miJcù NATIONS NATTONS UNJES
W O R L D H E A L T H O R G A N I Z A T I O N
O R G A N I S A T I O N M O N D I A L E D E L A S A N T É
E X P E R T C O M U T T E E ON YELLOVÏ' F E ^ / E R TfflO/YF/20 '•^
20 August 1953 Second S e s s i o n
Kampala, 14-19 September 1953 ORIGINAL: ENGLISH
THE PROaElî OF I.IAS3 V A C C I N A T I O N A G A I N S T Ï E L L O V ; F E V E R
by
Dr. G. S t u a r t
I . Development o f the Vaccines i n Current Use
For the a c t i v e immunization o f man a g a i n s t y e l l o w f e v e r , methods d e v i s e d by SAT/ER, KITŒEN and LLOYD'''^* """^ (1931, 1932) and by LLOYD''""'' (1935) c o n s i s t e d i n the i n o c u l a t i o n o f a s t r a i n o f v i r u s , the p a n t r o p i c p r o p e r t i e s o f -which had been m o d i f i e d b y l a b o r a t o r y t e c h n i q u e s , together w i t h s u f f i c i e n t immune o r hyper-
imiuune serura (as determined by p r e l i m i n a r y t i t r a t i o n i n rhesus) t o prevent the v i r u s from e n t e r i n g the c i r c u l a t i n g b l o o d o f the i n o c u l a t e d s u b j e c t . I n these serum-virus racthods, the a n t i g e n i c element i n the vaccine used by Savrycr and h i s collabora-tors was developed from the French s t r a i n o f v i r u s m o d i f i e d by mouse b r a i n passage and knov.-n as t h s French n e u r o t r o p i c y e l l o w - f e v e r v i r u s - t h a t used by L l o y d v;as developed from the A s i b i s t r a i n gro^m i n t i s s u e c u l t u r e c o n t a i n i n g minced mouse erabryonic t i s s u e p l u s 10 per cent normal monkey serum i n Tyrode's s o l u t i o n and IcnoTO as 17S, tha immune serum was obtained from persons who had recovered f r o n y e l l o w f e v e r o r had developed p r o t e c t i v e antibody a g a i n s t the v i r u s f o l l o v d n g v a c c i n a t i o n ; the hyperin.iune serum v;as produced i n horses, r a b b i t s , monkeys o r goats.
Other c o n s i d e r a t i o n s a s i d e , these serum-virus methods, althoug^i e f f i c i e n t , were not adapted t o mass v a c c i n a t i o n , because o f the l a r g e q u a n t i t i e s and the p r o h i b i t i v e c o s t o f the imrnune o r hyperimmune serm. which would be r e q u i r e d f o r the completion o f such immunization -orogrammes. >
A t t e n t i o n was, t h e r e f o r e , d i r e c t e d t o d i s c o v e r i n g methods Thereby l a r g e - s c a l e immunization c o u l d be e f f e c t e d by the a d m i n i s t r a t i o n o f a c t i v e m o d i f i e d v i r u s , w i t h o u t the simultaneous employment o f immune serum. A p p r o p r i a t e i n v e s t - i g a t i o n s l e d t o the development o f the two d i f f e r e n t v i r u s v a c c i n e s v;hich are i n c u r r e n t use: the French n e u r o t r o p i c and the 17D.
iiseo/ïF/20 page 2
1. The French n e i i r o t r o p i c v i r u s v a c c i n e
The n e u r o t r o p i c s t r a i n used i n t h i s v a c c i n e i s a d e r i v a t i v e o f t h e pan- t r o p i c French s t r a i n o f y e l l o w - f e v e r v i r u s which, d u r i n g prolonged s e r i s i l b r a i n - t o - b r a i n passage i n mice, had been shown by THEILER^'^ (1930) t o have l o s t i t s a b i l i t y t o produce v i s c e r a l y e l l o w f e v e r i n rhesus monkeys - animals w h i c h , vihen i n o c u l a t e d e x t r a n e u r a l l y v/ith the m o d i f i e d v i r u s , o r d i n a r i l y developed o n l y a m i l d n o n - f a t a l i n f e c t i o n and consequent s o l i d a c t i v e immunity. A t t h e same t i m e , however, the m o d i f i e d s t r a i n had a c q u i r e d an enhanced n e u r o t r o p i c
v i r u l e n c e f o r both mice and monkeys, producing i n these a n i m a l s , when i n j e c t e d i n t r a c e r e b r a l l y , a r a p i d l y d e v e l o p i n g f a t a l e n c e ^ i a l i t i s . The f a c t , hov/ever, t h a t the prolonged passage of the o r i g i n a l v i r u s i n mouse b r a i n had e f f e c t e d a marked r e d u c t i o n o f i t s v i s c e r o t r o p i c a f f i n i t y was h e l d t o make the use o f t h e s t r a i n , thus m o d i f i e d , f e a s i b l e f o r human v a c c i n a t i o n , w i t h the r e s u l t t h a t s i n c e 1934 immunization by means o f t h i s s t r a i n , vd.thout the s i m u l t a n e o u s
i n j e c t i o n o f immune serum, has been e x t e n s i v e l y p r a c t i s e d , p a r t i c u l a r l y by F r e n c h workers i n t r o p i c a l A f r i c a .
