical prob
bem, because man represents the end of
the line in the ecology and persistence of
rabies. In other words, if rabies did not oc
cur in animals there would be no medical I)nobbems as regards humans with this dis ease. The present situation in the United States concerning the prevalence and dis
tribution of rabies and the detection of the
animal reservoir is quite a bit different
from what it was 2@ on even 10 years ago. For years the dog bias been the chief source
of exposure of humans to rabies, and be cause of his unique relationships to man will probably continue to be so. However,
in recent years it has been repeatedly and dramatically demonstrated that proper methods of dog-control combined with area
wide vaccination can effectively eliminate canine rabies from an area.1 There is also increasing experience to indicate that the dog population can be kept free of this
disease if the control measures are con
tinned and if vaccination is repeated.
However, with a gradual decrease in the number of rabid dogs it has increasingly been recognized that the reservoir of rabies in other species in this country is not incon sidenabbe.2 Rabid foxes and skunks in a number of states continue to be a source of infection for dogs, farm animals and also man.3 In 1953 for the first time rabies was demonstrated in bats in Florida4 and with but a small effort by a few laboratories evidence for an important reservoir of rabies in bats in this country has already ac cumulated. The bats involved are the com mon fruit and insect eating species but thus far have been found to attack humans
only rarely. The difficulties involved in con
trol of rabies in these wild species are ob vious as reduction of the species popula tion is the only effective method.
The purpose of this review is to present
the current status of effective propliylaxis
against rabies in man. First, the immuno
logic and pathogenetic considerations on which prophylactic measures are based will be presented; then, the local treatment of bite wounds, the use of rabies vaccines and antinabies serum. Finally, the definitive rec ommendations for specific prophybaxis un den various possible conditions of exposure are listed, and a discussion of problems
yet to be solved in this field is provided.
BASICCONSIDERATION
PathogenesisStudies in experimental animals5 have shown that after rabies street virus is in
Dr. Habel is Chief, Basic Studies Section, Laboratory of Infectious 1)iseases, National Institute of Allergy and Infectious Diseases.
ADDRESS:Bethesda 14, Maryland.
troduced peripherally, as into the gastroc nemius muscle of mice, it can be demon strated at the site of inoculation for 4 days but by the second day is already present in the sciatic nerve. By the fourth day it is in the central nervous system. Previous
studies° in rabbits showed that once the virus reaches the central nervous system
it multiplies and again spreads along peniph eral nerves, including those which sup
ply the salivary glands. When it reaches the salivary glands it again multiplies, ap parently in the glandular tissue itself7 and is
excreted in the saliva, thus completing the
cycle. There is no evidence that viremia is pant of the usual pathogenesis of rabies.
Further considerations of interest to the medical clinician include the fact that, ex penimentabby, rabies street virus is not highly
virulent even when purposely inoculated
intramuscularly. It is difficult with any dose of the virus, for instance, to cause infection
in 100% of experimental dogs.8 Tremendous
(loses of virus must be given by mouth to
experimental animals to get any evidence of infection by this route.
Not all animals suffering from rabies have
virus in their salivary glands, however, and
attempts to demonstrate the virus in saliva of rabid dogs are frequently unsuccessful.8 From the little experimental evidence avail able, it would appear that virus is not likely to be present in the saliva until a few days before the animal is actually suffering from clinical rabies.9 Bats on the other hand, es
peciably vampire bats, are abbe to carry rabies virus in their salivary glands and ex
crete it in their saliva for months during which time they are symptom-free.1°
Rabies virus cannot invade the intact skin and only with difficulty can it invade through intact mucous membranes.
Time Factors
Rabies prophylaxis, as beast as far as the use of rabies vaccine is concerned, is a unique procedure for it is the only instance in medical practice where we try to produce an active immunity in the patient after he has been exposed to the infection. The only
reason this is a rational procedure is the relatively long incubation period in this disease. Under natural conditions of ex posure the incubation period of rabies varies from 10 days to as long as a year, but the majority of cases develop between 20 and 90 days following exposure. Though this bong incubation period is an advantage in specific prophylaxis of rabies in the mdi vidual, it is a definite disadvantage in at tempts to control the disease, as animals incubating the infection can travel long dis tances between the time they are exposed and the period in which they tliemiiselves become infectious.
