1-4 9

UNITED NATIONS NATIONS UNIES

W O R L D H E A L T H O R G A N I Z A T I O N

EXPERT COMMITTEE ON YELLOW FEVER Sjecond^ Cession

Ifempala7~Sul9 September 1953

ORGANISATION MONDIALE DE LA SANTÉ

WHO/YF/T 12 August 1953 ORIGINAL: ENGLISH

NHWOUS REACTIONS AND ANTIBODY RESPONSE IN INFANTS, FOLLOWING THE USE OF YELLOW-FEVER

IMMUNIZING VACCINES

G. S t u a r t , . M.D.

1. I s a n t l - y e l l o v - f e v e r X^jçcIjiatljjncjij-14y-Çj^.-"MgJ-,°"6 y e a r o f age lî^essa^ or_des\xB!o\e'i

T h i s problem i n v o l v e s c o n s i d e r a t i o n o f two q u e s t i o n s : ( l ) i s t h e r e g r e a t e r r i s k o f m e n i n g o - e n c e p h a l i t i c r e a c t i o n s among i n f a n t s who a r e v a c c i n a t e d w i t h i n • t h e i r f i r s t 12 months o f l i f e than t h e r e i s among c h i l d r e n o f one y e a r and

above; and (2) i s the immunity response t o v a c c i n a t i o n i n the under-ones s u f f i c i e n t t o ensure p r o t e c t i o n and t o j u s t i f y t h e i r b e i n g i s s u e d w i t h an i n t e r n a t i o n a l c e r t i f i c a t e o f v a c c i n a t i o n a g a i n s t y e l l o w f e v e r which has a v a l i d i t y o f 6 y e a r s ?

I s t h e r e g r e a t e r r i s k of J)os>-v_ac^^-nat^ the undertones?

While i t seems c l e a r , from a p e r u s a l o f the r e l e v a n t l i t e r a t u r e , t h a t r e a c t i o n s o f a m e n i n g o - e n c e p h a l i t i c nature tend t o occur most f r e q u e n t l y among the lower age groups, the number o f cases recorded as b e l o n g i n g t o the under-one sub-group i s t o o s m a l l t o permit g e n e r a l i z a t i o n on t h i s p o i n t . Thus, f o l l o w i n g t h e use o f t h e F r e n c h n e u r o t r o p i c v i r u s v a c c i n e i n Costa R i c a d u r i n g 1951; among 12 cases i n c h i l d r e n between t h e ages o f 9 months and 13 y e a r s , o n l y one was under t h e age o f one y e a r ; w h i l e i n N i g e r i a d u r i n g January 1952, when 19,358 c h i l d r e n under 10 y e a r s o l d were v a c c i n a t e d , o f the 73 cases o f e n c e p h a l i t i s r e c o r d e d , 33 f e l l w i t h i n t h e age-group 0-2 y e a r s , b u t the i n c i d e n c e among the under-ones i s n o t s p e c i f i e d . A g a i n , f o l l o w i n g t h e use o f 17D v i r u s v a c c i n e i n B r a z i l d u r i n g I9UI, t h e r e o c c u r r e d , d u r i n g a f u l l y c o n t r o l l e d f i e l d t r i a l i n

Southern Minas Gérais, 5 cases o f m e n i n g o - e n c o p h a l i t i s among 1 ^ 1 c h i l d r e n i n t h e age-group 1-4 y e a r s , b u t i n none o f these cases was t h e e x a c t age mentioned.

WHO/YF/7

page 2

Now, because of i t s enhanced neurotropism, the p o t e n t i a l hazards attendant . upon the use of French n e u r o t r i p i c v i r u s vaccine f o r , i n p a r t i c u l a r , the immunization of c h i l d r e n have been stressed by, among others, THEILER and WHITMAN (1955).

Bearing t h i s i n mind, the WHO Expert Committee on Quarantine took the view i n 19kj that f o r the safe immunization of very young children only iTD virus vaccine should be employed.

In t h i s connexion, although a number of cases of encephalitis following the use of 17D vaccine i n B r a z i l has been reported by FOX, LENNETTE et a l . (1942) as having occurred among adults and children i n 19^+1, the vaccine then employed had been prepared from a substrain of the v i r u s which, during a very small number of

subcultures away from the main stem, proved to have undergone a sudden a l t e r a t i o n i n character and acquired encephalitogenic properties. To preclude the p o s s i b i l i t y of recurrence of such serious nervous reactions, the technique of I7D vaccine

preparation was, i n 19^1, altered so that the vaccines used were i n i t i a t e d from primary and secondary seed l o t s of known character. The standardization of I7D vaccine preparation, following the adoption of t h i s "seed l o t system", achieved the desired r e s u l t : since 19^+2 no case of encephalitis following the a d m i n i s t r a t i o n of I7D has been recorded i n the l i t e r a t u r e .

