UNITED NATIONS
NATIONS UNIES
WORLD HEALTH ORGANIZATION EXPERT COît.UTTEE ON YELLOV/ F^VER Second Session Kampala. 14-19 September 1953
ORGANISATION MONDIALE DELASANTÉ ÏÏHn/YF/lÇ 18 August 1953 ORIGINAL: FTENGH
TWENTY YEARS OF YELLOT FEVER CONTROL THROUGH PREVENTIVE VACCI1>IATI0N
Dr. Jean L a i g r e t Membre Correspondant de l'Académie de Médecine D i r e c t e u r de l ' I n s t i t u t d'Pfygiène et de Dactériologie c ' . e Strasbourg (France)
vrao/yF/19 page 2 . •i • /,. r i ; •
CONTENTS
Page Epidemiological, Previous The economic and s o c i a l r e s u l t s of v a c c i n a t i o n ^ 4 5 , 7 10
c r i t i c i s m s of vaccination
f e b r i l e r e a c t i o n on the 6th-7th day
Post-vaccinal jaundice Post-vaccinal meningitis or meningo-encephalitis
The necessity f o r research on the i n t e r n a t i o n a l l e v e l t o determine the cause of such meningitis The l i n e s t o be followed by t h i s r e s e M ch Temporary measures which should be taken i n connexion w i t h vaccination of c h i l d r e n SUICJAHÏ the 22 23 13 15
^7H0/YF/19 page 3
E p i d e n a o l o g i c a l , economic and a o c i a l resvilts of vaccination The f i r s t t r i a l s of yellow fever v a c c i n a t i o n were made a l i t t l e more than 20 years ago. Next year w i l l mark the twentieth anniversary o f the f i r s t l a r g e - s c a l e a p p l i P r o g r e s s i v e l y t h e r e a f t e r a l a r g e part o f Next came the v a c c i n a t i o n campaigns o f
c a t i o n s o f the vaccine i n West A f r i c a .
t r o p i c a l and e q u a t o r i a l A f r i c a was immunized.
the R o c k e f e l l e r I n s t i t u t e i n America, the v a c c i n a t i o n o f numerous contingents of a l l i e d troops d u r i n g the v/ar and the v a c c i n a t i o n of the crew and passengers o f a i r c r a f t and ships. Novi/adfys, subjects vaccinated against yellow f e v e r can be counted i n m i l l i o n s .
lîhen the present p o s i t i o n i s comppred -.vith t h a t 20 y e a r s ago i t can e a s i l y be seen t h a t considerable progress has been made. r a r e disease. Yellow f e v e r has f a l l e n t o the l e v e l o f a
No longer do epidemics occur such as those which p e r i o d i c a l l y returned
t o sow panic i n A f r i c a and Vmerica, making i t necessary t o close p o r t s , quarantine ships and stop trade, thus adding commercial r u i n t o the heavy l o s s i n human l i f e . The d i s a s t e r s which yellow fever so often caused i n the past are being forgotten.
I t i s as veil, to r e c a l l them, so t h a t the importance o f the change brought about and the r e s u l t i n g advantages f o r t h e modern world may be r e a l i z e d .
Among the economic consequences of v a c c i n a t i o n , there i s one which should be s t r e s s e d , namely, t h a t i n v o l v i n g a v i a t i o n . were s e t up there was grave d i s q u i e t ; ÏJhen the f i r s t i n t e r c o n t i n e n t a l a i r l i n e s
i t was feared that a i r c r a f t would t r a n s p o r t There,'it would have found popu-
y e l l o w fever t o I n d i a , the Far East and the P a c i f i c .
l a t i o n s untouched t y t h e disease among whom the ravages i t would have caused may veil be imagined. By a fortunate coincidence, a t the very moment when such concern arose, i t s powerful preventive a c t i o n was soon recog-
v a c c i n a t i o n commenced t o be a p p l i e d ;
n i z e d and made use of f o r the immunization of the crev; and passengers o f a i r c r a f t . I n t h i s way, a i r t r a n s p o r t succeeded i n developing i t s network o f communications from
one country t o another vdthout the t h r e a t o f the development of new f o c i ever materializing. Since that time the number of human l i v e s safeguarded by the y e l l o w
f e v e r vaccine, the m a t e r i a l and f i n a n c i a l b e n e f i t s to trade, as v;ell as t o sea and a i r t r a n s p o r t , have g r e a t l y exceeded the hopes of t h e most o p t i m i s t i c workers d u r i n g the p e r i o d o f the f i r s t t r i a l s . The change observed i n 20 years can best be compared t o
V;H0/YF/19 page 4 the upheaval caused i n the epidendolcgical situation of the period "by Jenner»s v a c c i n e ; the yellow fever vaccine occupies tho same place i n the prevention of yellow fever as Jenner's vaccine does i n the prevention of smnllpox. As early as 1934, Charles N i c o l l e prophesied that yellov/ fever would be vanquished. r i s k that the effectiveness of the vaccine i v i l l be doubted. Previous c r i t i c i s m s of vaccination Nevertheless, doubts voiced i n this connexion were long included among the c r i t i c i s m s l e v e l l e d against vaccination. There was of course Max Theiler's seroprotection test which revealed the humoral signs of acquired immunity i n the blood o f vaccinated subjects, but opponents of the vaccine rejected this t e s t as being n o n - s p e c i f i c ^ They spread the t a l e , which now can only raise a smile, o f a cow i n India whose blood -was said to be positive to the Max Theiler t e s t , clear evidence that the l a t t e r was worth3e s s ! YelloT»r fever cases v»ere discovered among vaccinated subjects; the disease two years after vaccination. f i r s t i n j e c t i o n of vaccine; a woman had contracted Enquiry showed that she had received only the Today the World Health there i s no longer any
Organization affirms that vaccination i s absolutely r e l i a b l e ;
t h i s was at a time when vaccination was carried out, f o r
reasons of safety, i n three injections of which the f i r s t had a very low v i r u s content and was i n s u f f i c i e n t t o bring about immunization. Much more serious, the accusation was made that vaccin'"ted persons represented danger to those about them. Experiments, i n particular those of Roubaud i n France, had proved that the vaccine virus i s not transmitted t y mosquitos. were made against vaccination;
a
Despite t h i s , attacks such as the f o l l o w i n g
i n a railway station on the Dakar - St.Loviis l i n e , l i v e d the stationmaster alone had himself However,
a stationmaster vdth h i s wife and daughter;
vpccinated, f e e l i n g that he was the most exposed t y reason of his night duty.
the daughter who was v i s i t i n g friends at Rufisque followed t h e i r example and was also vaccinated, so that i n the family there were two vaccinated persons. was unvaccinated, and she contracted yellov/ fever and died. Only the mother
Could there be a better
proof of the effectiveness of the vaccine? however;
An o f f i c i a l report put matters d i f f e r e n t l y ,
according t o the report i t was the vaccine c i r c u l a t i n g i n the bloodstream o f The author of
the father and daughter which had infected the mother and k i l l e d her.
VjHO/YF/19 page 5
t h i s r e p o r t published a r t i c l e s w r i t t e n i n the same v e i n , a r t i c l e s vAich are s t i l l consulted i n good f a i t h by those studying v a c c i n a t i o n . shows how much confidence can be placed i n such r e p o r t s . T^hat has been s a i d above The l i t e r a t u r e
-
concerning
y e l l o w fevor v a c c i n a t i o n i s f u l l o f p u b l i c a t i o n s o f t h i s nature which mislead the uninformed reader. Having made t h i s point c l e a r , i t must nevertheless be recognized I t i s sometimes I n the f o l l o w i n g
that everything i s not p e r f e c t i n yellow fever v a c c i n a t i o n .
f o l l o w e d l y r e a c t i o n s which i t would be v e r y d e s i r a b l e t o a v o i d .
we s h a l l study them, commencing w i t h the simplest and most harmless, namely, the f e b r i l e r e a c t i o n on the 6th to 7th day. The f e b r i l e r e a c t i o n on the 6 t h to 7th day ' .