HANDLING OF BITING ANIMAL
The first problem arising in any medical situation concerning rabies actually is a veterinary problem, for it involves the diag
nosis of the clinical condition of the biting
animal. The importance of this aspect of rabies prophylaxis is obvious as there is no specific viral prophylaxis required if the exposure to saliva of an animal has not in volved the rabies virus. Furthermore, as will be discussed later, the specific prophylactic measures used in rabies are not without danger in themselves, and therefore should be employed only when a actual exposure to the virus has taken place.
tion—the usually friendly animal that sud
denly avoids his masters and wants to be
alone or the usually independent dog that suddenly seeks affection. Early signs include
drooping of upper eyelids and lower jaw
with protrusion of tongue followed by
weakness and paralysis of other muscle
groups, including those of deglutition.
If the animal at the time of biting on in
the subsequent 10 days develops signs con sistent with rabies, these signs should be al
lowed to progress uintil they are definite
(usually a matter of 1 to 3 days) before the
animal is killed for laboratory examination of the tissues. This is not true in the case of bat bites. Here the animal should be killed immediately for laboratory examina
tions.
The animal should be killed in a safe and
expeditious manner but not by any means
which will damage the brain. Frequently a bullet through the head has made the brain such a mess that laboratory examination has been difficult. The whole head should
immediately be removed and refrigerated
on tvet ice and taken to the nearest diag
nostic laboratory. There smears of the hip pocampus and other areas of the brain can
be made and the typical inclusion bodies of
nabies—Negni bodies—searched for. If
found, this establishes that the animal was rabid but does not necessarily prove that there was rabies virus in the saliva. For proof of this, emulsified salivary glands must be inoculated intracenebrally into mice in
an attempt to isolate the virus. If histo
logic examination of the brain is negative for Negni bodies this does not eliminate the
diagnosis of rabies, for it has been the gen
crab experience in several laboratories― where microscopic examinations have been routinely checked by inoculation of mice
with emulsions of brain, that about 12% of all brains from rabid dogs will be nega
tive microscopically even though rabies virus can be demonstrated subsequently. There fore a complete laboratory examination for
rabies includes histologic search for Negni
bodies and intracerebral inoculation of mice with emulsions of brain and salivary gland.
The inoculated mice are observed for 30
days before being regarded as negative.
Positive specimens will usually cause symp toms in the mice between the eighth and twelfth day. Some vmnobogists kill a few of the mice on the sixth or seventh day, even though no signs of illness are evident, and examine the brains for Negni bodies in or den to save precious time.
LOCALTREATMENT
OF BITEWOUND
Although the primary point of attack in
preventing rabies is elimination of the in fection from the animals to which man is cx posed, the first consideration in the human after exposure is the treatment of the bite wound itself. This procedure should be car ned out routinely whether the question of rabies is involved or not. Since, as has ab
ready been pointed out, the virus may per sist in the local wound for as long as 48 hours, treatment of the bite wound should be carried out whenever the patient is seen, although best results in ridding the wound of virus will be obtained the earlier treat ment is applied after the bite.
Free bleeding should be encouraged without trauma followed by thorough me chanical cleansing, using adequate amounts of water with soap or detergents. Vigorous
use of soapy water applied to all deep con
ners of the wound with a small catheter at tached to a 20-mI syringe is recommended.― The subsequent use of cauterizing or an tiseptic solutions is a subject on which there is not general agreement. For years fuming nitric acid has been considered almost a “¿specific―for treatment of bite wounds,'@ but experimental evidence for its efficacy is equivocal. Several important factors are in volved. In the first place, very few practic ing physicians keep fuming nitric acid on their medicine shelves. This substance is quite corrosive and may leave burns and
scars; if it traumatizes tissue and does not destroy all virus in the wound, the remain ing virus may invade more easily because of
sive wounds and probably should be ap plied on a probe to deep puncture wounds which are not available to more conserva tive mechanical cleansing procedures. Other materials such as Zephiran®'4 have been reported to be effective in some laboratory experiments and can be uised justifiably.
In a subsequment section dealing with anti
rabies hypenimmune serum we shall discuss
injection of serum about the wound.
Of course, besides this local treatment of
the bite wound, such general procedures as
antitetanus prophybaxis, in the case of punc
tune wounds, and antibacterial therapy,
should the wound become infected, are in dicated.