A t f i r s t the v i r u s v a c c i n e vrais a d m i n i s t e r e d by subcutaneous i n o c u l a t i o n , 9 10
Thus UIGRET ' (1934) prepared, a v a c c i n e c o n s i s t i n g o f the mouse b r a i n v i r u s a t t e n u a t e d by exposure, i n g l y c e r i n e , to a temperature of 20°C and d r i e d i n the presence o f sodium phosphate; t h r e e i n j e c t i o n s o f v i r u s exposed t o t h i s temperature f o r f o u r days, tvro days and one day r e s p e c t i v e l y were g i v e n a t tvrenty-day i n t e r v a l s . L a t e r , i n o r d e r t o reduce the number o f i n j e c t i o n s and t h e r e b y t o make immunization more w i d e l y a p p l i c a b l e , NICOLLE and LAIGRET''"^
(1935) i n t r o d u c e d a s i n g l e - d o s e method o f v a c c i n a t i o n , employing mouse-brain v i r u s which, a f t e r one day's exposure i n g l y c e r i n e t o 20°C and subsequent d e s i c c a t i o n , was, ^vith the o b j e c t o f r e t a r d i n g the d i f f u s i o n o f the v i r u s f r o m the s i t e o f i n o c u l a t i o n , coated w i t h a l a y e r o f egg y o l k . The L a i g r e t mouse- adapted v i r u s , prepared from the French s t r a i n a t i t s 130th t o 1 8 5 t h passage i n mice, v/as the f i r s t t o be used on a r e l a t i v e l y v/ide s c a l e . Thus i n French West A f r i c a between June 1934 and December 1935 t h e r e were 9,592 persons immunized by the t h r e e - i n j e c t i o n method, w h i l e by 1937 t h e r e had been over
^i!H0/YF/20 page 3
24,000 persons inun\mized i n t h a t t e r r i t o r y by one o r o t h e r o f t h e L a i g r e t methods r e f e r r e d t o .
Subcutaneous i n o c u l a t i o n m t h the mouse-adapted v i r u s d i d not, hoi/ever, f o r v a r i o u s reasons, adequately meet the requirements o f the French A u t h o r i t i e s viho, c o n f r o n t e d w i t h the problem o f y e l l o v / - f e v e r c o n t r o l i n t h e i r v a s t c o l o n i a l
t e r r i t o r i e s i n t r o p i c a l A f r i c a , r e c o g n i z e d as o f paramount importance the need f o r mass immunization o f the indigenous p o p u l a t i o n s t h e r e .
Search f o r a v a c c i n e vrfiich would oe a t once s a f e , e f f e c t i v e , e a s i l y a d m i n i s t e r e d and i n e x p e n s i v e , \/as, t h e r e f o r e , pxirsued, p a r t i c u l a r l y a t the P a s t e u r I n s t i t u t e , Dakar, and r e s u l t e d i n t h e development by PELTIER, DURIEUX, JONCHERE and ARQUIE"*"^' '^^ (1939, 1940) o f t h e n e u r o t r o p i c y e l l o v z - f e v e r v i r u s a t i t s 238th passage through mouse b r a i n s , v ^ i i c h c o u l d be a p p l i e d t o tho s k i n b y m i l d s c a r i f i c a t i o n , thereby r e p l a c i n g subcutaneous i n o c u l a t i o n and o v e r - coming such major d i f f i c u l t i e s i n h e r e n t i n mass immunization programmes as the p r o v i s i o n , i n adequate q u a n t i t i e s , o f s y r i n g e s and needles t h o r o u g h l y
s t e r i l i z e d .