In a personal communication dated 22 June I955, however. Dr. P. lEPIKE of the Pasteur I n s t i t u t e , P a r i s , expresses himself as being unable to agree that the use of I7D vaccine i s never concerned i n the production of meningo-encephalitic

reactions, and c i t e s , i n support of h i s contention, the following instances which have come under h i s own observation w i t h i n the past two years:

- 1 case among 8OO children of from 6 months to one year of agej and - k cases among 1,000 c h i l d r e n of from b i r t h to 6 months o l d .

A l l 5 cases recovered completely.

Among 40,000 adults vaccinated during the same period, no case of meningo- e n c e p h a l i t i s occurred.

In t h i s connexion i t i s stated that a l l these children and adults had been

immunized with the same vaccine - a vaccine prepared from a I7D (Rockefeller)

s t r a i n and r i g o r o u s l y t i t r a t e d p r i o r to use.

WHO/YF/7 page 3

The main p a r t i c u l a r s of the 5 cases c i t e d are shown i n the subjoined Table.

Summary of observations on 5 encephalo-myelitic r e a c t i o n s f o l l o w i n g v a c c i n a t i o n v i t h '^'f^.'^^o'^Jpp[y^§b'}f-^^3) on the

Pasteur Institute_^ P a r i s

1

Case Age ' Sex

I

C l i n i c a l L .

p i c t u r e j u r a t i o n

R e s u l t o f sero- , p r o t e c t i o n t e s t

1. 7 months F. 19 days •

— — 1 Convulsive i s e i z i i r e s ; then j hemiplegia.

Cerebro-spinal f l u i d : 12 c e l l s per 1 cram

48 hours

2. iy2 mnths. M. 11 days Repeated con- v u l s i v e seizures (6 per day) - l e f t - s i d e d

48 hours not t e s t e d

3. ^{1 month M. 12 days} Repeated con-

v u l s i v e seizures

48 hoiurs Negative :

= l e s s than

4.

temperature 38- 59°C; vomiting;

i=LS, f l u i d : 120 c e l l s per 1 cmm Treated w i t h streptomycin;

spectacular imp- rovement ,

5 days

!

not t e s t e d

5.

f k months y .

j

10 days

i

H o s p i t a l i z e d f o r high temperat\ire (40OC). Lumbar puncture on 15th day ( s l i g h t tens- i o n over the font- j a n e l l e ) . C.S.F.:

150 c e l l s per 1 or Return to normal a

16th day, without t h e r a p e u t i c t r e a t - ment.

1

\

1 5 days i 1

. 1 1

m

m

• i l •M.IM

blood taken:

not completed

WHO/YF/7 page h

In Dr. Lépine's view a d i s t i n c t i o n must be drawn between case No.l and the other h cases. Case No.l was a c h i l d of the black race, was over 6 months' o l d and developed a s a t i s f a c t o r y immunity response to the v a c c i n a t i o n ; i n t h i s case the p e r i o d between v a c c i n a t i o n and onset of e n c e p h a l i t i c signs was 19 days.

In c o n t r a s t w i t h the experience of Dr. Lépine, that of STEFANOPOULO and DUVOLON (1947) may be c i t e d . The last-named authors, i n a review of t h e i r 10 years experience with yellow-fever immunization at the Pasteur I n s t i t u t e , P a r i s (1956-|4'6), drew a t t e n t i o n to the l a c k of harmful r e a c t i o n s f o l l o w i n g the use of I 7 D . Thej observed no nervous r e a c t i o n s i n 2 , ^ 7 0 c h i l d r e n of from 15 days t o 10 years' o l d and compared t h i s with the o c c a s i o n a l l y severe nervous r e a c t i o n s which had followed the use of French neurotropic v i r u s vaccine i n young c h i l d r e n .