ANTIRABIES
VACCINE
Antirabies vaccine is the crudest of all biologic products for parenteral use in man. It consists of a whole, unpurified, heavy suspension of the brains of laboratory animals that have been infected with rabies virus. This is a vaccine (not a serum) con taming the rabies virus itseff, which acts as an antigen to produce an active type of
immunity. Its use is based on the same
principles of active immunization that are involved in vaccines against pentussis,
typhoid fever, influenza and poliomyehitis
with a striking difference—it is expected to produce an active immunity to an infection
after the infecting agent has been intro
duced into the human body. The rationale behind this unusual time relationship is based on the bong incubation period of the disease, and the assumption that intensive active immunization will produce an im
munity rapidly enough to “¿catchup― with
the developing infection. Thus the infection would be overcome before the virus in vaded and destroyed vital centers of the nervous system.
Types of Vaccine
Over the years, and even today, there have been a number of different kinds of rabies vaccines used in man. In general they are divided into those containing live rabies virus and those in which the virus
has been inactivated or “¿killed.―Live-virus
rabies vaccines derive from the original Pasteur type but have tended to decrease in popularity because they do not easily lend themselves to decentralized treatment, where the vaccine is made at a central laboratory and distributed thnoughouit a large geographical area. In other words, there is the practical problem of detenio nation of the live virus in the vaccine when it is shipped from the laboratory and stoned under various local conditions. The live virus in these vaccines, and also the “¿killed― virus in other types, is the “¿fixed―virus of Pasteur as contrasted to “¿street―virus which is the virus found in animals under natumral conditions. Fixed virus is standardized and “¿fixed―in its properties by many passages in laboratory animals and most vaccines in use today are made from derivatives of the particular strain of fixed virus ongmnally used by Pasteur.'5 However, there is no evidence that these live-virus rabies vac cines act like other truly live-virus vaccines in man. It is known that the efficacy of smallpox and yellow fever vaccines in man depend on the fact that an attenuated live virus actually multiplies in the vaccinated individual, thus simulating the disease it self but without any serious manifestations of the infection. This is not true of live virus rabies vaccines for there is no evidence that the fixed virus multiplies in the human. Therefore, it acts as “¿dead―or inactivated virus; its only advantage being that unal tered virus might be a better “¿dead―antigen than virus which has been treatc(l in @orne way to render it nonviable. As of today, in the United States only one commercial
laboratory and one state laboratory issue
about half the vaccine used is of the Semple type, and about half is a type in which the virus is inactivated with ultraviolet light.'8
Potency of Vaccines
Up until 1939 there was no practical
method of testing rabies vaccines for poten cy; they were made by arbitrary methods
and assumed to be potent when used. How
ever, when standard testing methods were devised1 20 it was found that most rabies vaccines manufactured in the United States were lacking in potency. In the next few years more attention to production technics
resulted in the availability of safe potent vaccines. Today most any method of pro
duction of rabies vaccine is acceptable
provided the product is proven safe and potent by actual test.
The question of immunologic variation in strains of rabies virus in various areas of the world (and the possibility that vaccine made from one strain may not protect against another) does not enter into the problem of rabies immunization as it does in such vaccines as influenza. The Pasteur Institute in Paris has studied street rabies
virus strains from many pants of the world
and found them all quite similar immuno
logically.
Dosage Schedules
Because the rapidity with which active
immunity develops is all important when
using rabies vaccine prophylactically after
exposure, relatively barge and frequent
doses are given. For ordinary exposures without severe trauma to any part of the body, other than a bite on the head and neck, a course of 14 daily injections is usually
recommended; whereas 21 daily doses are given to those bitten on the head and neck or where severe trauma has been inflicted on any part of the body. In some countries
only seven doses are used for the bess severe exposures.
Each dose is usually the equivalent of
2 ml of a 5% brain emulsion. Recently
several manufacturers in this country are supplying a 0.5 ml dose of 20% emulsion.
In some parts of the world much larger daily doses are used. All doses are given subcutaneously and the usual practice is to give them in the quadrants of the ab dominal wall in rotation.