Since 1940 t h i s " s c r a t c h " method o f immunization has been adopted f o r use, m a i n l y by the French A u t h o r i t i e s and p a r t i c u l a r l y i n French t r o p i c a l A f r i c a , w h e r e i n t o date over 36 m i l l i o n v a c c i n a t i o n s have been so performed.
The technique o f p r e p a r i n g and a d m i n i s t e r i n g the v a c c i n e i n q u e s t i o n v/as d e s c r i b e d by P E L T I E R " ^ i n 1946, when i t was s t a t e d t h a t the v a c c i n e v/as made from t h e b r a i n s of mice i n o c u l a t e d w i t h the French s t r a i n o f v i r u s a t i t s 256th t o i t s 258th passage i n mice. The v a c c i n e i s commonly c a l l e d the Dakar v a c c i n e .
There can be no doubt about the h i g h immunizing p r o p e r t y possessed by t h i s mouse-brain v i r u s a p p l i e d by s c a r i f i c a t i o n c i t h e r alone o r , as i s commonly p r a c t i s e d i n French t r o p i c a l A f r i c a , i n combination w i t h smallpox v a c c i n e .
7JH0/ÏF/20 page 4
2, 17D v i r u s vaccine
Because of tho view held by such v/orkers as
F I N D U Y ^(1934) and THEILER and V/HITMN'^''' (1935) that tho increased neurotropism, for mice and monkeys, of the mouse-adapted French s t r a i n rendered that s t r a i n , i f used alone, p o t e n t i a l l y dangerous f o r human vaccination, search v/as made to discover a method f o r modifying yellov/-fever v i r u s i n such a v/ay as to reduce not only i t s v i s c e r o - tropism but also i t s neurotropism. The desired modification was f i n a l l y
achieved by the prolonged c u l t i v a t i o n i n t i s s u e i n v i t r o , by LLOYD, THEILER and RICCI"^^ (1936) and by THEILER and SIHTH^^' (1937 a and b), of the h i g h l y v i r u l e n t pantropic A s i b i s t r a i n . These vrorkers, using successively minced mouse embryo-iyrode's s o l u t i o n (18 passages), vvhole chick embryo-Tyrode 's
s o l u t i o n (58 generations), and thereafter a medium i n vAiich the t i s s u e component ï>ras minced chick embryo, from which the b r a i n and s p i n a l cord had been removed before mincing, i n i t i a t e d the branch knovm as 17D - a variant v/hich shov/ed, not only a l o s s of neurotropism f o r mice and monkeys a l i k e , but also a markedly diminished viscerotropism f o r the l a t t e r animals. Thus i n mice, although the s t r a i n could s t i l l produce e n c e p h a l i t i s , i t coxild do so only a f t e r a somewhat increased incubation period; i n monkeys, i t had altogether l o s t i t s a b i l i t y , v/hen inoculated i n t r a c e r e b r a l l y , to produce f a t a l e n c e p h a l i t i s . Monkeys
inoc\iLated extraneurally v/ith t h i s 17D v i r u s had no fever or othor signs of i l l n e s s ; t h o i r blood contained but minimal amounts of v i r u s ; they v/crc shovm to have developed s p e c i f i c antibodies and they were s o l i d l y immxme to h i g h l y v i r u l e n t pantropic s t r a i n s .
Tho l o s s of both v i s c e r o t r o p i c and neurotropic a f f i n i t i e s , as demonstrated i n monkeys, made t h i s v a r i a n t , i n the opinion of American and E n g l i s h workers, the v i r u s of choice f o r human vaccination.
Vaccino i s prepared from developing chick embryos - fresh, f e r t i l e , hen
eggs a f t e r seven to nine days' incubation being inoculated v/ith 0.05 cc of the
200th to 300th subpassage m a t e r i a l . The vaccine i s , and since 1942 has been,
of the aqueous-base (scrum-free) type; the technique of i t s production i s
described by HARGETT, BURRUSS and
DONOVAN'^(1943).