2. Is the immunity response to v a c c l n a t i o n i n c n i l d r e n under one year o f a ^ s u f f i c i e n t t o ensure- t h e i r p r o t e c t i o n against yellow f e v e r and to J u s t i f y t h e i r h e l n g _ i s s u e ^ with'an i n t e r n a t l o n a T ce^^ of v a c c i n a t i o n a g a i n s t

yellow f e v e r l / h i c h has a v a l i d f x y of 6 ^ears? ~ "

The p o s s i b i l i t y t h a t the response of an i n f a n t under one year of age t o a yellow-fever v a c c i n a t i o n may be n e g l i g i b l e has from time to time been suggested but a review of the l i t e r a t u r e f a i l s to uncover data to confirm or r e f u t e t h i s

suggestion.

I t i s t r u e t h a t , f o l l o w i n g a mass v a c c i n a t i o n v i t h I7D v i r u s of the t o t a l population (114-5,000) of the Toro D i s t r i c t i n Western Uganda i n 1 9 ^ 1 , when

i n d l v i d \ i a l s of a l l ages from babies at the breast to the e l d e r l y were v a c c i n a t e d , SMITHBURN and MAHAFFY (19^5) reported t c the e f f e c t t h a t " a f t e r the mass i n o c u - l a t i o n s the incidence of immunity was of q u i t e even d i s t r i b u t i o n ... and t h a t the r a t e i n c h i l d r e n was as high as that m ad.i2.ts. F u r t h e ^ o r e , 5 years a f t e r completion of the v a c c i n a t i o n programme, the c h i l d r e n r e t a i n e d t h e i r immunity as w e l l as the a d u l t s " . These authors a l s o concluded that "the v a l i d i t y of the v a c c i n a t i o n c e r t i f i c a t e may s a f e l y be extended beyond 5 years, without r e f e r e n c e t o the age o f the v a c c i n a t e d person". I t i s a l s o true that p o s t - v a c c i n a t i o n surveys made by DICK and SyiTHBURl^ (19^9) i n 19^6 and 19^7 on the i n h a b i t a n t s o f c e r t a i n l o c a l i t i e s w i t h i n the above-iccaL.; ore voocir-^LJon area - l o c a l i t i e s a t

WHO/ÏF/7 page 5

about an a l t i t u d e o f 5,000 f e e t and where no yellow fever had occurred - toxinà among 53 c h i l d r e n of the 5 or 6-9 years' age-group, who had been vaccinated 5 o r 6 years p r e v i o u s l y , 28 immunes (84.8^) and, on more d e t a i l e d a n a l y s i s o f these f i g u r e s f o r the age-group i n question, that 16 out o f 21 t e s t e d were immune 5 years a f t e r v a c c i n a t i o n (76.2^^) and 12 out o f 12 t e s t e d (lOO^t) 6 years a f t e r

v a c c i n a t i o n . From the r e s u l t s o f t h e i r surveys these authors concluded t h a t "there i s no s i g n i f i c a n t d i f f e r e n c e e i t h e r i n the percentage developing immiinity or i n the d u r a t i o n of the immune response when c h i l d r e n are compared with a d u l t s " .

Again, the studies o f AUDERSON and GAST GALVIS (19^7) i n Colombo show no s i g n i f i c a n t d i f f e r e n c e i n the immune response o f c h i l d r e n and a d u l t s . R e s u l t s o f n e u t r a l i z a t i o n t e s t s i n sera obtained from r e s i d e n t s o f h Colombian towns 5

years a f t e r v a c c i n a t i o n with 17D showed 579 out o f 625 vaccinated t o have p r o t e c t i v e antibody (95^). Because of the view expressed by FOX and CABRAL (19^3) t h a t

young c h i l d r e n give a poorer response t o v a c c i n a t i o n than do adiiLts, sera of the age-group 6-9 years r e c e i v e d p a r t i c u l a r a t t e n t i o n ; i n that group 59 of the 65 vaccinated and t e s t e d contained n e u t r a l i z i n g antibody (91^). 20 o f these 65

sera were taken from c h i l d r e n under 3 years of age a t the time of t h e i r v a c c i n a t i o n ; o f these, I6 (80^) contained a n t i b o d i e s . Of the sera from c h i l d r e n who were from 3-4 years' o l d a t the time o f v a c c i n a t i o n , 43 (96^) contained a n t i b o d i e s . ' These authors conclude, however, t h a t , " i n view o f the small groups compared, the d i f f e r e n c e i s not s t a t i s t i c a l l y s i g n i f i c a n t and that the response o f c h i l d r e n under 3 years o f age does not m a t e r i a l l y d i f f e r from t h a t o f older c h i l d r e n or a d u l t s " .