There are some special considerations required in the use of rabies vaccine in pediatrics. Evidence in experimental ani mals, and to some extent confirmed in experience with human beings, suggests
that young children are quantitatively more susceptible to rabies infection than olden
children on adults. Because of this, a bite in a child under 5 years of age is sometimes
treated, whereas for a similar bite in an
adult treatment would be deferred to await subsequent events in the biting animal. This will be covered more completely in the
section on Specific Recommendations. In young children (under 3 years of age) half
the volume of the adult dose is usually employed.
Complications
As mentioned before, rabies vaccine is the crudest biologic material injected into man and is not without (banger in itself, unrelated to exposure to rabies. As it is prepared from tissue of a foreign species
( rabbit) and repeated doses are used, prac
ticabby all treated individuals develop some sensitivity to the material (luring the course
of immunization. Usually about the time of the seventh daily dose large painful in durated swellings appear, not only at the site of the most recent inoculation, but fre quently at all previous sites. This is not a serious complication and is not an indication to discontinue the vaccine.
Another reaction based on sensitivity to species protein is an immediate general
hypersensitivity reaction following the first dose. This happens most frequently in pen sons who receive rabies vaccine for a second
immunization or more, and because it is based on sensitivity to rabbit protein can
usually be overcome by changing to a vac
sensitivity to rabbit protein or a history of severe general allergy, then a skin test with diluted vaccine should be performed before starting the course of immunization.
The most severe complication is based on the development of organ-specific sen sitivity. Postvaccinal paralysis or iso-allergic encephalitis appears to be due to develop ment of hypersensitivity to the brain tissue in the vaccine and leads to a demyehinating destruction of the patient's own central nervous system. The histologic and clinical picture of this complication can easily be produced in experimental 223 even when inoculated with an emulsion of its
own brain tissue. Although there is some
evidence indicating that this complication occurs more frequently in persons receiving a second course of vaccine'4 or more and in those with a previous history of allergy,'5 the actual incidence is quite low. Reports from the United States have varied from as much as 1 in 6002; immunizations to as little
as 1 in 7,@JØ1J,24and in some parts of the
world it is claimed to be practically non existent. In spite of some reports to the
contrary, it occurs following all types of
vaccine. The degree of involvement of the central nervous system varies from mild
transient weakness to a fatal ascending
paralysis of the Landry type. It is stated that the mortality from these reactions may
vary from 10 to 25% but in those who sun vive there are generally few residual
The only way to avoid this dangerous complication is the discriminate use of the vaccine. Rabies vaccine should be admin istered only when there is a definite indica tion. The mere presence of a proven rabid dog in a household is not an indication to
give vaccine to all members of the family, as has been done by some overanxious
practionens. Furthermore, if during the course of immunization the patient develops constitutional signs or symptoms such as headache, nausea, vomiting, tingling sensa
tions, general lymphadenopathy or manifes tations of general allergy (these usually occur after the seventh dose), then the
course of vaccine should be discontinued unless there had been a very severe type of exposure to a proven rabid animal. In that case cauttious use of smaller doses, perhaps at intervals of several (lays, may be indicated while observing the patient for signs of involvement of the central nerv ous system. Although there is no evidence from a controlled series of cases, it has been suggested, on the basis of experimental prevention of allergic encephalitis in guinea pigs with ACTH, that ACTH or cortisone and perhaps antihistaminics might be use ful both at this stage and when paralysis develops.
Of course the real preventive of iso
allergic encephalitis would be to use some product for prevention of rabies which did not contain brain tissue. Attempts have been made to remove the factor responsible for organ-specific sensitization'5 from the brain emulsion vaccine, but thus far no practical method has been found. Further possibili ties along this line will be discussed under Serum Prophylaxis and Future Problems.
Evidence of Efficacy of Vaccine
Although rabies vaccine has been in use for 70 years there are still questions raised
as to whether it really is effective in the
post-exposure prophybaxis of the “¿
It has been pointed out that the original
experiments by Pasteur involved small numbers of animals (now considered sta tisticably insignificant), that statistics on suits of treatment of humans are difficult to evaluate because the degree of exposure is so variable and in the majority of instances rabies is not proven in the biting animal,
and finally that well-designed and con
trolied experiments in animals have usually been negative for evidence of protection when exposure to street rabies virus is followed by a course of vaccine. While all these statements are true, nevertheless, when quantitative aspects of experiments are well balanced, protection—admittedly of low level—can be 7@8
The author's opinion in this matter can be
to rabies would not result in the disease even without any specific prophylaxis.
