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THE THEORY AND PRACTICE OF ANTI-RABIC
IMMUNISATION.
A
LMOST every Pasteur Institute has its own method of treatment differing
from that of other Institutes and from Pasteur's original scheme. These
differences show that immunity can be obtained by the administration of protect-
ive material in amounts which may vary within wide limits. In the light which
research has thrown upon the problems of immunity in recent years we may ask
ourselves which of the various methods of anti-rabic treatment is to be regarded
as best combining accuracy of dosage with the establishment of protection.
The enquiry may even be pushed further and include a consideration of the advis-
ability or otherwise of adopting an entirely new method of procedure—one more
conformable with that accepted as satisfactory for anti-bacterial immunisation.
Some of the differences in treatment as at present practised are more apparent
than real. Thus, in one place the rabbits used are smaller and yield in consequence
thinner spinal cords. Drying will be more rapid in the case of the thinner
than the thicker cords, and therefore larger doses of the former ( i.e., greater
lengths or weights) will correspond to smaller doses of the latter. Again, the
character and type of patient treated has to be taken into account. Patients
of comparatively poor physique and deficient stamina will have to be treated
more carefully and with smaller doses than robust patients lest they be disturbed
in general health by the treatment and so require an enforced and undesirable
rest from inoculation. There are many other reasons which singly or col-
lectively serve to justify the adoption of particular formulæ of treatment ; and
it would be satisfactory if some consensus of opinion were reached at all events
on such points as the following :—
(1) The effect which various degrees of desiccation or other treatment to
which rabies material may be subjected has upon its infectivity or upon its vac-
cinal power, and the expression of this effect in terms of some definite unit.
(2) What total amount in units of fixed virus should be administered to a
patient under given conditions and within a given period of time in order to
produce as rapidly and satisfactorily as possible a maximum power of resistance
to rabies infection.
B
3
We should then be able to say that for a light case or a severe case at least
so many units must be given within a certain period. We have endeavoured—as
we show later—to obtain a basis on which a calculation of this sort may be made.
Meanwhile we may exemplify our meaning by taking an arbitrary value and
applying it to the elucidation of the simplest of all the schemes of treatment—that
of the late Prof. Höyges. The next step will be to correlate the scheme of
Höyges with other schemes which proceed on a different basis, and then we
should finally be in a position to arrive at some general conclusion.
Let us say then, for the sake of our example, that 0. 2 cc. of a 1 per cent.
emulsion of fresh rabies material is equal to 1,000 units,—quite an arbitrary value
of course—then 0. 2 cc. of a 1/1,000 emulsion= 100 units and 0.2 cc. of a 1/10,000 e m u l s i o n
= 10 units. From this we can give an exact value to Höyges' schemes, light
and intensive.
Three cubic centimetres (the dose administered) of a 1/1 0 , 0 0 0d
i l u t i o n w i l l b e
equal to 150 units, and so on. Thus in Höyges' light scheme the patient re-
ceives on the first day 887.5 units ; on the second 800 units ; and so on for the
succeeding days.
B 2
4
TABLE I.
HÖYGES' LIGHT SCHEME.1
Day.
Dilution.
Dose.
No. of units.
1st
. . .
1 / 1 0 , 0 0 0 + 1 / 8 , 0 0 0
3 cc. + 3 cc. . .
887.5
1 / 6 , 0 0 0 + 1 / 5 , 0 0 0
3 cc. + 3 cc.,
2nd
. .
1 /
5 , 0 0 0
+ 1 /
2 , 0 0 0
3 cc. + 2 cc.
.
.
800.0
3rd .
. .
1 /
2 , 0 0 0
+ 1
/ 1 , 0 0 0
2 cc. + 1.5 cc.
.
.
1,250
4th .
.
.
1/1,000 + 1/500
1.5 cc. + 1 cc.
. . .
1,750
5th .
. .
1 / 2 0 0
1 cc. . . .
.
2,500
6th .
.
.
1 / 6 , 0 0 0 + 1 /
5 , 0 0
3 cc.
+ 3 cc
.
.
1,050
1 / 2 , 0 0 0
2 cc.