Reactions were only t o be expected since every form of v a c c i n a t i o n produces them, above a l l those emplc^ring a l i v i n g vaccine, as i s used f o r y e l l o w fever immunization.
I t i s w e l l known t h a t the vaccine used i s the o r i g i n a l y e l l o w fever v i r u s which, i n the hands o f S e l l a r d s and Max T h e i l e r , underwent a mutation i n v o l v i n g the l o s s o f the power t o b r i n g about yellow f e v e r . I t paralyzes the mouse when i n o c u l a t e d i n t r a c e r e b r a l l y so t h a t i t i s c a l l e d " n e u r o t r o p i c " y e l l o w fever v i r u s . I t immunizes man t y causing an asymptomatic ; .„ _
i n f e c t i o n during which i t m u l t i p l i e s i n the human body, and t h i s i n f e c t i o n loads t o immunity comparalie i n every way w i t h that f o l l o w i n g recovery from the n a t u r a l disease. Charles N i c o l l e s a i d t h a t , f o r e f f e c t i v e v a c c i n a t i o n w i t h a l i v i n g v i r u s , the aim should be always t o remain on "the b o r d e r l i n e between asymptomatic i n f e c t i o n and disease". I n pr??ctice there i s al'/ays an i n v o l u n t a r y d e v i a t i o n one way or the other, when i t i s below, immunity i s not produced or i s
e i t h e r above or beloiï t h i s l i m i t ; inadequate;
v/hen i t i s above, r e a c t i o n s are caused which come w i t h i n the f i e l d o f
c l i n i c a l i n f e c t i o n but which, nevertheless, do not f o r b i d the use o f the vaccine i n the case o f symptoms which are r e a l l y m i l d and o f short d u r a t i o n . This i s the case
w i t h the f e b r i l e r e a c t i o n s which are observed during y e l l o w f e v e r v a c c i n a t i o n s i x or seven days a f t e r the i n o c u l a t i o n , I noted these r e a c t i o n s during our f i r s t t r i a l s a t the Tunis Pasteur I n s t i t u t e and subsequently observed them again i n Viest A f r i c a , Since then everyone who has c a r r i e d
Y:HO/YF/19 page 6
out v a c c i n a t i o n a g a i n s t y e l l o w fever has seen them.
They i n v o l v e an a t t a c k o f f e v e r
resembling a m i l d m a l a r i a ?ttac"!î and t e r m i n a t i n g a t l a t e s t on the f o l l o w i n g day o r t h e day a f t e r t h a t . alarmed. The i n c i d e n c e of these r e a c t i o n s i s d i f f i c u l t t o define p r e c i s e l y . experience I n ny Vaccinated subjects, provided they have been v;arned, never become
they are always r a r e i n c h i l d r e n , rare or very r a r e i n women and d i s t i n c t l y -
more frequent i n a d u l t men, although never exceeding 25 per cent o f those v a c c i n a t e d , I attempted t o f i n d a connexion between these f e b r i l e r e a c t i o n s on t h e 6th day and the v i r u l e n c e o f the vaccine, the l a t t e r being evaluated i n mouse u n i t s , i . e . minimal l e t h a l doses f o r the mouse. I could not f i n d any r e l a t i o n s h i p j a very small
Amount o f v i r u s , l e s s than one u n i t , i s a l l t h a t i s r e q u i r e d t o b r i n g about t h e f e b r i l e r e a c t i o n i n one subject, v/hereas other subjects r e c e i v i n g 100 or 500 u n i t s do n o t r e a c t I a l s o looked f o r a connexion between t h e f e b r i l e r e a c t i o n and the development o f immunity. Again, there i s none; vaccinated subjects who do not r e a c t a r e as s t r o n g l y
immunized as the others and w i t h i n the same p e r i o d o f time. One t h i n g i s c e r t a i n , namely, t h a t those r e a c t i n g a r e alv/ays s u b j e c t s v a c c i n a t e d for the f i r s t time; the f e b r i l e r e a c t i o n i s never seén i n r e v a c c i n a t e d persons. ?/hen
we c a r r i e d out v a c c i n a t i o n i n three steps, using f i r s t , l e s s than one mouse u n i t , n e x t two u n i t s and then 20 u n i t s , v/ith an i n t e r v a l o f two or three weeks, a s m a l l number ot f e b r i l e r e a c t i o n s occurred a f t e r the f i r s t i n j e c t i o n . They were p a r t i c u l a r l y frequent
a f t e r the second and exceptional a f t e r the t h i r d i n j e c t i o n , because a l l o r almost a l l s u b j e c t s were already immunized by the f i r s t two i n j e c t i o n s , as confirmed tests. Some workers hpve wondered whether there i s not R r e l a t i o n s h i p between t h e febril© r e a c t i o n on the 6th day and the l a t e meningeal r e a c t i o n s which we s h a l l d i s c u s s l a t e r on. I can ansr/er t h i s point s t r a i g h t away; the 6th dsy f e v e r i n no way i n d i c a t e s t h a t conversely, the n e u r a l r e a c t i o n , when i t by s e r o l o g i c a l
a n e u r a l r e a c t i o n w i l l subsequently appear;
does occur, may e q u a l l y w e l l have been preceded o r not preceded t y a 6th day f e v e r ; the tvYO
r e a c t i o n s a r e q u i t e independent-of one another.
D i s q u i e t has a l s o been caused by the presence o f t h e v i r u s i n the blood during t h e
lTHO/YF/19 page 7
febrile reaction.
To t h i s we have already given the answer i n d e f i n i n g v a c c i n a t i o n
as "an i n f e c t i o n , u s u a l l y asymptomatic, d u r i n g v/hich the v i r u s m u l t i p l i e s i n the body". The v i r u s i s found i n the blood of n o n - f e b r i l e vaccinated subjects j u s t as i t i s i n that of f e b r i l e vaccin^ited subjects. In the study of v i r a l , r i c k e t t s i a l and s p i r o and
c h e t a l i n f e c t i o n s , t h i s v i r u l e n c e of the blood i s f r e q u e n t l y observed both i n man animals,
even i n the absenoe of any symptom, and t h i s i s a l l the more so when a f e v e r i s h The presence o f the v i r u s i n the blood can have no pathogenic or i t i s merely a s i g n of the
stage occurs.
p r o g n o s t i c s i g n i f i c a n c e any more than can the fever i t s e l f ;
i n v i v o m u l t i p l i c a t i o n of the v i r u s , a m u l t i p l i c a t i o n necessary f o r the development of immunity. Cases are c i t e d of what some authors c a l l e d "prolonged" 6th day r e a c t i o n s . occur i n vaccinated subjects who develop fever, d i g e s t i v e upsets and g e n e r a l l y an I have I found These
enlarged l i v e r and remain i n t h i s s t a t e f o r one, two or sometimes three weeks. seen cases o f t h i s k i n d i n VJest A f r i c a and mentioned them i n ny 1934 r e p o r t .
t h a t these p a t i e n t s were always o l d c o l o n i a l r e s i d e n t s , t i r e d by a long period spent i n the c o l o n i e s ; vaccination. s e v e r a l had already s u f f e r e d from t r o u b l e s of the same k i n d before
Everything seemed to p o i n t to h e p a t i t i s of a type f a i r l y common i n hot
c o u n t r i e s and, indeed, d u r i n g the thousands of v a c c i n a t i o n s which I have c a r r i e d out i n temperate zones, I have never seen s i m i l a r cases. Colleagues i n charge of y e l l o w Consequently,
f e v e r v a c c i n a t i o n centres i n France have a l s o never reported such casos. something other than a v a c c i n a l r e a c t i o n i s i n v o l v e d .