Many severe exposures, where the incuba
tion period may be short, will result in fatal
rabies infection no matter how much vac
cine is given—most vaccine failures occur between the twentieth and thirtieth days after exposure. However, there is a large
group of individuals receiving moderate exposure for whom the prompt use of vac cine will spell the difference between sun vival, and death from rabies after a pro longed incubation period.
ANTIRABIES
SERUM
Experimental Basis for UseTheoretically, rabies is the ideal disease
for passive immunization with immune
serum. In what other infectious disease do
we know the exact minute of exposure, the exact individual responsible for the ex
posure and the exact location on the body where the infection was introduced? All these facts plus the long incubation period
and the evidence that the virus stays local ized in the wound for several days before l)eimig demonstrated in the nervous system
made a trial of antinabies serum obvious to
the early workers in the field. However,
early experimental results were equivo
3' and the difficulty of interpreting field results'2' 33 led to a loss of interest in
this type of prophylaxis. More recently, laboratory experiments using modern cx penimental methods have again demon
stnated the high efficacy of a potent anti
serum in preventing rabies in animals.'@' is
Later results indicated that antiserum alone
was much superior to a course of vaccine
alone but that the use of both gave the best
results.3u It was also shown that if antiserum was uised locally to infiltrate the site of the bite-wound, its effectiveness was in
creased.―
Results of Field Trial
In 1950 the World Health Organization's Expert Committee on Rabies38 expressed
an opinion that the new experimental evi dence justified antirabies serum being given
a limited but severe test in the field. It was
known that in Iran rabid wolves not in frequently attack groups of natives living
in mountainous areas, and usually inflict severe bites especially about the head and neck. Previous experience'9 had shown that in this extremely severe type of exposuine the mortality rate was 40 to 50%, in spite of a full course of active immunization with potent rabies vaccine. This seemed an ideal situation in which to test whether use of antiserum in addition to vaccine would reduce this high mortality. Not until 1954 did an opportunity again present itself,40 when 27 individuals were bitten by a single proven rabid wolf, 17 of them on the head. These 17 were divided into three treatment groups: one received vaccine alone as usual, a second received one dose of antirabies
serum plus a course of vaccine, and the
third group was given t@vo doses of anti serum 5 days apart along with a course of vaccine. Three of five persons treated with vaccine alone died of rabies, one of five in the one-dose antiserum group, and none of the seven in the two-dose antiserum group.
Present Status
Studies on formation of antibody in in dividuals involved in the Iran field triai@' and in normal people given various sched ules of vaccine and antiserum, under the au spices of the World Health Organization,4' indicate that a single on double dose of antiserum given at the start of treatment, followed by 14 or 21 daily doses of rabies vaccine, gives a significant level of cinculat ing antibodies continuously from the first
day through as bong as 50 days. The anti body found early is supplied passively by
the dose of antiserum, and after the tenth
day the patient develops his own antibody as the result of the vaccine.
In view of the results of experimental and field trials, it is now felt that antiserum
plus vaccine provides the best prophylaxis
of rabies in man and the combination should always be used in cases of severe
exposure. In cases of severe bites, but where
animal was rabid, antiserum may be given
and use of vaccine reserved until the condi tion of the biting animal may be assessed adequately. There is no contraindication to the use of antiserum in milder types of exposure but here vaccine alone is usually sufficient. Although experimental studies in dicate that antiserum alone is more effective than vaccine alone,― there are no field trial results to substantiate these findings. At the present time it is believed that antiserum should be used in conjunction with a course of vaccination.
The antirabies serum currently available in this country is a partially purified and concentrated horse-serum product. It is given in a dose of 0.5 ml/kg of body weight; in severe exposures a second dose is given 4 to 5 days
@ In the meantime the usual
course of vaccination is started. As much
of the total dose of antiserum as is practical should be infiltrated around and under the site of the bite wound; the nest being given
intramuscularly in the buttock or thigh. It
must be remembered that this is a horse serum product and therefore before use a skin on ophthalmic test for sensitivity must be negative. Also the purification of this antiserum has not rendered it free from the proteins in horse serum responsible for serum sickness. This complication occurs as frequently as with other horse-serum products.
