S tud y of the disease

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O K ( ; A N I S A T I Q N M O N D I A L E D E L A S A N T E

GUIDE FOR THE CONTROL OF EMERGENCIES CAUSED BY YELLOW FEVER I N AFRICA

V I R / Y F / 8 3 . 1 ENGLISH ONLY

INDEXED

D a k a r , 30 May t o 3 June 1983 D r a f t Agenda Item 9

WHO COLLABORATIVE STUDIES by

Dr P. Brès, I n s t i t u t P a s t e u r , P a r i s

I t i s p e r h a p s t h e s u c c e s s f u l d e v e l o p m e n t o f a s a f e and v e r y e f f i c i e n t v a c c i n e w h i c h has s l o w e d down f u r t h e r r e s e a r c h on y e l l o w f e v e r d u r i n g t h e p a s t t h r e e d e c a d e s . As a r e s u l t , t h e r e a r e s e v e r a l i m p o r t a n t a s p e c t s o f y e l l o w f e v e r w h i c h a r e s t i l l l i t t l e u n d e r s t o o d .

R e s e a r c h has a l s o made l i t t l e p r o g r e s s b e c a u s e t h e d i s e a s e i s m a i n l y o b s e r v e d i n remote r e g i o n s , c l o s e t o i t s s y l v a t i c c y c l e , where l a b o r a t o r y c a p a b i l i t i e s a r e m i s s i n g . Whenever t h e v i r u s c a u s e s an e p i d e m i c t h e most v a l u a b l e m a t e r i a l w h i c h w o u l d b e a v a i l a b l e c a n n o t b e c o m p l e t e l y u t i l i z e d b e c a u s e r e s e a r c h was n o t o r g a n i z e d i n advance and o n l y i m m e d i a t e c o n t r o l a c t i v i t i e s a r e s e t i n m o t i o n d u r i n g t h e o u t b r e a k .

The o b j e c t o f t h i s s e c t i o n i s t o p i n p o i n t some o f t h e i m p o r t a n t q u e r i e s w h i c h c o u l d be s t u d i e d d u r i n g t h e n e x t e p i d e m i c s o r d u r i n g t h e i n t e r - e p i d e m i c p e r i o d . They c o n c e r n t h e v i r u s i t s e l f , i t s e c o l o g y , t h e d i s e a s e , i t s t r e a t m e n t and t h e v a c c i n e .

9.1 V i r o l o g i c a l s t u d i e s

R e c e n t s t u d i e s have p r o v i d e d a b e t t e r i n s i g h t i n t o t h e m o l e c u l a r s t r u c t u r e o f t h e v i r u s and t h e components w h i c h d e t e r m i n e i t s a n t i g e n i c i t y . F u r t h e r s t u d i e s a r e n e c e s s a r y t o e l u c i d a t e t h e d i f f e r e n c e i n v i r u l e n c e w h i c h seems t o e x i s t b e t w e e n s y l v a t i c s t r a i n s and e p i d e m i c s t r a i n s . T h i s m i g h t b e due t o t h e p a s s a g e h i s t o r y b e t w e e n v e r t e b r a t e s and i n v e r t e - b r a t e s a t d i f f e r e n t t e m p e r a t u r e s and a t d i f f e r e n t r a p i d i t y . The a t t a c h m e n t s i t e o f t h e v i r u s

to t h e s u r f a c e o f s e n s i t i v e c e l l s m i g h t be s t u d i e d . 9 . 2 E c o l o g i c a l s t u d i e s

An i m p o r t a n t p r o g r e s s h a s r e c e n t l y shown how t h e c i r c u l a t i o n o f t h e v i r u s i s enhanced a t t h e b e g i n n i n g o f t h e r a i n y s e a s o n and t h e d i f f e r e n t r o l e p l a y e d by s e v e r a l s y l v a t i c m o s q u i t o s p e c i e s . The m a i n t e n a n c e o f t h e v i r u s d u r i n g t h e d r y s e a s o n seems t o b e e x p l a i n e d by t h e t r a n s o v a r i a l t r a n s m i s s i o n i n m o s q u i t o o r by l o n g - t e r m i n f e c t i o n o f o t h e r a n i m a l s such as t i c k s and p o s s i b l y some s t i l l u n c o v e r e d v e r t e b r a t e s such as t h e h e d g e h o g , whose p o s s i b l e r o l e has been f o r g o t t e n . The a v a i l a b i l i t y o f more s e n s i t i v e methods f o r i s o l a t i o n o f t h e v i r u s i n c e l l c u l t u r e o r i n m o s q u i t o s s h o u l d be u t i l i z e d f o r s u c h s t u d i e s .