7th
. . .
1 / 2 , 0 0 0
+ 1 /
1 , 0 0 0
2 cc.
+ 1.5 cc .
. .
1,250
8th
. . .
1/
1,000 + 1/500
1.5 cc. + 1cc . . .
1,750
9th .
.
.
1/ 200
1 cc. . . . .
2,500
10th
.
.
1 /6
, 0 0 0 + 1 /
5 , 0 0 0
3 cc. +
3 cc . .
1,050
1 /
2 , 0 0 0
2 cc.
11th.
.
.
1 /
2 , 0 0 0 + 1 / 1 , 0 0 0
2 cc. +
1.5 cc .
.
.
1,250
12th.
. .
1 /
1 , 0 0 0 + 1 / 5 0 0
1.5 cc. + 1 cc .
.
.
1,750
13th.
. .
I
/ 2 0 0
1 CC.
.
. . .
2,500
14th.
. .
1 /
1 0 0
1 cc .
.
. . .
5,000
TOTAL
.
25,287.5
1 Deutsch &amp; Feistmantel "Impfstoffe und Sera," p. 154.
5
But it is obvious that the amounts in units given in this scheme may be
made up in a variety of ways. Thus instead of the patient receiving 3 cc.
of 1/ 10, 000, 1/ 8, 000, 1/ 6, 000, and 1/ 5, 000 di l ut i ons on t he f i r s t day, he mi ght r ecei ve i ns t ead t wo
d o s e s ( 3 c c . e a c h ) o f 1 / 9 0 0 0 a n d t w o d o s e s ( 3 c c . e a c h ) o f 1 / 5 , 5 0 0 d i l u t i o n s . I n f a c t
the whole treatment might be carried through with the use of a comparatively
s m a l l n u m b e r o f d i l u t i o n s — s a y 1 / 4 , 0 0 0 , 1 / 1 , 0 0 0 , 1 / 2 0 0 — a n d y e t b e e x a c t l y e q u i v a l e n t a m o u n t
for amount with that set forth in the more complicated scheme. Further we may
ask, is there any advantage in making numerous inoculations where one or at
most two would suffice ? Why give on the first day 3 cc. of 1/10,00 0 0 , 1 / 8 , 0 0 0 ,
1/6,000, 1/5,000 instead of what is exactly equivalent, two inoculations, 4.87 cc. of 1/5,000 and 4.005 cc.
of 1/5,000, or, simpler still, one inoculation, 3.55 cc. of 1/2,000? In this the analogy
with other diseases in which immunity is produced by artificial inoculation
may help us. It has been observed (Bannerman), for instance, that the immunity
prophylactically obtainable against plague is greater when the dose of in-
oculation material is divided up and inoculated in several places. Such an
idea too is in harmony with the conception that anti-bodies are largely produced
by those body cells which are in the neighbourhood of the inoculation. 1
E a c h
new place inoculated constitutes a new factory of anti-bodies, whilst within
certain obvious limits the more of these there are and the more cells directly
stimulated to produce anti-bodies the greater will be the amount of anti-body
production and the greater will be the resistance set up against the originally
contracted infection. The endeavour of the operator must be to induce the
maximum amount of anti-body production and to avoid any chance of the
excessive development of that " negative phase " condition in which the person
inoculated is rendered less rather than more resistant to attack. In spite of
the fact, however, that there is some evidence to show that several small
inoculations in different parts of the body produce a better or more rapid
immunity than does the same total amount inoculated in fewer places, we
find the general practice, e.g., in the cases of plague, typhoid fever, cholera,
staphylococcus infection, is to give only two or three properly interspaced
injections. We may therefore legitimately ask ourselves whether it would be
possible to apply this method likewise to the prophylactic treatment of rabies
and whether this would be as good a method as that of the daily inoculation
which is at present the only one practised. It would be a great boon to patients
if, for example, they received one injection upon arrival at the Pasteur Institute
and a final one, say, 10 days later. The question which must certainly be
asked is whether the procedure would be safe or not. We have given massive
1 Wassermann and Citron Deutsch. Med. Woch., 1905, No. 15, p. 573,
Zeitschr f. Hyg., May 19th, 1905, p. 331.