RECOMMENDATIONSREGARDING
SPECIFIC PROPHYLAXIS
Certain items of information are neces sany before the practicing physician can give a scientific judgment as to whether specific prophylaxis is required in a given situation, and what type of prophylaxis should be used. These items include:
0 More recent experiments indicate that on cer
tam dosage schedules rabies antiserum may inter fere with the antigenicity of the vaccine. It has, therefore, been recommended that the entire cal culated dose of antiserum be given in a single dose at the start of treatment and this should be followed with at least 14 daily doses of vaccine.
whether the biting animal is known and apprehended; the clinical and laboratory evidence for rabies in the biting animal; the presence or absence of rabies in the area; the nature of the exposure (whether lick or bite) and, if bite, the site, severity and whether through clothing; the age of the patient; time relationships. The vac cination status of the biting animal should not enter into the decision because pro phylactic immunization of dogs against rabies is not 100% effective. The implications of most of these factors are set forth in out line form in Table
@
Status of Animal Responsible for Exposure
If the biting animal is not identifiable nor apprehended, the clinician has practi caily no information on which to make a decision, and in carrying out his respon sibilities to the patient he can only assume that the animal may have been rabid and act accordingly. This is especially true where rabies is known to exist amongst the dogs or wild life in the area. In areas which have been free of rabies for some time and the geographical location, such as island
countries, makes reintroduction of the dis
ease unlikely, the physician or health au thonities may feel justified in this situation in not recommending treatment.
Where the animal is apprehended and can be observed, his condition concerning rabies is important, both at the time of the exposure and during the subsequent 10-day period. Even if the animal should develop proven rabies later than 10 days after exposure, it is felt that specific treat ment is not required because rabies virus would not have been in the saliva that long before the development of clinical mani festations of rabies. This is not true in the case of bites by bats! In fact a bite by any wild animal should be consided an exposure and treatment started. If the wild animal
( other than a bat) is under observation,
@\‘a1nreof Expo.iureCondition
of Biting AnimalRecommended
TreatmentAt Time of Exposure.
.
During Observation
Period of 10 Days
TABLE I
INDICATIONS FOR SPECIFIC TREATMENT AFTER EXPOSURE TO RABIES*
I. N@oleSU)118in(lirect
contact @@)I1ly
II. Licks:
(1) unahrade(l skin
(@)abradedskin, aIi(l abraded
or unabraded mucosa
III. Bites:
(1) simpleexposure
(2) severeexposure;
(multiple; or
biteson face,
head, or neck)
Rabid
Rabid (a) healthy (h) healthy
(c) sigmissuggestiveofrabies
(d) rabid, escaped, killed, or unknown
(a) healthy
(b) healthy
(e) signssuggestiveofrabies
(d) rabid, escaped, killed, or unknown; or any bite by wolf, jackal, fox, or other wild animal.
(a) healthy
(I)) healthy
(il) rabid, escaped, killed, or
unknown. Any l)ite by
wild amnmi@al.
Nonet
Nonet None
St@artvaccine at first signs of rabies in animal.
Start vaccine immediately; stop treatment if animal is
normal on fifth day after
exposure.** Start vaccine immediately.
None
Start vaccine at first signs of rabies in animal.
Start vaccine immediately; Stop treatment if animal is
miormnalon fifth day after exposure.**
Start vaccine immediately.
Hyperimmune serum im. mediately; 110 vaccine a@ long as animal remains normal.
ilyperimmune serum im mediately; start vaccine at first sign of rabies. Hyperimmune serum ha
mediately, followed by
vaccine; vaccine may he
stopped if animal is nor mimIon fifth (lay after ex posure.
Hyperimmune seruimi un
mnediately, followed by vaccine.
Healthy
Clinical signs of rabies or proven rabid. Healthy
Healthy
Clinical signs of rabies proven rabid. Healthy
Healthy
Clinical signs of rabies or proven ral)id.
(c) signs suggestive of rabies Healthy
* From Report of Expert Committee on Rabies, \V.lT.O., p. 1@2.' This Table has been slightly revised and ex pallded in Report on the Third Session of the Expert Committee on Rabies. Wid. 111th. Org. Techn. Rep. 5cr. —¿tobe published.
t Start vaccine immediately in young children and in patients for whom a reliable history cannot he obtained. ** An alternative treatment would be to give hyperimmune serum and not start vaccine as long as the animal
remained normal.