In connexion w i t h the question under c o n s i d e r a t i o n , however, i t w i l l be

noted t h a t i n none o f the three a r t i c l e s mentioned above i s any s p e c i f i c information provided on the immunity response to v a c c i n a t i o n o f the 0-1 year age-group or t o the d u r a t i o n o f such immunity as may have been conferred. Moreover t h i s comment a p p l i e s a l s o t o the r e s u l t s o f ITD v a c c i n a t i o n published by FOX and CABRAL (1945);

from t h e i r studies i n Southern B r a z i l , these authors found t h a t i n the case o f populations l a r g e l y or e n t i r e l y composed o f young c h i l d r e n the e a r l y response t o v a c c i n a t i o n was much le^^s s a t i s f a c t o r y than i n populations comprising mainly adults and a more r a p i d d e c l i n e i n the immittie l e v e l was apparent. The age-groups on which such observations vere made, however, were: 5-9, 10-l4, 15-19, 20-29, and

WHO/YF/7

page 6

50+ years. I n respect of vaccinations c a r r i e d out on i n d i v i d u a l s of these age- groups, FOX, KOSSOBUDSKI and FONSECA DA CUNHA (19^5) stated that evidence was adduced that the immune response to I7D v i r u s i n i n d i v i d u a l s up to ik years

i s d i r e c t l y r e l a t e d t o age, the average protective capacity of the sera i n c r e a s i n g with the age o f the donors. Later, FOX, FONSECA DA CUNHA and KOSSOBUDSKI (1948), reviewing the r e s u l t s and extending the investigations recorded i n the two p r e v i o u s papers, found that the differences between the r e s u l t s with sera of c h i l d r e n i n the 5-l4 years' age-group and those of adults i n the I5 years and over age-group were not s t a t i s t i c a l l y s i g n i f i c a n t .

As previously stated, therefore, i t i s quite possible that the response o f a very young i n f a n t t o a yellow-fever vaccination might be n e g l i g i b l e , but no data are to be found i n the a v a i l a b l e l i t e r a t u r e which could confirm or r e f u t e t h e hypothesis. The answer to the question could be provided only by the r e s u l t s o f a c a r e f u l l y planned experiment of adequate s i z e .

While t h i s experiment i s being c a r r i e d out, (unless i n addition t o the one n o v provided by Dr. Lépine - a sero-protection t e s t on an i n f a n t one month o l d showing a negative resxilt - convincing figures i n support of the hypothesis are i n the meantime produced), some i n t e r i m arrangements may be considered t o be e s s e n t i a l . I f so, then the operative considerations would seem to be:

(1) i t i s not possible t o exclude from vaccination a l l infants under one year o l d ;

(2) \inprotected i n f a n t s are, so f a r as i t can be learned, l i a b l e t o

contract and carry yellow fever i n the same way as adults? ' ; (5) i n o c u l a t i o n of i n f a n t s under one year old probably confers

l i m i t e d p r o t e c t i o n ; and

(4) i n o c u l a t i o n of i n f a n t s

one year old probably confers protection which w i l l l a s t the accepted s i x years.

In the circumstances i t has been suggested that the only s o l u t i o n t o the p r o b l e m - admittedly not a very s a t i s f a c t o r y one - i s t o have a s p e c i a l c e r t i f i c a t e f o r

the under-ones, v a l i d f o r one year, and t o require these i n f a n t s to be revaccinâtes

at the end of that time, when they can be given a normal s i x years' c e r t i f i c a t e .

WHO/YF/7 page 7

The only J u s t i f i c a t i o n f o r postponing v a c c i n a t i o n u n t i l the c h i l d i s over one year o l d , and a l l o w i n g those under t h a t age to t r a v e l unprotected, would be the production of i r r e f u t a b l e evidence that Infants under one cannot c o n t r a c t yellow f e v e r .

"So f a r as i s known, however, man i s n a t u r a l l y more or l e s s \uiiformly s u s c e p t i b l e to i n f e c t i o n with yellow-fever v i r u s , with the p o s s i b l e exception of i n f a n t s bom of immune mothers? such i n f a n t s may be immune f o r the f i r s t few months of t h e i r l i v e s . "

(TAYLOR,

1951).

" (SOPER,

1958).

1951).