I t would seem c e r t a i n t h a t
v a c c i n a t i o n favours the outbreak of such disturbances i n persons whose l i v e r i s more or l e s s impaired, but other types of v a c c i n a t i o n would have the same e f f e c t . Thus, there
are no groimds f o r speaking of "prolonged 6th day f e b r i l e r e a c t i o n s " as some workers have done. Post-vaccinal jaundice chapter,
I have i n t e n t i o n a l l y l e f t the question o f jaundice on one side i n the l a s t
although i t i s i m p l i c i t l y i n c l u d e d , since the h e p a t i t i s seen i n hot c o u n t r i e s which has sometimes been taken to be a v a c c i n a l r e a c t i o n , i s u s u a l l y accompanied t y jaundice or m i l d jaundice. have made. Indeed, t h i s i s p r e c i s e l y the cause of the e r r o r which some authors
I t seemed n a t u r a l to them t h a t the vaccine should b r i n g about i n c e r t a i n
IHOAF/19 page 8 subjects a m i l d jaxmdicc, a k i n d of 'hniniature yellOT/ fever " ( t h i s e x p r e s s i o n has
a c t u a l l y been employed) appearing as a c l i n i c a l proof o f tho potency of the v a c c i n e . U n f o r t u n a t e l y , t h i s reasoning does not h o l d and I f e e l t h a t i t i s worth w h i l e a l i t t l e time to g i v i n g the reason f o r t h i s . I t i s knovm t h a t n a t u r a l yellovr fever has benign forms. Formerly i t was not serodevoting
known hav7 t o diagnose them but today they can r e a d i l y be i d e n t i f i e d , thanks t o logical tests.
Numerous cases were seen during the surveys c a r r i e d out t o d e l i n e a t e they are short-term fevers without jaundice. Jaundice
the endemic zonesj
The absence of jaundice i n these m i l d forms can r e a d i l y be understood.
i s a symptom which appears only i n the second phase of yellow f e v e r , a s s o c i a t e d w i t h haemorrhage, together vdth which i t c o n s t i t u t e s the grave syndrome of the t e r m i n a l period. Before t h i s , there i s the i n i t i a l period which d u r i n g the f i r s t t h r e e or
fovir days i s simple f e v e r without jaundice.
The benign forms o f y e l l o w f e v e r are
a b o r t i v e , truncated forms and recovery commences immediately a f t e r the f i r s t phase, before tha syndrome of the second phase has developed. jaundice nor are they ever s e r i o u s , lilhen
Thus such forms never i n v o l v e
i t i s not completely
asymptomatic, v a c c i n a t i o n takes a form s i m i l a r t o a
benign n a t u r a l i n f e c t i o n but s t i l l more reduced, being l i m i t e d to an attack o f f e v e r on the 6th-7th day which cannot i n c l u d e jaundice among i t s symptoms any more than a natural mild attack. I t i s thus an error t o a t t r i b u t e jaundice t o the v a c c i n e and to b e l i e v e i t capable of causing "miniature y e l l o w f e v e r " , t a k i n g the form of benign j a u n d i c e . jaundice develops f o l l o v d n g v a c c i n a t i o n , seme other f a c t o r i s i n v o l v e d and i n hot c o u n t r i e s t h i s i s f r e q u e n t l y long-standing h e p a t i t i s , e i t h e r known or unknown, w h i c h becomes a c t i v e f o l l o w i n g v a c c i n a t i o n , Hcnvever, an a s s o c i a t e d v i r u s may a l s o be r e s p o n s i b l e . To t h i s category belong t h e TAien . . . can
cases of jaundice which f o l l o w e d , f i r s t of a l l , F i n d l a y ' s s e r o - v a c c i n a t i o n experiments i n Gpjnbia and then, d u r i n g the war, the i n o c u l a t i o n s w i t h vaccine 17D which was
recognized to be contaminated w i t h the v i r u s of epidemic h e p a t i t i s . In the same connexion, I may mention two personal cases which g r e a t l y disttirbed me
Y/HO/YF/19 page 9
. i n Tunis d\iring our f i r s t t r i a l s . of v a c c i n a t e d s u b j e c t s .
Two grave cases of jaundice appeared among a. group
The neurotropic v i r u s had a t t h a t time only undergone a pathogenic
r e l a t i v e l y small number of mouse passages so that the r e t u r n of i t s o r i g i n a l power'was to be feared and was n a t u r a l l y my f i r s t i d e a .
However, these cases seemed
to d i f f e r from y e l l o w fever i n s e v e r a l d e t a i l s , i . e . javindice appeared at an e a r l y stage,- almost at the same tirae as the f e v e r ; jaundice nor of yellov; f e v e r ; the i n t e n s e c o l o u r was n e i t h e r t h a t of
the p a t i e n t s d i d not vomit but they spat blood, which F i n a l l y , thfe
came from pulmonary h e p a t i z a t i o n f o c i detectable on a u s c u l t a t i o n . d i s e a s e was found to be l e p t o s p i r o s i s . chaetesj t h i s d i a g n o s i s was
The blood, u r i n e and sputa contained s p i r o Both p a t i e n t s
confirmed by i n o c u l a t i o n o f guinea p i g s .
belonged t o a community l i v i n g i n deplorable c o n d i t i o n s , i n contact w i t h r a t s , dogs and other animals. These two cases have often made me think of Noguchi's mistake. ' The p a t i e n t s
Noguchi encountered at Guayaquil and b e l i e v e d i n f e c t e d w i t h y e l l o w fever were c e r t a i n l y of t h i s type. Perhaps they were indeed s u f f e r i n g from t h i s disease a t the same S e l l a r d s found l e p t o s p i r a s i n the blood and u r i n e o f a monkey As regards the two vaccinated Tunisians, they were
time, as l e p t o s p i r o s i s .
i n o c u l a t e d w i t h yellow f e v e r .
i n f e c t e d both w i t h L e p t o s p i r a and w i t h the neurotropic yellow fever v i r u s w i t h whioh they had been i n o c u l a t e d f o r purposes of These are f a c t s which unmistakably immunization. i n d i c a t e an a s s o c i a t i o n o f v i r u s e s and there i s Nevertheless, i t should be mentioned t h a t
no doubt t h a t they warrant our a t t e n t i o n .
s i n c e that time, out of m i l l i o n s o f subjects v a c c i n a t e d w i t h the French neurotropic s t r a i n , no f u r t h e r cases of such grave jaundice have over occurred. Tunis were t h e r e f o r e i s o l a t e d ones and consequently drawing general conclusions from them. The two cases i n
care should be taken t o avoid
However, i t should be noted that when faced
w i t h these cases the f i r s t i d e a t o a r i s e was t h a t the nature of the vaccine had changed, for i t must be admitted that there were serious reasons f o r b e l i e v i n g t h i s . Neveragent
t h e l e s s , nothing of the k i n d had occvu-red and i t was a concomitant pathogenic which had caused these a c c i d e n t s .