Note: To be effective hyperimmune serum must be given within 7@hours of exposure. Dose: 0.5 mI/kg of body weight (for serum potency, see Annex @,page @5').
It is important to remember that a nega tive laboratory diagnosis of rabies based on microscopic examination of the brain may
be only 90% valid. Therefore, if a veterinary diagnosis on clinical grounds is made but
laboratory results are negative, still con sider the exposure to have been a real one.
Nature of Exposure
One of the most frequent decisions that
has to be made concerns whether or not a
lick, rather than a bite, constitutes an cx posure. If the lick is on intact skin, it is not considered an exposure. If the lick is over freshly abraded area of skin or on mucous membranes, this is an exposure. Old cuts or abrasions now crusted over, i.e., dry, should be considered the same as in tact skin. Most rabies experts outside the United States would not agree with this recommendation; however, we feel justified in making it for two reasons : First, the chances of developing iso-allergic encepha litis from vaccine are probably greater than the chances of developing rabies from a lick on intact skin; secondly, the experience in the state of Georgia,44 where rabies has been a continuous problem and many re ceive vaccine each year, shows that in over 30 years of refusing to give vaccine under these circumstances not a single case of rabies has developed. It will be noted in Table I that some authorities hold the opinion that young children are an excep tion to this general recommendation be
cause of their greater susceptibility.
The site and severity of the bite by a rabid animal determine the type of specific
prophylaxis to be used. Deep penetrating
bites, those inflicting severe trauma and multiple bites should be considered severe
exposures no matter where located, just as any bite on the head and neck is also so considered. As these severe types of cx
posure are those in which a short incuba tion period is anticipated, treatment is started immediately no matter what the status of the biting animal at the time of the bite. A single dose of antiserum should be given immediately or if antiserum is
not available vaccine should be started. Subsequent procedure depends on whether the biting animal remains healthy for 10
days, butt where full treatment is indicated
21 daily doses of vaccine are recommended and injection of antiserum shoumid be re peated on the fifth
@
For simple exposures, only 14 daily doses of vaccine are used but there is no contra indication to the combined use of antiserum and vaccine in such cases. If the biting ani mal remains normal after a dose of anti serum has been given to the exposed in
dividual, no further treatment need be
given; if vaccine has been started and the animal is normal 5 days after exposure, no further vaccine is indicated providing the animal remains well the entire 10 days of the observation period.
Although a bite through clothing greatly
reduces the opportunity for saliva and virus
to enter the wound, it nevertheless cannot influence the decision as to indication for
prophylaxis. This is also true if the biting
animal has been recently vaccinated against rabies; the chances of the dog being rabid are less but there are some failures in vac cination of animals so the exposure of the patient cannot be evaluated any differently.
Age of Patient
As it is assumed that children under 5 years of age may be more susceptible to invasion of the rabies virus, these patients are sometimes started on prophylaxis im
mediately whereas under the same con
ditions it could be withheld pending de vebopments in the case of older children and adults. Thus indirect contact or a lick on intact skin by a rabid animal would be considered an exposure in young children. Also a simple type of exposure of a young child to an apparently healthy animal in a
0 More recent experiments indicate that on cer
locality where rabies is known to exist could justify the start of treatment.
Time Relationships
Because one is already at a disadvantage
when beginning immunization after cx
posure to an infection, it is obvious that the sooner vaccine is given the better. The
use of an initial dose of antiserum can justifiably coven a delay in starting vaccine, because passive immunity in the form of
antibodies gives early protection and tends to slow up the progression of the infection
( in animal experiments antiserum alone,
even if not effective in completely prevent
ing rabies infection, greatly prolongs the
incubation peniod).17 However, where the indications for specific prophylaxis are de finite, it should be instituted no matter how
much time has elapsed since the exposure.
If antiserum was given on vaccination started immediately because of the nature of the exposure, and the biting animal is still clinically healthy on the fifth day of observation, no further treatment need he
given so long as the animal remains healthy through the tenth day. However, if the animal develops symptoms consistent with rabies between the fifth and tenth (bays, then OflC should give a second dose
of antiserum plus a course of 21 (loses of
vaccine in the case of severe exposures, and should complete the course of 14 doses of vaccine in simple exposures.° If the animal
is healthy on the tenth day, the possibility
of exposure to rabies can be excluded.