T h i s transmission of a t r a n s i t o r y immunity from the immione mother t o her

o f f s p r i n g n a t u r a l l y r a i s e s the question of whether or not very young i n f a n t s belonging to t h i s category r e q u i r e v a c c i n a t i o n . I f the mother i s immune, her o f f s p r i n g

v i l l probably have s u f f i c i e n t immunity to r e s u l t i n p r o t e c t i o n f o r some weeks or a few months. /The longest demonstrated p e r s i s t e n c e of the i n h e r i t e d immunity has been 6 months i n c h i l d r e n _ J "However, the time of disappearance o f the a n t i - body i s v a r i a b l e and i t s presence can be determined only by t e s t . I f the c h i l d

i s l i v i n g i n an endemic area, the a d m i n i s t r a t i o n of the vaccine should not be delayed more than about 2 months, or perhaps not at a l l during epidemics. The presence o f the antibody i n the i n f a n t ' s blood would render the vaccine i n e f f e c t u a l ; y e t t o withhold the vaccine might be hazardous i n the event t h a t the antibody had disappeared." (SMITHBURN, 1951).

WHO/YF/7 page 8

REFERENCES

ANDERSON, C.R. 8e GAST GALVIS, A. (1947). Immunity to yellow fever f i v e years a f t e r v a c c i n a t i o n . Am. J .

Hyg-45:

DICK, G.W.A., and SMITHBURN, K.C. (1949). Immunity t o yellow f e v e r s i x y e a r s a f t e r v a c c i n a t i o n . Am. J . Trop. Med. 29: 57-61

FOX, J.P., and CABRAL, A.S. (1945). Duration o f immunity f o l l o w i n g v a c c i n a t i o n w i t h I7D s t r a i n o f yellow f e v e r v i r u s . Am. J . Hyg. ^J: 95-120.

, FONSECA DA CUNHA, J., and KOSSOBUDSKI, S.L. (1948). A d d i t i o n a l observations on duration of humoral immianity f o l l o w i n g v a c c i n a t i o n with I7D s t r a i n o f yellow-fever v i r u s . Am.J. Hyg. 47: 64-70

, KOSSOBUDSKI, S.L., and FONSECA DA CUNHA, J . (1945). Immune response t o I7D yellow-fever v i r u s . Am. J . Hyg. 5^: 115-158.

, LENNEITE, E.H., MANSO, C , and SOUZA AGUIAR, J.R. (1942). E n c e p h a l i t i s i n man f o l l o w i n g v a c c i n a t i o n with 17D yellow f e v e r v i r u s . Am. J . Hyg. 36:

117-142. — KERR, J . AUSTIN. ( I 9 5 l ) . "The C l i n i c a l aspects and diagnosis of yellow f e v e r " .

Text book on yellow f e v e r . Chap. 7, p. 5-90. McGRAW-HILL BOOK Co. I n c . LEPINE, P. (1953). Personal communication.

SMITHBURN, K.C. (1951). "Immunology". Text book on yellow f e v e r . Chap. 4, p. 205. McGRAW-HILL BOOK Co. I n c .

, and MAHAFFY, A.F. (1945). Immunization against yellow f e v e r j studies on time o f development and duration o f induced immimity. Am. J . T r o p

Med. 25: 217-225.

SOPER, F.L. (1958). Yellow Fever. The present s i t u a t i o n , (October 1958), ^{w i t h} s p e c i a l reference t o South America. Trans. Roy. Soc. Trop. Med, & Hyg. 52»

297-352. ^ — STEFANOPOULO, G.J, and DUVOLON, S. (1947). Reactions observées au cours de l a

v a c c i n a t i o n contre l a fièvre Jaune par v i r u s atténué de c u l t u r e (souche I7D).

A propos de 20,000 v a c c i n a t i o n s pratiquées par ce procédé à l ' I n s t i t u t P a s t e u r de P a r i s (1936-46). B u l l , e t Mém. Soc, Méd. Hopit. de P a r i s . 32/35: 990-1000.

TAYLOR, R.M, (1951). "Epidemiology". Textbook on yellow f e v e r . Chap. 8, p . 447 McGRAW-HILL BOOK Co. I n c .

THEILER, M. and WHITMAN, L. (1955). l e danger de l a v a c c i n a t i o n par l e v i r u s a m a r i l neurotrope s e u l . B u l l . O f f i c e i n t e r n a t . d'Hyg. pub. 2^: 1542-1547.