The g e n e t i c c h a r a c t e r i z a t i o n o f m o s q u i t o s has a l s o p r o g r e s s e d . I t i s f o r t u n a t e , b u t n o n e t h e l e s s p u z z l i n g , t h a t t h e u r b a n Aedes a e g y p t i w h i c h p r o l i f e r a t e s a t p r e s e n t i n c i t i e s , and i t s c o u s i n i n t h e n e a r b y f o r e s t h a v e s t a y e d i n d i f f e r e n t t o t h e e p i z o o t i c waves o f s y l v a t i c y e l l o w f e v e r i n West and C e n t r a l A f r i c a . A r e t h e y s t i l l a b l e t o t r a n s m i t y e l l o w f e v e r o r a r e t h e y g e n e t i c a l l y i m p o t e n t , o r does t h e t o d a y new v i r u s n o t l i k e them? The d i f f e r e n c e i n a b i l i t y f o r t r a n s m i s s i o n o f y e l l o w f e v e r o f Aedes a e g y p t i and Aedes s i m p s o n i i n West and E a s t A f r i c a d e s e r v e s f u r t h e r s t u d y .

The issue ot this document does not constitute formal publication. It should not be reviewed, abstracted or quoted without the agreement of the World Health Organization. Authors alone are responsible for views expressed in signed articles.

Ce document ne constitue pas une publication.

Il ne doit faire l'objet d'aucun compte rendu ou résumé ni d'aucune citation sans l'autorisation de l'Organisation mondiale de la Santé. Les opinions exprimées dans les articles signés n'engagent que leurs auteurs.

VI R/YF / 83 . 1 page 2

S tud y of the disease

The clini ca l aspe c t s of t he di sease have be

n des

ribed wi t h many r efi nements for three cen t uries and thi s i s s t i ll continuing in re

nt epidemi

no progress has bee n mad e in

the s tud y of the phys i o-path ologi ca l co ndition . I s th e haemorrhagic diathesis primary or seco ndar y to liver infection? Is the vas c ular collapse and dea th in hypo thermia similar to the sh ock syndrome of dengue haemo rrhag i c feve r, which a l so show

Co un cilman b odies in liver sections? D o the parenchymatous lesions prec ede the mesenchymat ous and reticuloendothelia l pro liferation of the virus or vice-versa? Are the renal l es i ons of an imrnunocomplex nature or caused by autoimrnunity? A battery of tests mi ght be devised in advance to throw some light on these points when an outbreak provides during a few day s the material for such studies.

Fortunately, most patients explanation in the HLA system?

adverse or favourable role?

Treatment

suffer from a mild form of the disease. Is there a genetic Did their previous infection with other flavivirus play an

At present, the therapy is mainly sy mptomati c and dire c t ed t o liver function, clotting factors and renal clearance. Chemical antivirals are appearin g , interferon becomes more easily available and protocols for trial of such drugs should be elaborated in advance.

A beneficial effect has been attributed to immune pl asma or immunog lobulins in B olivian haemorrhagic fever, in Ebola haemorrhagic fever and In Lassa fever, when admini s tered early in

the disease

Would it be so with yellow fever?

Vaccine improvement

A WHO-PAHO meeting held in IJashington in 1981 anal ysed the present bott le-n ecks in th e production of the traditional vaccine and proposed i ts modernization by adaptation of the modern t echnology for cell culture vaccines

The progress should bear on enhancing the yield

(which will decrease the price and in c rea se the availabilit y of the vaccine), improving the thermostability, dec rea si ng the ri s k of si de-ef fects and permitting the administration by scarification.

The application of geneti c engineering methods would also cons iderably improve th e yield of an immunizin g specifi c pro tein, but a killed vaccine might r equire several doses, which might or might not be a disadvanta ge in comparison with an improved live vaccin e.

C ollaborative studies

The necessary technology for these studies has recently made great progress and a full use of it implies a multidisciplinary coordinated research. Such a col laborative re search under the aegis of WHO proved s uccessful for the study of th e immunopathological mechanisms of dengue haemorrhagic fever. Collaborative protocols might be defined with WHO assistance

involvin g several groups of s cientists in such collabora tive multidisciplinary studies of

yellow fever.