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WORLD H L A L T H ORGANIZATION OK(;ANISATIQN MONDIALE DE L A SANTE
VIR/YF/83.1 ENGLISH ONLY
GUIDE FOR THE CONTROL OF EMERGENCIES CAUSED BY YELLOW FEVER I N AFRICA Dakar, 30 May t o 3 June 1983 D r a f t Agenda Item 9
INDEXED
WHO COLLABORATIVE STUDIES by Dr P. Brès, I n s t i t u t P a s t e u r , Paris
I t i s perhaps t h e s u c c e s s f u l development 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 which has slowed 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 decades. As a r e s u l t , there are s e v e r a l important aspects of y e l l o w f e v e r which are s t i l l l i t t l e understood. Research has a l s o made l i t t l e p r o g r e s s because 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 to 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 causes 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 would be a v a i l a b l e cannot be c o m p l e t e l y u t i l i z e d because 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 immediate c o n t r o l a c t i v i t i e s are 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 the 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 the v a c c i n e . 9.1 Virological studies
Recent 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 which 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 to e l u c i d a t e the 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 between s y l v a t i c s t r a i n s and epidemic s t r a i n s . T h i s might be due t o t h e passage h i s t o r y between 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 might be s t u d i e d . 9 .2 Ecological studies
An i m p o r t a n t p r o g r e s s has 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 the b e g i n n i n g o f t h e r a i n y season 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 species. The maintenance 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 be 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 of 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 hedgehog, 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 such 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 of 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 fortunate, but 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 urban 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 nearby f o r e s t have 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 they s t i l l a b l e to t r a n s m i t y e l l o w f e v e r o r a r e they 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 today 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 .
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VI R/YF / 8 3 . 1 page 2 Stud y of the disease The clini ca l aspe c t s o f t he di sease have be en des c ribed wi t h man y r efi nements for three cen t urie s and thi s i s s t i ll continuin g in re ce nt epidemi cs but no progress has b ee n mad e in the s tud y of the ph ys i o-path olog i ca l co ndition . I s th e haemorrhagic diathesis primary or secondary to liver infection? Is the vas cular collapse a nd dea th in hy po thermia similar to the sh ock syndrome of dengue haemo rrhag i c feve r, which a l so show s Co un c ilman b odies in liver sections? Do the parenchymatous lesions prec ede the mese nchymat ous and reticuloendotheli a l pro liferation of the virus or vice-versa? Are the renal l es i ons of an imrnunocomplex nature or c aused 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 suffer from a mild form of the disease. Is there a genetic Did their previous infection with other flavivirus play an explanation in the HLA system? adverse or favourable role? Treatment 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 o r immun og lobulins in Bo livian haemorrhagic fever, in Ebola haemorrhagic fever and In Lassa fe ver, 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 yse d 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 inc rea se the availabilit y of the vacc ine), 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. Collaborative studies The necessary technology for these studies has re cently 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 o f th e immunopathological mechanisms of dengue haemorrhagic fever. Collaborative protocols might be defined with WHO assistance involvin g several gr oups of s cientists in such collabora tive multidisciplinary studies of yellow fever.