The i n t r u d e r was r e l a t i v e l y easy t o detect and
i d e n t i f y , but i t might have been an unknown or l i t t l e known v i r u s which we would have been unable to detect and we should then have continued to hold the vaccine r e s p o n s i b l e
WHO/YF/19
page 10 for what had happened. We must be careful not to conclude too h a s t i l y that the
virulence of the vaccine has changed; t h i s i s doubtless the most useful lesson t o be learnt from t h i s chapter on post-vaccinal jaundice. Post-vaccinal meningitis or meningo-encephalitis As compared with the 6th-7th day fever, the neural reactions are always l a t e . They appear most often between the 11th and 15th day, sometimes a l i t t l e e a r l i e r , sometimes a l i t t l e l a t e r , the longest incubation period seeming to have been 23 days. As mentioned above, they may or may not have been preceded by fever on the 7th day. i t s e l f , i . e . an i n i t i a l peak i s followed by an apyrexlc i n t e r v a l , then there i s renewed fever, accompanied t h i s time by meningo-encephalitic symptoms. , These symptoms, i t may b r i e f l y be recalled are: headache, photophobia, a more or l e s s In addition, the reaction Lumbar This state continues marked stiffness i n the nape of the neck, Kernig's sign f a i r l y often only s l i g h t , paresla of the limbs, obnubilation and somnolence. commences with convulsions i n children, which are alarming f o r the family. puncture yields a clear, hyperlymphocytic, hypertensive l i q u i d . for four-five days; exceptionally i t may l a s t ten-twelve days. 6th-
When the two reactions follow one another, the temperature curve repeats
U n t i l recent years the general view was that such accidents are always curable. The neural symptoms disappear as suddenly as they come, the fever f a l l s and recovery ensues without sequelae. The cases observed i n French West A f r i c a (including the f i r s t two which I reported i n 195^) recovered i n t h i s way as w e l l as cases observed subsequently i n France and i n North A f r i c a , whether they developed following the use of the French vaccine or of vaccine 17B, as i n the recent cases of Professor P. Lépine.^ Following the events which occurred In 1951, the same confidence i s no longer f e l t as regards prognosis. There were f a t a l cases i n Costa Rica and Nigeria. The
conditions under which these accidents appeared were appreciably the same, but they took a different course and were f a t a l i n a proportion reaching, and i n Nigeria even exceeding, a t h i r d of the cases. Thus we are faced no longer with benign neural
reactions but with grave accidents, at least i n the circumstances which we have j u s t mentioned. ' • . • '.-:? f m , » , ; -
See document WHO/YF/7
WHO/YP/19 page 11
In the past, as at the present time, post-vaccinal meningitis has happily alvays been r a r e . In h i s report Dr. G. Stuart has brought together data published concerning
the number of such cases.
I do not v l s h to add anything t o t h i s excellent report
other than a simple personal s t a t i s t i c a l d e t a i l , the absence of vhich from my e a r l i e r p u b l i c a t i o n s vas noted by Dr. Stuart and vhich I v i s h t o give him: Betveen 1 9 3 ^ ^ and 1 9 1 + 6 , tvelve cases of meningitis came to my knovledge out of a t o t a l o f 25,000 vaccinations c a r r i e d out by myself or by colleagues t o vhom I sent vaccine and vho kept me accurately informed o f the r e s u l t s of t h e i r i n o c u l a t i o n s . I c a r r i e d out, or made i t possible t o carry out by supplying vaccine, many other v a c c i n a t i o n s , but I have only taken into consideration the above t o t a l , a l l of vhich v e r e supervised i n a more or l e s s experimental manner. Thus, out of 25,000
vaccinated persons there vere t v e l v e cases of meningitis, i . e . 0.50 per thousand. Of these, 9,000 had been vaccinated i n three steps, t h i s being our i n i t i a l method. F i v e of these cases developed meningitis, i . e . 0.55 per thousand.
The vaccine enclosed i n egg yolk vas administered
i n a single inoculation to per thousand. Above a l l .
l6,000 subjects.
These developed meningitis i n seven cases, i . e . O.hk
The d i f f e r e n c e i n favour of the second vaccine i s extremely small.
I t should be noted that the o v e r a l l proportion i n d i c a t e s , i n round f i g u r e s , a frequency of one case out o f every 2,000 persons vaccinated. This i s the proportion
v h i c h i s found t o recur v i t h l i t t l e v a r i a t i o n i n other s t a t i s t i c s , provided that the averages have been c a l c u l a t e d on a s u f f i c i e n t number of persons and over a s u f f i c i e n t length of time. Thus, t o take the example o f N i g e r i a vhere f a t a l accidents occurred,
the 1951 reports f o r t h i s country give a t o t a l of lU2,000 persons vaccinated among whom there vere 85 cases of meningo-encephalitis, be seen, t h i s f i g u r e i s pretty close t o our ovn. Hovever, a l l t h i s only makes i t p o s s i b l e t o state that, on the vhole, the proportion o f neural reactions Is lov. I t i s much more i n s t r u c t i v e t o consider the i . e . 0.59 per thousand. As can
s t a t i s t i c s from the vievpolnt of age, as has been done by Dr. Stuart i n h i s important paper and, i n a d d i t i o n , by Professor Lépine i n a note vhich he vas kind enough t o communicate t o us.
WHOAF/I9 page 12
Indeed, my personal s t a t i s t i c s showed 3 adults and 9 c h i l d r e n out of 12 c a s e s , but as we had vaccinated many more a d u l t s (21,000) than c h i l d r e n (^,000), t h e r e s p e c t i v e frequencies were: O.lh per thousand among a d u l t s and 2.25 per thousand among
c h i l d r e n , i . e . l 6 times more c h i l d r e n than adults f o r the same number of v a c c i n a t e d subjects. I should mention, on the one hand that we counted adolescents up t o t h e age o f 15 as c h i l d r e n and, on the other hand, that a t t h i s e a r l y stage very small c h i l d r e n were not vaccinated. Now that the r e g u l a t i o n s p r e s c r i b e v a c c i n a t i o n from b i r t h ,
the s e n s i t i v i t y of c h i l d r e n Is even more n o t i c e a b l e , so t h a t Professor P. Lépine found using vaccine 17D i n P a r i s , a p r o p o r t i o n of h cases o f m e n i n g i t i s p e r thousand i n f a n t s vaccinated between 0 and 6 months of age. Dr. S t u a r t ' s report indicates
the h i g h p r o p o r t i o n o f young c h i l d r e n a f f e c t e d i n Costa R i c a ; c h i l d r e n and above a l l i n f a n t s were attacked.
i n Nigeria, only
Consequently, although m e n i n g i t i s may f o l l o w v a c c i n a t i o n a t any age, i t i s much more frequent among c h i l d r e n , the frequency i n c r e a s i n g t h e younger the c h i l d . p o i n t can be regarded as d e f i n i t e l y e s t a b l i s h e d . There i s another f a c t o r , not a f f e c t e d by any question of age, namely t h e existence o f a d e f i n i t e tendency f o r such cases t o be grouped together. In countries This
such as French West A f r i c a , i t seemed a t c e r t a i n times t h a t t h e n e u r a l r e a c t i o n s had disappeared and then one, two o r more cases developed over a short period o f t i m e and i n one and the same place, whereas elsewhere the a f t e r - e f f e c t s of v a c c i n a t i o n continued t o take t h e i r normal course. I n France P r o f e s s o r Lépine and myself use t h e I n two y e a r s
same vaccine 17D prepared a t t h e Pasteur I n s t i t u t e f o r v a c c i n a t i o n .
P r o f e s s o r Lépine has observed f i v e cases of m e n i n g i t i s i n P a r i s whereas i n S t r a s b o u r g none have come t o our n o t i c e . The f a c t t h a t p o s t - v a c c i n a l meningitis which i s b e n i g n i n Prance, North A f r i c a and French West A f r i c a , has caused deaths i n B r a z i l , C o s t a R i c a and N i g e r i a I s apparently due t o c o n d i t i o n s o f l o c a l i z a t i o n and time w h i c h a r e a p p r e c i a b l y t h e same.
* Doc. WHO/YF/6
WHO/YF/19 page 15
E x a c t l y s i m i l a r phenomena have been observed t o f o l l o w smallpox v a c c i n a t i o n .
There
have been v e r i t a b l e outbreaks of e n c e p h a l i t i s i n c e r t a i n coxmtrles a t a given p e r i o d , the cases v a r y i n g i n number and i n seriousness, whereas s i m i l a r v a c c i n a t i o n c a r r i e d out i n neighbouring be without I n c i d e n t . I t has been necessary t o suspend smallpox v a c c i n a t i o n In s e v e r a l s i t u a t i o n s of t h i s k i n d and s i m i l a r l y we have seen the a u t h o r i t i e s i n Costa E l c a and N i g e r i a I n t e r r u p t t h e i r y e l l o w - f e v e r v a c c i n a t i o n campaigns, so t h a t not only l o s s of human l i f e i s t o be deplored but a l s o the very f u t u r e of y e l l o w - f e v e r p r o p h y l a x i s , which we b e l i e v e d f i n a l l y assvured, i s compromised t o some extent. The n e c e s s i t y f o r research on the i n t e r n a t i o n a l l e v e l t o determine t h e cause of such m e n i n g i t i s The p o s i t i o n l e s e r i o u s . We are faced w i t h a dilemma whose s o l u t i o n cannot be coxmtrles and even i n neighbouring l o c a l i t i e s , has continued to
seen a t present, and e i t h e r v a c c i n a t i o n can be continued and f u r t h e r accidents w i l l c e r t a i n l y occur, or the f e a r of such accidents w i l l lead t o a f a l l i n g off In v a c c i n a t i o n , yellow f e v e r w i l l r e g a i n the upper hand and we know only too w e l l what e p i d e m i o l o g i c a l d i s a s t e r s t h i s may lead t o .