MO/YF/20 page 5
For mass inimunization 17D vaccine has since 1937 been administered by s\i)cutaneous inoculation and to t h i s end over 40 m i l l i o n doses have been
d i s t r i b u t e d . I n South America alone, between 1937 and 1950, there were eight m i l l i o n persons protected by t h i s vaccine, while i n c e r t a i n B r i t i s h and other t e r r i t o r i e s i n A f r i c a i t has also been extensively employed,
I I , The Dakar and the 17D vaccines compared
In the follovdng paragraphs the two vaccines currently employed i n mass vaccination campaigns w i l l be compared from the points of view of t h e i r r e l a t i v e e f f i c i e n c y , safety, ease of administration, and cost.
(a) E f f i c i e n c y
I n 1945 a comparison w;as made between the s c a r i f i c a t i o n method using the Dakar vaccine and the subcutaneous inoculation of 17D vaccine; the findings
28
published by UNRRA (1946) - the body which had i n i t i a t e d the necessary i n v e s t i g a t i o n s - showed that 98.94 per cent of p o s i t i v e resialts were obtained i n the sera of a group of 210 French s o l d i e r s s c a r i f i e d with the Dakar vaccine, as compared vri.th 64.29 per cent i n the sera of a comparable group inoculated subcutaneously with 17D vaccine. The findings represented a combination of the r e s u l t s of n e u t r a l i z a t i o n t e s t s made on the sera at three d i f f e r e n t l a b o r a t o r i e s , located respectively at Dakar, Montana and Rio de Janeiro. At Dakar and Rio de Janeiro an i n t r a c e r e b r a l t e s t vïas employed, while at Montana the t e s t s were made by the i n t r a p e r i t o n e a l technique. Of the sera tested by the i n t r a - peritoneal technique, 100 per cent of those vaccinated vd.th Dakar vaccine and 97.96 per cent of those vaccinated ^vith 17D were p o s i t i v e . The apparent
discrepancies i n r e s u l t s with sera of those r e c e i v i n g 17D vaccine, v;hen the sera were tested i n the three d i f f e r e n t l a b o r a t o r i e s , may be explained by the f a c t
that a t Montana use was made of a more s e n s i t i v e mouse-protection t o s t than that employed a t the two other l a b o r a t o r i e s , for i t i s w e l l recognized that the more d e l i c a t e i n t r a p e r i t o n e a l t e s t may indicate the presence of n e u t r a l i z i n g
antibodies vihich are not demonstrable by an i n t r a c e r e b r a l t e s t . Although,
then, the r e s u l t s of the above i n v e s t i g a t i o n showed that the response induced
WHOAF/20 page 6
by the Dakar vaccine l o d t o the formation of more antibody per person than t h a t evoked by the 17D vaccine, nevertheloss experience has abundantly proved t h a t the immunity induced by ITD vaccine i s adequate for protection.
(b) Safety • • ' 21
I n t h i s respect SMITHBURN (1951) observes: "The use of the n e u r o t r o p i c v i r u s , T/hich i s known to be more pathogenic for man, rhesus monkey, and mouse than i s the 17D v i r u s , may be a p o t e n t i a l hazard. Even though e n c e p h a l i t i s has not been prevalent among persons vaccinated by t h i s (the Dakar) method, the
p o s s i b i l i t y cannot be ignored that i t may on occasion occur". ^ h a t i t can occur has been r e c e n t l y exemplified by tvro serious outbreaks of e n c e p h a l i t i s : one i n Costa Rica during 1951, the other i n Nigeria d\u"ing 1952, v/here ..
r e s p e c t i v e l y 12 cases, vdth 3 deaths, and 83 cases, with 32 deaths, were
reported/. "The use of mouse b r a i n v i r u s seems", according to Smithbvirn, " t o be a more objectionable feature. There i s always the p o s s i b i l i t y t h a t the yellow-fever v i r u s may become contaminated with another v i r u s that the mouse may be harbouring - lymphocytic choriomeningitis, f o r example - with r e s i i l t a n t
accidental i n f e c t i o n i n r e c i p i e n t s of the vaccine. L a s t l y , there i s a l s o the p o t e n t i a l hazard, i*ienever mammalian t i s s u e i s employed i n a vaccine, o f
a l l e r g i c demyelinating encephalomyelitis."