6
doses of fresh rabies virus to various animals with no ill effect. We have also
produced immunity to subdural inoculation in dogs by as few as one, two, and
four subcutaneous inoculations (separate trials) of fresh rabies virus (vide
pp. 23-24). These experiments we refer to later, but in any case we go no further
in this paper than to afford our testimony and give our support to those workers
who advocate a diminution of the number of anti-rabic inoculations with an
increase in their daily strength.
Another point of discussion which is suggested by an examination of
Höyges' sc-heme of treatment (and it is equally suggested by other schemes)
is the necessity for returning to a weaker dose after having once reached a
stronger. Would there, for example, be any serious apprehension of danger or
of insufficient protection if Höyges' light scheme were altered as follows ?
TABLE II.
Day of inoculation.
Number of units given.
1st
.
.
.
.
.
.
800
2nd . . . . . . . .
887.5
3rd
.
. . . . . .
1,050
4th
. . . . . . . .
1,050
5th
.
.
.
.
.
.
.
1,250
6th .
.
.
.
.
.
.
.
1,250
7th
. . . . .
1 , 2 5 0
8th
.
. . . . . . .
1,750
9th
.
.
. . .
. .
1,750
10 th . . . . . . .
1 , 7 5 0
1 1 t h
.
.
.
.
.
.
.
.
2,500
12th
.
. . . . .
2,500
13th
. . . . . .
2 , 5 0 0
14th
. .
. .
. . .
.
5,000
TOTAL .
25,287.5
7
It is said that it is important that a patient should be introduced as quickly
as possible to virulent material. This, however, does not seem to us to be
sufficient reason for a return immediately thereafter to less virulent, or, in the
case of Höyges' scheme, to smaller amounts of virus. In Höyges' scheme the
strongest dose given is 1 cc. of 1/100 dilution (5,000 units). It can scarcely be
t hat a 1/ 100 di l ut i on i sp e r
s e
more dangerous than a 1/2000 dilution; for 0.5 cc. of
1/100 dilution (2,500 units) is equal as regards content in virus to 4 cc. of 1/100 dilu-
tion. We consider, therefore, that some such alteration of Höyges' scheme as
that given above (Table II) would be as satisfactory as the scheme in general
use, or, if it were essential to hasten the earlier stages, it might be altered some-
what as follows :—
TABLE III.
Day of inoculation.
No. of units.
1st
.
.
.
.
.
.
.
.
.
8 0 0
2nd .
.
.
.
.
•
.
.
.
1,000
3rd .
.
.
.
.
.
.
.
.
1,000
4th
.
.
.
.
.
.
•
.
.
2,000
5th .
.
.
.
.
.
.
.
2,000
6th
.
.
.
.
.
.
. . .
2,000
7th .
.
.
.
.
.
.
•
.
2,000
8th
.
.
.
.
.
.
. .
.
2,000
9th
.
. . . . . . .
2,000
• 1 0
t h
,
.
.
.
•
.
.
.
,
2,000
11th .
. . . . . . • . .
2,000
12th .
.
.
.
.
.
.
.
.
2,000
13th .
.
.
.
.
.
.
. .
3,000
14th .
.
.
. . . . . .
4,000
TOTAL
.
27,800
Again, when we consider that the intensive scheme (Höyges') results in the
administration in 11 days of an amount (24,287.5 units) very nearly the same
as the total amount given in 14 days in the light scheme (25,287.5 units), we
may well ask whether some 25,000 or 26,000 units administered in 10 or 11 days
8
might not suffice for a light form of treatment and so save the patient the neces-
sity of waiting longer. Let the patient have 25,000 units in 11 days and then
depart. This idea (rapid immunisation) has been referred to by other authors,
and has actually been put into practice (Ferrans, 1 Nitsch 2). It is one to which
we think earnest consideration should be given.
We may now sum up our position so far as we have yet discussed it.