Our d i f f i c u l t y i s due s o l e l y t o the f a c t t h a t we do not know the cause of the nexiral a c c i d e n t s . However, there has been no l a c k of opportunity t o study t h i s Unfortunately,
d u r i n g the period of almost 20 years since the f i r s t cases were reported.
Instead of these neural r e a c t i o n s being studied, they were c i t e d a g a i n s t the method, t h e f i r s t used on a l a r g e s c a l e , which was held r e s p o n s i b l e f o r them. An attempt
vas made thereby t o s u b s t i t u t e other procedures, which were s t a t e d i n advance t o be incapable of causing m e n i n g i t i s . The f i r s t of these was sero-vacclnatlon. I may
s t a t e d t h a t i t would be unsuccessful;
t h a t the a d d i t i o n of an Immune serum
n e u t r a l i z e part of the v i r u s but does not change the nature of the remainder; moreover, s e r o - v a c c l n a t l o n was not p r a c t i c a l , being i l l - a d a p t e d t o the Immunization of l a r g e population masses. Nevertheless, i t was a p p l i e d . As a r e s u l t , cases of
v i r u s Jaundice occurred, without any Improvement as regards the meningeal r e a c t i o n s . Indeed, the most severe r e a c t i o n of t h i s k i n d seen a t the P a r i s Pasteur followed on s e r o - v a c c l n a t l o n . Institute
WHP/YF/19
page Ik
L a t e r the c u l t u r e vaccines were t r i e d .
T h e i r method of p r e p a r a t i o n was t o •
e l i m i n a t e e v e r y t h i n g thought capable of maintaining the "neurotropism" of t h e s t r a i n . True, these vaccines produced e n c e p h a l i t i s i n monkeys, but t h e i r harmlessness was guaranteed. f o r man
The deceptive but f a i r l y long periods during which n e u r a l r e a c t i o n
may not appear l e d t o the b e l i e f t h a t t h i s timethe aim had r e a l l y been a t t a i n e d and many were deceived i n t h i s way. At the present time we know t h a t c u l t u r e v a c c i n e s Thus, d u r i n g A l l that
cause m e n i n g i t i s i n the same way as vaccine prepared from mouse b r a i n . 20 years, no progress was made as concerns t h i s question o f m e n i n g i t i s .
was done was t o repeat the mistake of b e l i e v i n g t h a t by modifying the technique e m p i r i c a l l y , i t would be p o s s i b l e t o prevent an accident o f whose o r i g i n , n a t u r e and c o n d i t i o n s of appearance we have no d e f i n i t e knowledge. L a b o r a t o r i e s have been l a c k i n g i n the s p i r i t of co-operation necessary t o s o l v e t h i s e s s e n t i a l problem. I f workers i n the d i f f e r e n t c o u n t r i e s would share t h e i r
knowledge, t h e i r f a c i l i t i e s and t h e i r e f f o r t s , I have no doubt t h a t they would r a p i d l y be able t o give v a c c i n a t i o n the one Improvement necessary t o make i t p e r f e c t l y satisfactory. Y e l l o w - f e v e r v a c c i n a t i o n reached at the very outset a degree o f an equal c e r t a i n t y of i n n o c u i t y i s There i s no doubt t h a t
e f f e c t i v e n e s s almost unknown i n such a f i e l d ;
l a c k i n g , above a l l as concerns immunization o f c h i l d r e n .
we could succeed i n g i v i n g such a guarantee o f harmlessness, but t h i s goal w i l l o n l y be reached a f t e r we have discovered e x a c t l y what should be avoided. We should have l e a r n t from the cases of m e n i n g i t i s w h i c h have occurred i n v a r i o u s places throughout the wnrld; there have been e n q u i r i e s , even experimental r e s e a r c h ,
but n e i t h e r one nor the other seems t o have been c a r r i e d on under the c o n d i t i o n s necessary f o r u s e f u l i n t e r p r e t a t i o n of t h e r e s u l t s . Among other t h i n g s , as f a r as
p o s s i b l e , the same observers should have compared what happened i n one r e g i o n w i t h what happened i n another, but t h i s was not done. have been shown. F i n a l l y , mûre o b j e c t i v i t y should
Faced w i t h a danger of as i n t e r n a t i o n a l a nature as y e l l o w f e v e r ,
there can be no progress, a t the p o i n t where we now a r e , w i t h o u t the I n t e r n a t i o n a l co-operation of r e s e a r c h workers.
WHO/YP/19 page 15
The U n e s to be f o l l o v e d by research No attempt w i l l be made here to l a y down or even o u t l i n e a research programme, since t h i s can be done only a f t e r Joint conversations and discussions among specialists. Moreover, laboratory experts would not s u f f i c e , since the epidemiolo-
g i s t s have a l s o something t o say on a c e r t a i n niimber of p o i n t s . We have stated, and t h i s w i l l have been generally approved, I f e e l , that yellowf e v e r v a c c i n a t i o n Is a procedure which Is perfect and beyond any c r i t i c i s m , except
as concerns neural reactions and, more p a r t i c u l a r l y , neural r e a c t i o n s In c h i l d r e n . T h i s already defines the f i e l d In which e f f o r t s should be concentrated. Another point should be made c l e a r and w i l l greatly s i m p l i f y the work, namely, t h a t there i s no longer any reason to d i s t i n g u i s h between the two methods of preparing vaccine, i . e . In v i v o culture of the v i r u s In the mouse brain, and c u l t u r e i n the embryonnated chicken's egg give the same r e s u l t s , ensure the same p r o t e c t i v e power and unfortiinately spring the same surprises as concerns neural r e a c t i o n s . The
advantages of one or the other technique on the more or l e s s i n d u s t r i a l lével of manufacture have become of secondary i n t e r e s t ; such d e t a i l s . Having cleared the ground i n t h i s way, we are thus l e f t with a vaccine which the problem concerning ue i s above
sometimes causes simple f e b r i l e r e a c t i o n s which can be neglected i n p r a c t i c e , since they cause no inconvenience, but a l s o , although more r a r e l y , serious oenlngo-
e n c e p h a l l t l c symptoms which are sometimes f a t a l and which should be prevented at a l l costs. This meningo-encephalitis i s c e r t a i n l y i n f e c t i o u s ; i t i s caused by a
v i r u s (using the word In I t s widest sense) which Is e i t h e r the v i r u s c o n s t i t u t i n g the vaccine I t s e l f or a v i r u s f o r e i g n to the vaccine. f o r e i g n v i r u s may In the l a t t e r case, the
e i t h e r be introduced by the vaccine on Inocvilation or may be préSuch are, i n my opinion, the three
existent i n the body of the vaccinated person.
e s s e n t i a l Ideas upon which work should be concentrated. There are data f o r and against each of them which should be checked and made use of. I t Is here, above a l l , that the present report cannot claim to be complete.