As regards 17D: t h e o r e t i c a l l y the use of a s t r a i n , which has been
rendered e s s e n t i a l l y a v i r u l e n t n e u r o t r o p i c a l l y as w e l l as v i s c c r o t r o p i c a l l y , vrtiile s t i l l r e t a i n i n g i n large measure i t s antigenic potency, should preclude the occurrence of cases of severe reactions i n v o l v i n g the c e n t r a l nervous system. To judge from a perusal of tho relevant l i t e r a t u r e , t h i s assumption has i n the main been Confirmed. Exceptions, hovrever, have been: ( i ) a case recorded by SOPER and SMITH^^ (1938) as having occurred one month a f t e r
vaccination, with d e f i n i t e meningeal signs, the r e l a t i o n of vAiich to v a c c i n - a t i o n rms considered very d o u b t f u l ; and ( i i ) a serious outbreak of
e n c e p h a l i t i s during 1941 i n B r a z i l , whore, as reported by FOX, LENNETTE, MANSO and SOUZA AGUIAR^ (1942), 254 cases, vdth one f a t a l i t y , occurred among 69,843 persons vaccinated w i t h c e r t a i n l o t s of vaccine prepared from severàl substrains
TOO/YF/20 page 7
of the o r i g i n a l 17D v i r u s . I n v e s t i g a t i o n s c a r r i e d out by these authors proved t h a t a sudden a l t e r a t i o n i n c h a r a c t e r o f the 17D v i r u s had taken p l a c e d u r i n g a v e r y s m a l l number o f s u b c u l t u r e s away from the parent stem. The demonstrated v a r i a t i o n i n p a t h o g e n i c i t y o f d i f f e r e n t s u b s t r a i n s o f the 17D v i r u s and the
consequent v a r i a t i o n of the response i n man i n o c u l a t e d w i t h these s u b s t r a i n s l e d t o tho s t a n d a r d i z a t i o n o f the manufacture o f 17D v a c c i n e - a procedure
•v/hich ensured t h a t a l l the v a c c i n e s used v/ere i n i t i a t e d f r o n primary and secondary seed batches o f knovm c h a r a c t e r o n l y . Since t h a t time no case of e n c e p h a l i t i s has been recorded i n l i t e r a t u r e as f o l l o w i n g the use o f 17D v i r u s v a c c i n e ; indeed, a c c o r d i n g t o THEILER (1948), any r e a c t i o n s which have
o c c u r r e d have been, as a r u l e , e x t r e m e l y m i l d . 20
I n r e g a r d to (a) and (b) SMITH (1951) s t a t e s : " I t appears t h a t the Dakar v a c c i n e produces a g r e a t e r degree o f immunity as measiired by serum
a n t i b o d y response. T h i s i s accompanied by a g r e a t e r danger of s e r i o u s n e u r o l o g i c r e a c t i o n s from the n e u r o t r o p i c v a c c i n e , as w e l l as the r i s k o f extraneous i n f e c t i o n s from l a t e n t v i r u s e s of mice t h a t may be pathogenic f o r man. I t appears r e a s o n a b l e , t h e r e f o r e , i n view o f the s a t i s f a c t o r y e x p e r i e n c e w i t h 17D v a c c i n e i n l a r g e - s c a l e immunization campaigns over a p o r i o d o f 13 y e a r s , t h a t i t s g r e a t e r s a f e t y would recommend i t above the Dakar v a c c i n e f o r general use". That the number o f r e a c t i o n s a f t e r v a c c i n a t i o n v/ith Dakar v a c c i n e i s g r e a t e r t h a n t h a t of those v/hich occur a f t o r the use of 17D v a c c i n e i s s t a t e d b y THEILER^'^ (1948) i n a r e c e n t a r t i c l e .
( c ) Ease of a d m i n i s t r a t i o n
One p o i n t g r e a t l y i n f a v o u r o f Dakar v a c c i n e f o r mass v a c c i n a t i o n i s t h a t i m m i m i z a t i o n i s e f f e c t e d by simple a p p l i c a t i o n o f v i n i s t o cutaneous
s c a r i f i c a t i o n s . This o b v i o u s l y i s t o be p r e f e r r e d to any method i n v o l v i n g the a d m i n i s t r a t i o n o f v a c c i n e by means o f s y r i n g e s and needles v/hich r e q u i r e
r i g o r o u s s t e r i l i z a t i o n p r i o r to use.