(1) The variations among different schemes of treatment are probably to
a large extent only apparent and do not necessarily imply any great divergence
of opinion. Anti-rabic treatment consists in the administration of rabies virus
in various amounts with the view of producing what is probably entirely an anti-
microbic immunity* as distinguished from an anti-toxic. We have taken as an
example one scheme and shown how an infinite number of variations in the
method of its application are possible. The same applies to other schemes, only
that it is a little more difficult in them to demonstrate the fact owing to the quan-
titative relations between the different strengths of vaccine not being so easily
estimated.
(2) The justification of the administration of small doses frequently repeated
possibly lies in this, that by so doing a greater area of anti-body producing cells
is brought into action.
(3) It is possible and might even be advantageous so to alter the method of
anti-rabic treatment as to bring it into line with the prophylactic treatment of
plague, typhoid fever, etc. Such a method as this, even though not applied
in the case of human beings, might be eminently serviceable in India for the treat-
ment of the lower animals. The difficulty here is that delay might occur in
obtaining the necessary material of inoculation. In such a case, if available,
the brain of the biting animal might serve for the administration of a first
subcutaneous injection. In some ten days, when a second injection would be
due, the specially prepared fixed virus from a Pasteur Institute would have
had time to arrive. Of course it might not always be possible to obtain the
brain of the biting animal. In that case if the requisite material arrived late
from the nearest Pasteur Institute, it might be necessary to adopt the
method of intravenous inoculation of fixed virus which Roux and Nocard, 3
Protopoff,4 Moncet5 and others have shown to be of service in the rapid
1 Ferrans using fresh rabies material has reduced the period of treatment in ordinary cases to five
days—Handbuch der Path. Mikr. Kolle & Wassermann Suppl. Art. 'Lyssa' (Frosch.), p. 647.
2 Nitsch "Remarques sur la méthode pasteurienne du traitement préventif de la rage" Extr. Bull
de l' Inst. Past., 1906, p. 1057.
3 Ann. de l' Inst. Pasteur, 1888, p. 341.
4 , ,
, , , , , , , , 1 8 8 8 , p . 4 6 2 .
5 ,, ,, ,, ,, ,, 1902, p, 398.
* To be yet more fully taken up later with the experimental evidence.
9
production of immunity to rabies. As a purely prophylactic measure, in antici-
pation of the possibility of being bitten by a rabid animal, anti-rabic inoculation is
not accepted as expedient in the case of human beings. In India, however,
where every year numbers of valuable dogs and other animals develop rabies,
the question of a yearly inoculation of fresh rabies material as a preventive
might commend itself to owners. This would be the more feasible if, say,
one inoculation per year should prove to be sufficient to establish and maintain a
satisfactory degree of immunity and yet be itself quite safe. The point requires
more experimental work (vide pp. 23—24) than we have been able to devote
to its elucidation.
We have now considered our subject from a general and more or less intro-
ductory point of view, and may now proceed to set forth certain experimental
investigations carried out by us with their results. We shall consider—
I. The infective power of dried rabies spinal cords relatively to fresh
rabies virus.
II. The rate of desiccation of rabies spinal cord by the ordinary procedure
and its bearing upon the use of the cord for immunising purposes.
III. The reduction of systems of immunisation to uniformity.
IV. The effects obtained by the use of massive doses of fresh fixed virus
in anti-rabic immunisation.
V. The question of the existence or non-existence of a rabies toxin.
VI. The standard fixed virus and how to maintain it.
I.—The infective power of dried rabies spinal cords relatively
to fresh rabies virus.
1.—Degree of infectivity of rabies virus a function of loss of weight in water
by drying.
By infectivity here we understand the power of producing rabies in an
animal and the capability of that disease to be propagated by further inoculation
into other animals. In many infections other than rabies the term minimum
lethal dose is a familiar one. A priori there would seem to be no reason why
this measure should not be employed as a standard one in the case of rabies
also. But the death-point is variable even in the case of fixed virus, and there-
fore the criterion of ' fixity' of rabies virus has by universal consent been taken
to be, that symptoms should supervene in a given time (6-7 days) after the date
of subdural inoculation. In our experiments we make use of the term mini-
mum infective dose (M. I. D.) and indicate thereby the smallest amount
C