WHO/YF/19
page 16 since ve are obliged to l i m i t the details given. c l i n i c a l finding previously noted: another or may exist separately. Here i s one Indication based on a one
the f e b r i l e reaction on the 6th day and the n e \ i r a l The f i r s t i n point of time, i . e . the f e b r i l e This i s proved by This seems to I n d i c a t e be
reaction occur as tvo phenomena Independent of one another, they may f o l l o v attack on the 6th day, i s certainly due to the vaccine virus. the fact that i t i s never seen i n cases of re-vaccinatlon. veak i f there vere nothing more to support i t .
that the neural reaction i s connected v i t h another factor, but t h i s argument vould
I t i s hovever supported and considerably strengthened by the fact that the n e u r a l reaction can develop vhen the blood already exercises a protective function; very Important. One example has been reported by Savyer, and I myself have The tvo vaccinated persons i n question vere seroobserved a second such case. this is
l o g i c a l l y Immune to yellov fever vhen the meningitis developed. I t i s understandable vhy there are not a large number of examples to quote, since normally the neural reaction appears before the body has had the time to manufacture antibodies. Special cases are necessary, vhere the antibodies appear very But the very f a c t t h a t early and the meningitis at a r e l a t i v e l y very late stage.
tvo duly authenticated cases have already been observed varrants serious a t t e n t i o n . Further examples should be sought for In man and brought about experimentally, i f possible, i n monkeys. In connexion v i t h experiments on monkeys, some comment i s called f o r . sometimes been misleading? I s i t not
true to say that the results given by intracerebral inoculation of monkeys have Theiler's v i r u s , vhen d i r e c t l y injected Into the b r a i n , These are experimental paralyses and k i l l s mice and, i n general, guinea pigs also; there i s nothing surp r i s i n g to f i n d that i t acts i n the seime vay on monkeys. conditions so remote from those of human vaccination that i t appears very d i f f i c u l t to drav any lesson from them; hov many of the other common vaccines vould be found harmless i f they vere tested i n t h i s vay?
WHO/YF/19 page 17
On the contrary, subcutaneous i n o c u l a t i o n of monkeys or infsculation by s c a r i f i c a t i o n o f the s k i n i s of the greatest i n t e r e s t . human v a c c i n a t i o n : T h i s e x a c t l y reproduces the process o f
e i t h e r the animals become immunized without Incident, or c u r a b l e But the question
neviral r e a c t i o n s are seen, o r , f i n a l l y , f a t a l e n c e p h a l i t i s develops.
then a r i s e s , w i t h the monkey as w i t h man, as t o whether, when e n c e p h a l i t i s occurs, i t I s caused by the vaccine I t s e l f , by a v i r u s contaminating the v a c c i n e , or by v i r u s a l r e a d y present In the anlmalT Perhaps the experiments on monkeys have not been
s u f f i c i e n t l y studied from t h i s p o i n t of view, but r a t h e r on the b a s i s of the vague concept, today a l i t t l e obsolete, of neurotropism. Such experiments should be taken
up a g a i n w i t h the aim of supplying an answer to the q u e s t i o n which has j u s t been r a i s e d and i n the exact terms i n which i t has been stated} I f e e l t h a t t h i s would
be an important p a r t of the r e s e a r c h programme which should be e s t a b l i s h e d . What s i g n i f i c a n c e should be a t t r i b u t e d to the presence of v a c c i n a l y e l l o w - f e v e r v i r u s i n the b r a i n o f the monkey or of man i n the event of death f o l l o w e d by autopsy? Dr. Macnamara performed f i v e a u t o p s i e s i n N i g e r i a a f t e r death from e n c e p h a l i t i s and i n f o u r cases found Max T h e i l e r ' s v i r u s l i v i n g and a c t i v e i n the b r a i n matter of the corpses. report. However, i t i s not p e r m i s s i b l e t o conclude as does Dr. Macnamara, t h a t i n such cases the vaccine v i r u s c e r t a i n l y caused the e n c e p h a l i t i s . Vaccinated monkeys not T h i s I n t e r e s t i n g i n f o r m a t i o n I s given In Dr. S t u a r t ' s well-documented
s u f f e r i n g from e n c e p h a l i t i s which are s a c r i f i c e d In the second week f o l l o w i n g v a c c i n a t i o n have a l s o the v i r u s In t h e i r b r a i n s . T h i s i s i n no way s u r p r i s i n g since the t h i s Is the
v a c c i n e v i r u s m u l t i p l i e s i n the organism of a l l vaccinated s u b j e c t s ; very p r i n c i p l e of Immunization by means of l i v i n g vaccine v i r u s .
T h i s point may, perhaps, be b e t t e r understood i f I quote an example which I myself observed, q u i t e outside the q u e s t i o n o f y e l l o w - f e v e r v a c c i n a t i o n . A person
who had been b i t t e n was undergoing p r e v e n t i v e treatment a g a i n s t r a b i e s by the c l a s s i c Pasteur method; on l e a v i n g the I n s t i t u t e , where he came every day f o r treatment, he I performed the autopsy and removed a fragment these developed the u s u a l p a r a l y s i s
was k i l l e d i n a motor c y c l e a c c i d e n t .
of the b r a i n which I Inoculated i n t o r a b b i t s ; caused by the f i x e d r a b i e s v i r u s .
I f the same man had been vaccinated a g a i n s t
WHO/YF/19 page 18
y e l l o w f e v e r one o r two weeks before h i s accident I t would c e r t a i n l y have been p o s s i b l e t o f i n d T h e i l e r ' s v i r u s i n h i s b r a i n In the same way. However, i t w o u l d
doubtless not have been found a t a l a t e r date a f t e r the appearance of t h e a n t i b o d i e s . Nevertheless, t h i s does not prevent e n c e p h a l i t i s making I t s appearance a t such a
l a t e p e r i o d and t h i s Is probably why Dr. Macnamara f a i l e d t o f i n d t h e v i r u s i n one of t h e f i v e autopsies he c a r r i e d out, thus i n d i r e c t l y confirming both Sawyer's observation and my own. Some years ago I reported a case o f m e n i n g i t i s f o l l o w i n g on y e l l o w - f e v e r vaccination where the c e r e b r o - s p i n a l f l u i d d i d not c o n t a i n T h e i l e r ' s v i r u s b u t At t h e time c h o r l o - m e n l n g l t l s
another v i r u s which was pathogenic f o r t h e guinea p i g .
had hardly commenced t o be discussed and moreover I was i n f l u e n c e d by t h e f a i r l y general view that meningeal accidents were caused by the vaccine, so t h a t t h e c a s e was not p r o p e r l y studied. from c h o r i o - m e n i n g i t i s . Thus I wrote t h a t the mice bred by us were c e r t a i n l y free
Today I have a b e t t e r knowledge of asymptomatic i n f e c t i o n s I a l s o reported, without being
and would not make t h e same a s s e r t i o n so r e a d i l y .
a b l e t o i n t e r p r e t i t , a f a c t which seemed curious t o me: recovered
guinea p i g s which had
from typhus were r e s i s t a n t t o the v i r u s o f m e n i n g i t i s but, on t h e o t h e r from t h e l a t t e r d i s e a s e were not immune t o I sub-
hand, guinea p i g s which had recovered
typhus, i . e . the immunity a p p l i e d i n one d i r e c t i o n and not i n t h e other. sequently discovered the reason f o r t h i s anomaly:
our typhus s t r a i n had been
passaged on mice, l i k e most typhus s t r a i n s a t t h a t time moreover, s i n c e we were accustomed t o make use of mice i n exchanging exanthematic typhus v i r u s e s between laboratories. simultaneously I n t h i s way, on i n o c u l a t i n g t h e guinea p i g s w i t h typhus we had i n o c u l a t e d them w i t h t h e v i r u s o f c h o r l o - m e n l n g l t l s ; they were t h u s
Immunized a g a i n s t both diseases without our knowing i t .