Y/HO/YF/20
page 8
(d) Cost
Dakar vaccine i s also l e s s expensive to produce than 17D. In the Dakar vaccine, v;hich i n c i d e n t a l l y has the advantage of a greater s i m p l i c i t y of
preparation than 17D, the vriiolc v i r u s - i n f e c t e d mouse brain i s used, and, accord- ing to PELTIER"''^
( 1 9 4 6 ) ,one-tenth of a b r a i n y i e l d s 100 doses of vaccine. I n the manufacture of 17D vaccine only the supernatant f l u i d s of the embryo
suspensions are employed and the vinas-rich sediments, which arc about o n o - t h i r d by volume, are discarded, with a considerable l o s s of p o t e n t i a l vaccino v i r u s
(DICK^
1S;D;,I t i s true that i n the Americas the cost of producing 17D vaccine.has been estimated at about 0.025 US d o l l a r per dose i n Nev; York and
22
about
0 . 0 2 5US d o l l a r per dose i n Rio de Janeiro (SOPER and SMITH 1938) ;
t h i s f i g u r e i s low, but ;vhen the cost of a p p l i c a t i o n i s added, mass immunization by means of 17D becomes, according to SMITH'^*^
( 1 9 5 1 ) ,"a burdensome expense".
From the foregoing i e emerges that f o r mass vaccination:
(a) Dakar vaccine has much to recommend i t , not only by v i r t u e of i t s
demonstrated effectiveness as a method of immunization, but also because of i t s cheapness and s i m p l i c i t y of preparation, as w e l l as i t s ease of administ- r a t i o n . On the othor hand, tv;o main objections to t h i s vaccine have beon voiced, because of the p o s s i b i l i t y that: ( i ) the mouse brains employed i n i t s preparation may be cuntarainated with a v i r u s pathogenic f o r man although l a t e n t i n mice (e.g. lymphocytic choriomeningitis), or may be the cause of
demyelinating encephalomyelitis; ( i i ) the use, as antigen, of a v i r u s vdth enhanced neurotropic properties may be followed by serious reactions i n v o l v i n g the c e n t r a l nervous system;
(b) 17D vaccine, although e l i c i t i n g an antibody response q u a n t i t a t i v e l y l e s s
than that evoked by Dakar vaccine, nevertheless confers an immunity •vjhich i s
adequate f o r p r o t e c t i o n . Moreover, since the standardization, i n 1942, of the
seed v i r u s used i n i t s preparation, any reactions f o l l o w i n g i t s administration
have been, as a r u l e , extremely m i l d . On the other hand, 17D vaccine has,
p a r t i c u l a r l y f o r mass vaccinations, c e r t a i n disadvantages, of which the chief
VJ-HO/YF/20
page 9.
a r e : ( i ) i t s c o s t of p r e p a r a t i o n ; and ( i i ) the n e c e s s i t y o f u s i n g , f o r i t s a d m i n i s t r a t i o n , l a r g e numbers of s t e r i l i z e d s y r i n g e s and n e e d l e s .
I I I . Suggestions f o r improving the v a c c i n e s i n c u r r e n t use
From a c o n s i d e r a t i o n o f the r e l a t i v e m e r i t s o f the Dakar and 17D v a c c i n e s , the i d e a l f o r mass immunization vrould appear t o be a method combining the advantages, and e l i m i n a t i n g the disadvantages, of b o t h . To t h i s end - the development o f a v a c c i n o , v.hich ivould be not o n l y safe and e f f i c i e n t b u t a l s o comparable v;ith the Dakar v a c c i n e i n i t s s u i t a b i l i t y f o r mass v a c c i n a t i o n i n the f i e l d and i n i t s lov:
c o s t o f p r o d u c t i o n and a p p l i c a t i o n - i n v e s t i g a t i o n s i n t o the p o s s i b i l i t y o f employ- i n g 17D v i r u s v a c c i n e by s c r a t c h v/ere begun i n 1947 a t the Yellov/ Fever Research I n s t i t u t e i n Lagos, N i g e r i a . H/J-IN^ (1951) d e s c r i b e s the mode o f p r e p a r a t i o n o f the v a c c i n e and the r e s u l t s o b t a i n e d from i t s use. The v a c c i n e , produced by g r i n d i n g the v/hole v i r u s - i n f e c t e d c h i c k embryos m t h gum a r a b i c s o l u t i o n and d e s i c c a t i n g the homogenized mixture t o powder form, proved, ^±en r e c o n s t i t u t e d i n s t e r i l e d i s t i l l e d T/ater a t the time o f use, easy o f a d m i n i s t r a t i o n by the s c r a t c h teclanique.