Re-exposure and Immunization Against
Anticipated Exposure
Not infrequently in certain groups of in
dividuials, such as veterinarians and dog
handlers, a person previously exposed to rabies and treated is re-exposed. If this
re-exposure occurs within 3 months of the
0 More recent experiments indicate that on cer tam dosage schedules rabies antiserum may inter fore with the antigenicity of the vaccine. It has, therefore, l)cen recommended that the entire cal culated (lose of antiserum be given in a single
dose at the startof treatment and thisshould be
followed with at least 14 daily doses of vaccine.
original treated exposure, no prophylaxis is necessary unless it is a very severe type of exposure; if between 3 and 6 months, then two doses of vaccine 1 week apart will suffice; but if the interval is greaten than 6 months, a schedule of full treatment should be followed.―
In individuals likely to be repeatedly cx posed to bites of dogs and living in areas where rabies is known to occur, the question arises as to the feasibility of immunization as a protective measure in advance of any exposure. For this purpose three doses of vaccine at 2-week intervals would establish a good basic immunity. Indications for subsequent treatment in case of actual cx posune would be the same as in the preced ing paragraph.
There is some reason to believe that when a basic immunity is once established, a booster type of response will follow sub sequent immunization even after several
years, but the evidence at the present time
is too scanty to depend on this.@―46
PROBLEMS FOR FUTURE RESEARCH
Research in the field of prophybaxis of
rabies in man is aimed first at reducing or eliminating the dangers due to the prophy lactic measures themselves and improving the efficacy of these measures, and finally searching for more efficient and more prac tical new methods.
Relating to a Vaccine
A source of virus for preparation of vac
cines, not containing brain tissue, should
eliminate the occurrence of the complica tions of iso-allergic encephalitis and post vaccinal paralysis. At the present time two
such vaccines, both prepared from rabies
infected avian embryos, are being investi
gated. One4' is a live, attenuated-virus vac cine similar to Flury's chick embryo vac
doses call forth an antibody response com parable to that produced by the brain-type vaccines.4' The other vaccine is an macti vated-virus vaccine produced from rabies infected duck embryos.48 Here, too, anti body response in man appears comparable to that following vaccines in current use, and this vaccine is now licensed for use in man.
Use of tissue cultures as possible sources of virus to be used for preparing inactivated vaccines is being investigated in several laboratories. Thus far not enough virus is produced by these tissue culture systems to expect them to make potent vaccines.
As more experimental information is forthcoming concerning the chemical na tune of the factor in brain responsible for producing iso-allergic encephalitis, pro cedunes in vaccine production to eliminate it may be developed.
Experimental studies are in progress to determine if the number of doses of vaccine can be reduced with different spacing of doses while still retaining the efficacy now obtained with 14 on 21 daily doses. It is hoped that fewer doses of vaccine may ne
duce the incidence of post-vaccinalparaly
sis.
Relating to Antiserum
Increased potency and purification to re move the sensitizing serum proteins are the
goals of research on rabies antiserum as
well as for other types of antisera. Further experimental studies in man and in animals are being carried out to determine the interrelationships between antiserum and vaccine. There is already some indication that the antigenic stimulus of fewer doses of vaccine may be inhibited by antiserum given at the same time.4' These quantitative relationships must be worked out in more detail.0
0 More recent experiments indicate that on cer tam dosage schedules rabies antiserum may inter fere with the antigenicity of the vaccine. It has,
therefore, been recommended that the entire cal
culated dose of antiserum be given in a single dose at the start of treatment and this should be followed with at least 14 daily doses of vaccine.
Although exceedingly difficult to carry out and to evaluate, some attempt should be made to test under field conditions the efficacy of antiserum alone after simple exposures. If this were proven to be suf ficient protection it would at the same time eliminate the severe complication of post vaccinal paralysis.
Relating to Chemotherapy
Rabies offers an ideal situation for the use of an antivinal agent because the exact time of exposure is known. Certainly rabies virus should be included in any program aimed at the development and testing of substances for action against viruses.
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1957;19;923
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Karl Habel
RABIES PROPHYLAXIS IN MAN
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