LAIGRET, J . (1937) I-es v a c c i n a t i o n s contre l a fièvre Jaune. Ann. Méd., h2, U63-^77
WHO/YF/19 page 19 However t h i s may be, i t i s c e r t a i n that the vaccinated subject i n question, s u f f e r i n g from curable meningitis ( l i k e a l l our other cases i n North A f r i c a and France) c a r r i e d a c h o r l o - m e n i n g i t i s v i r u s of the Armstrong type o r a r e l a t e d type m h i s cerebro-spinal f l u i d . On seeing t h e a i n l c a l s i m i l a r i t y e x i s t i n g between
lymphocytic m e n i n g i t i s , g e n e r a l l y benign, caused by Armstrong's v i r u s and the neural r e a c t i o n s , a l s o benign, a t l e a s t so f a r i n our part o f the world, f o l l o w i n g y e l l o w f e v e r v a c c i n a t i o n , one i s struck by the f a c t that a v i r u s i d e n t i c a l t o Armstrong's v i r u s has been I s o l a t e d from the c e r e b r o - s p i n a l f l u i d o f a vaccinated person s u f f e r i n g from p o s t - v a c c i n a l m e n i n g i t i s . This I s a s o l i t a r y case, but I f i t were
confirmed, i t would be of almost d e c i s i v e s i g n i f i c a n c e . Our vaccines prepared w i t h mouse b r a i n may be contaminated w i t h t h e v i r u s of chorlo-menlngltls. anbryo. On one occasion I a l s o i s o l a t e d t h i s v i r u s from t h e c h i c k
Since then I have made i t a r u l e t o check the a n t i - y e l l o w - f e v e r vaccines Any
which we produce, by means of i n o c u l a t i o n i n t o the guinea p i g peritoneum.
vaccine causing fever In the guinea p i g should be considered as p o s s i b l y contaminated -with the v i r u s of c h o r l o - m e n l n g l t l s and should be r e j e c t e d . I n one of the preceding chapters, e n t i t l e d " P o s t - v a c c i n a l jaundice", we have drawn t h e a t t e n t i o n of the reader t o a c e r t a i n number of cases o f v i r u s a s s o c i a t i o n concerning yellow f e v e r and v a c c i n a t i o n against yellow fever. We a r e now brought
t o t h i s question of v i r u s a s s o c i a t i o n i n connexion w i t h the case which we have j u s t c i t e d o f the i n f e c t i o n o f a vaccinated subject by the chorlo-menlngltls v i r u s and we are much i n c l i n e d t o b e l i e v e that associated v i r u s e s c o n s t i t u t e the p r i n c i p a l element i n t h e problem o f meningo-encephalitic f e v e r vaccine v i r u s accidents. We do not deny a p r i o r i that theyeUow i n the present f a c t could
by i t s e l f may have caused cases c f m e n i n g i t i s ;
s t a t e o f our knowledge such a d e n i a l would be baseless.
No experimental
•be c i t e d i n support of i t , no l o r e , moreover, than i t could i n favour o f the opposing view a t t r i b u t i n g these meningeal accidents t o "neurotropism". The myth o f neurotropism
d i r e c t e d against the vaccine of the Pasteur I n s t i t u t e a t Tunis and Dakar, c o l l a p s e s when confronted w i t h the f a c t that the c u l t u r e vaccine causes the same r e a c t i o n s i n the nervous system. Together w i t h t h i s myth disappears an almost senseless phraseology
where the words "organotropism", " v i s c e r o t r o p i s m " and "pantropism" c l a i m t o e x p l a i n
WH0/yF/i9 page 20
everything.
There Is no experimental
fact showing whether or not the v a c c i n e
alone fact
Is capable of causing neural accidents an:', against t h i s view must be placed the that these accidents are r a r e l y seen and that ths immense majority of v a c c i n a t e d subjects undergo v a c c i n a t i o n without reaction.
In favour of the associated viruses theory, on the contrary, there i s d e f i n i t e evidence which although l i m i t e d i s unmistakably p o s i t i v e . duly confirmed Thus, i n two cases the
i n t r u s i o n of Leptospira brought about severe jaundice f o l l o w i n g
v a c c i n a t i o n and t h i s i s a l l the more s i g n i f i c a n t i n that laboratory i n v e s t i g a t i o n has now without revealed the unsuspected frequen'^y of l e p t o s p i r a l jaundice. meningo-encephalitis
There i s a l s o the d e f i n i t e presence of a chorlo-menlngltls v i r u s
m the cerebrospinal f l u i d during a curable menineo-lymphocytic r e a c t i o n f o l l o w i n g vaccination. F i n a l l y , although I cannot go into i t here i n d e t a i l , there i s the which I was encouraged to take up by Charles N i c o l l e and have continued research since h i s in particular
death, with mixtures of d i f f e r e n t v i r u s e s .
Cwlng to circumstances, and,
distance from yellow-fever zones, and a l s o the lack of monkeys, my i n v e s t i g a t i o n s have been d i r e c t e d towards v i r u s a s s o c i a t i o n s other than those which might concern the neural accidents f o l l o w i n g yellow-fever vaccination. The experiments under way
a t present on t h i s subject are too incomplete f o r any d e t a i l s to be given. m other f i e l d s of v i r o l o g y , experimental study of v i r u s a s s o c i a t i o n s has The most important
However revealed
f a c t s of considerable general s i g n i f i c a n c e .
i s the f o l l o w i n g :
on a s s o c i a t i n g two viruses whose a c t i o n taken separately generally r e s u l t s ( f o r a given animal species) i n an asymptomatic i n f e c t i o n , c l i n i c a l disease i s brought about. Thus, ectromelia i s u s u a l l y asymptomatic or tskes the form of irdld l e s i o n s the same anliral becomes i n f e c t e d with murine typhus only i n an On a s s o c i a t i n g both v i r u s e s i n the mouse, however, severe typhus
i n the mouse;
asymptomatic form.
i s provoked, with Intense m u l t i p l i c a t i o n of the r l c k e t t s i a s and p a r a l y s i s , r e g u l a r l y ending i n death. The r a t , which i s r e s i s t a n t to ectromelia, on being inoculated here experimental ectromelia . ; . . .
with the same mixture succumbs to a f a t a l paraly_si_s; m the r a t i s an e n t i r e l y new
disease which a v i r u s a s s o c i a t i o n has created from
WHO/YF/19 page 21
f i r s t to last.
From t h i s can be drawn, not conclusions (which would not be
p e r m i s s i b l e ) as regards the a e t i o l o g y o f neural a c c i d e n t s f o l l o w i n g yellow-fever v a c c i n a t i o n , but an idea f o r research capable o f s o l v i n g t h i s problem which i s so d i s t x i r b i n g i n the present circumstances.
There can be no doubt that t h e c h o r l o - m e n l n g l t l s v i r u s already e x i s t s In c e r t a i n s u b j e c t s , since we see spontaneous cases o f m e n i n g i t i s brought about by i t s a c t i o n . I t a t t a c k s c h i l d r e n above a l l . Does t h i s not i n d i c a t e t h a t y e l l o w - f e v e r v a c c i n a t i o n
may b r i n g about m e n i n g i t i s by a s s o c i a t i o n o f the two v i r u s e s In c h i l d r e n w i t h asymptomatic chorlo-meningitis? On the other hand, as the c h i l d becomes o l d e r t h e immunized a g a i n s t c h o r l o - m e n i n g i t i s ,
chances Increase that i t w i l l be spontaneously
r e n d e r i n g neural accidents f o l l o w i n g the v a c c i n a t i o n o f o l d e r c h i l d r e n and a d u l t s more and more r a r e . However, v i r u s e s other than that of c h o r l o - m e n l n g l t l s are c e r t a i n l y able t o p l a y a p a r t i n the same circumstances and i n the same way. T h i s r a i s e s the question
of t h e e x i s t e n c e o f r e l a t e d but d i f f e r e n t e n c e p h a l i t i s v i r u s e s , which are endemic i n the v a r i o u s regions, and whose study, already undertaken f o r other reasons, should be
taken up anew from the viewpoint of the r e l a t i o n s h i p which these v i r u s e s may have t o yellow-fever vaccination. maintained I f , as appears probable, some o f these v i r u s e s a r e
by murine e n z o o t i c s , the v a r i a b i l i t y o f t h e i r potency, combined w i t h
t h e i r geographic d i s t r i b u t i o n , would only confirm what we already know o f other groups o f diseases having the rodents as n a t u r a l r e s e r v o i r s . The v a r i a b i l i t y i n
v i r u l e n c e towards man i n p a r t i c u l a r would e x p l a i n the d i f f e r e n c e s i n the s e v e r i t y of cases o f meningo-encephalitis f o l l o w i n g v a c c i n a t i o n o c c u r r i n g i n d i f f e r e n t c o u n t r i e s , without i t being necessary t o a t t r i b u t e t h e ^ ^ d i f f e r e n c e s t o changes i n the v i r u l e n c e of the vaccine. There i s no need t o add, since the reader w i l l r e a l i z e t h i s himself, t h a t such research a l s o concerns t h e sometimes dangerous cases o f e n c e p h a l i t i s f o l l o w i n g smallpox v a c c i n a t i o n . T h i s only serveo t o c t r e s s the need f o r the i n t e r n a t i o n a l
co-operation o f research workers In the s o l u t i o n o f these two grave problems, which f i n a l l y we may w e l l be l e d t o regard as one and the same problem, common t o the two great forms o f v a c c i n a t i o n which represent part o f our armament i n the f i g h t against the quarantine diseases, namely y e l l o w - f e v e r v a c c i n a t i o n and smallpox v a c c i n a t i o n .