From r e s u l t s o b t a i n e d both i n the l a b o r a t o r y and i n a f i e l d t r i a l a t Kumba F i a n g o , B r i t i s h Cameroons, where 3,80S of the i n h a b i t a n t s were immunized by t h i s method, Hahn concluded t h a t the 17D s t r a i n o f y e l l o w - f e v e r v i r u s c o u l d be a p p l i e d by
s c r a t c h " w i t h the p r o d u c t i o n o f a l e v e l of immunity o f the same order as t h a t r e s u l t i n g from subcutaneous i n o c u l a t i o n of the v i r u s " . F u r t h e r evidence i n t h i s
sense i s adduced by HORGAN^^ (1950, 1951), by DICK^ (1952), and by DICK and HORGAN (1952) i n r e s p e c t o f 153 A f r i c a n v o l u n t e e r s immunized by t h i s method i n Uganda, No untov/ard r e a c t i o n s were r e p o r t e d e i t h e r by HAHN^ (1951) or by DICK and HORGAN (1952) r e s p e c t i v e l y .
A l t e r n a t i v e t o the use o f a 17D v a c c i n e produced as d e s c r i b e d above by Hahn, i t has been suggested by DICIC*" (1952) t h a t " s t u d i e s should be made on the a n t i g e n i c i t y o f 17D mouse-brain v i r u s as a s c a r i f i c a t i o n v a c c i n e " . ^ h e o b j e c t i o n t o the use of a mouse-brain p r e p a r a t i o n , because o f the p o s s i b i l i t y t h a t the mouse b r a i n s employed i n making the v a c c i n e might become contaminated w i t h a v i r u s pathogenic f o r man a l t h o u g h l a t e n t i n mice, i s c o n s i d e r e d by D i c k t o be perhaps soraev/hat acadomic,
VJHO/YF/20 page 10
s i n c e PELTIER (1948) does not record the occurrence o f any such a c c i d e n t i n a t o t a l of 20,053,338 v a c c i n a t i o n s f o r v/hich Dakar mouse-brain vaccine vras
used_.7
I n h i s summary o f y e l l o w - f e v e r v a c c i n a t i o n by s c a r i f i c a t i o n , DIGIC^ (1952) suggests t h a t by u s i n g e i t h e r (a) a crude (see above) e x t r a c t of c h i c k embryos i n f e c t e d m t h 17D v i r u s or (b) 17D mouse-brain v i r u s , "a p r e p a r a t i o n o f 17D v a c c i n e could be administered by s c a r i f i c a t i o n v/hich might prove to be a s a t i s f a c t o r y method of mass v a c c i n a t i o n o f persons l i v i n g i n endemic y e l l o w f e v e r a r e a s . The use o f such a p r e p a r a t i o n would reduce the cost of the v a c c i n e , and the d i s p e n s i n g v / i t h s y r i n g e s vrovld f a c i l i t a t e mass v a c c i n a t i o n s and reduce the chance o f the s y r i n g e t r a n s m i s s i o n of d i s e a s e . " ^ h e danger o f t r a n s m i s s i o n o f disease by the s y r i n g e i s d e a l t v/ith by HUGHES (1946) and by EVANS and SPOONER-^ (1950)?.
I V , Siaimary
1 . The development of the two vaccines i n c u r r e n t use f o r mass i m m u n i z a t i o n a g a i n s t y e l l o w f e v e r has been d e s c r i b e d .
2 . The r e l a t i v e m e r i t s o f the Dakar and the 17D vaccines have been d i s c u s s e d , 3 . Recent work on, and suggestions f o r , the development o f a v a c c i n e t o
f u l f i l the p r e r e q u i s i t e s f o r mass v a c c i n a t i o n - s a f e t y , e f f i c i e n c y , ease o f a d m i n i s t r a t i o n and lowness o f cost o f p r o d u c t i o n and a p p l i c a t i o n - have been i n d i c a t e d .
WO/YF/20 page 11
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i