WHO/YF/19 page 22
Temporary measures v h i c h should be taken In connexion w i t h the vaccination of children I f e e l t h a t In the meantime c e r t a i n measures should be taken as regards t h e v a c c i n a t i o n of very young c h i l d r e n . This Is c a l l e d f o r by c e r t a i n centres i n Europe These c e n t r e s
empowered t o v a c c i n a t e passengers t r a v e l l i n g t o overseas t e r r i t o r i e s .
are d i s t u r b e d by the Increase i n the number o f cases of m e n i n g i t i s s i n c e I t became o b l i g a t o r y t o v a c c i n a t e i n f a n t s before embarkation, without any lower age l i m i t . The French Acadeny of Medicine d e a l t a few years ago w i t h t h i s q u e s t i o n o f t h e v a c c i n a t i o n of c h i l d r e n a g a i n s t yellow fever but, confident In t h e r e p o r t e d h a r m l e s s n e s s of c u l t u r e vaccines, i t recommended t h a t only vaccine 17D should be used. as i s knovn, nothing vas gained from t h i s . The p e r s i s t e n c e of meningeal r e a c t i o n s thus p r o g r e s s i v e l y l e d v a c c i n a t o r s t o Inoculate c h i l d r e n only v i t h very small doses of vaccine, thus c r e a t i n g an l l l u s o j r y secvirity, v h i c h vas nevertheless guaranteed by a c e r t i f i c a t e v a l i d f o r s i x y e a r s . I t would be i n f i n i t e l y b e t t e r as P r o f e s s o r Lépine has remarked, t o delay v a c c i n a t i o n somewhat, but t o make I t c e r t a i n . Professor Lépine adds t h a t , according t o h i s observations, young c h i l d r e n respond poorly t o the vaccine from t h e v i e v p o l n t of antibody production. I have However,
not had the opportunity o f v e r i f y i n g t h i s , since I have not c a r r i e d out many s e r o l o g i c a l t e s t s on v a c c i n a t i o n subjects of t h i s age. But there Is nothing s u r p r i s i n g
i n vhat P r o f e s s o r Lépine says, since i t Is a general r u l e t h a t Immunity a g a i n s t most antigens I s d i f f i c u l t t o impart before one year o f age. T h i s i s vhy, as con-
cerns smallpox v a c c i n a t i o n f o r example, French l a v does not r e q u i r e t h a t v a c c i n a t i o n be c a r r i e d out from b i r t h , but only during the f i r s t year o f l i f e , except In t h e event o f an epidemic. S i m i l a r l y , v a c c i n a t i o n against d i p h t h e r i a and tetanus i s
only compulsory In many c o u n t r i e s d u r i n g the second o r even t h i r d year, v h i c h i s a little late.
I n my o p i n i o n there v o u l d be no dravback, on departure from non-endemic zones, m v a c c i n a t i n g only c h i l d r e n more than one year o f age a g a i n s t y e l l o v f e v e r ; i t v o u l d then be f o r t h e a u t h o r i t i e s i n t h e endemic c o u n t r i e s t o take those measures
WHO/YF/19 page 23
c a l l e d f o r "by the l o c a l sanitary conditions with respect to these Infants.
This
wovild reduce to a considerable extent the number of meningitis cases u n t i l such time as accxirate knowledge of the cause of these accidents makes I t possible to avoid them completely which, I repeat. Is not beyond our powers provided that these are properly employed.
SUMMARY
Vaccination against yellow fever has had the most happy e f f e c t s on the health and economic p o s i t i o n of the regions concerned; kinds are considerable. the r e s u l t i n g advantages of a l l beyond doubt, these
The effectiveness of t h i s vaccine Is now
but I t has the drawback of causing c e r t a i n reactions In the nervous system; take the form of meningitis or meningo-encephalitis. These accidents are rare. They a f f e c t c h i l d r e n above a l l .
For a long time cases
they were i n v a r i a b l y followed by recovery; have been reported i n c e r t a i n countries. Incapable
however f o r about two years f a t a l The culture vaccine, although
said to be
of causing such accidents, a c t u a l l y does so.
There Is nothing making It p o s s i b l e to say whether or not the vaccine v i r u s alone Is Involved. There are cases where meningitis has appeared when n e u t r a l i z i n g
a n t i b o d i e s were already present i n quantity i n the blood of the vaccinated subject; t h i s i s very Important and should be confirmed.
In one case the author i s o l a t e d from cerebrospinal f l u i d , a v i r u s I d e n t i c a l o r c l o s e l y r e l a t e d to that of chorlo-menlngltls. Such a v i r u s may be derived It
from the brains of mice or the chick-embryos used i n preparing the vaccine. i s f a i r l y easy to detect t h i s contamination guinea p i g . However, t h i s v i r u s may already be present
by i n t r a p e r i t o n e a l i n o c u l a t i o n of the
i n the organism of the vaccinated and particularly
subject, since there are spontaneous cases of chorlo-menlngltls i n man i n children.
Other types of meningitis or meningo-encephalitis v i r u s can c e r t a i n l y
WHO/YF/19 page 2k
er-t.st •'n man as asymptomatic i n f e c t i o n s arid na^' cause accidents f o l l o w i n g v a c c i n a t i o n , by a s s o c i a t i o n w i t h t h e vaccine v i r u s . D i f f e r e n c e s i n the nature of these v i r u s e s ,
according t o the endemic zones where they a r c prevalent, would e x p l a i n t h e v a r y i n g s e v e r i t y of the a t t a c k s from one country to another. F i n a l l y , the problem seems t o be fundamentally t h i s should be v e r i f i e d . one of v i r u s a s s o c i a t i o n , b u t
These neural accidents are compromising the f u t u r e o f the establishment of a research
y e l l o w - f e v e r p r o p h y l a x i s by means of v a c c i n a t i o n ;
programme i s a matter of urgency so as to f i n d out the cause of the m e n i n g i t i s and how t o avoid i t . Such a programme can only be s u c c e s s f u l l y c a r r i e d out on t h e
I n t e r n a t i o n a l l e v e l by co-operation betveen research workers i n t h e d i f f e r e n t countries. ,
I n the men.nwhile, «s concerns v a c c i n a t i o n on l e a v i n g zones f r e e from t h e d i s e a s e , i t would be s u f f i c i e n t t o r e q u i r e the v a c c i n a t i o n o f c h i l d r e n from one year o f age onwards, which would a ^ o l d a r e l a t i v e l y high number of a c c i d e n t s o c c u r r i n g d u r i n g the f i r s t months of l i f e . • . •