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WORLD HEALTH ORGANIZATION ORGANISATION M O N D I A L E D E L A SANTÉ
VIRAF/71/^2 E N G L I S H ONLY
EXPERT CCWMITTEE ON YELLOW FEVER IK
Entebbe, 9-15 March 1971 METHODS OF SURVEILLANCE FOR YELLOW FEVER Conduct of s e r o l o g i c a l surveys i n huinan beings (mode of sampling sera, number r e q u i r e d , multipurpose sera, areas and groups of p r i o r i t y , e t c ) by P. Brès, M.D., V i r u s Diseases The conducting of s e r o l o g i c a l surveys i n human beings i n the p r a c t i c e of permanent s u r v e i l l a n c e of yellow fever i s u s u a l l y done i n b e t t e r c o n d i t i o n s that i n e a r l y r e c o g n i t i o n of suspected cases, with no pressure from events. One may even say that r e l i a b i l i t y of the r e s u l t s w i l l depend on the e f f i c i e n c y o f the o r g a n i z a t i o n o f the survey; sampling of the population and c o l l e c t i o n of the sera. 1. Sampling of the population to detect the c i r c u l a t i o n
The sampling must f i t i n with the two aims of the survey: of the virus £ind to evaluate the population a t r i s k .
Detection of the c i r c u l a t i o n of the v i r u s i s the detection of known or unknown endemic f o c i i n permanent o r t r a n s i e n t a c t i v i t y . This implies a geographical f a c t o r and a p e r i o d i c a l follow-up. The geographical f a c t o r i s dependent on the ecology of the v i r u s , and the choice o f d i f f e r e n t favourable environments w i l l lead t o procedure o f the sampling by the s t r a t i f i c a t i o n technique. Hot and humid e q u a t o r i a l f o r e s t s are favourable t o the permanence of vectors which maintain a continuous c y c l e of transmission of the v i r u s . P e r i o d i c a l l y dry savanna and f l u c t u a n t populations o f vectors w i l l support episodic i n c u r s i o n s o f the v i r u s , mostly during and soon a f t e r the r a i n y season. The most s e n s i t i v e zone i s the f r i n g e o f mosaic f o r e s t . Such studies may be coupled with advantage w i t h animal and entomological surveys. Contacts w i t h the v i r u s are dependent upon the bionomics o f man. Chances o f contact d i f f e r according to age, sex, h a b i t a t , occupation and length of residence. The maximum prevalence w i l l be looked f o r i n o l d e r age groups, but a major i n t e r e s t i s t o define the time of the i n f e c t i o u s contact. In America, endemic yellow fever, o r Jungle yellow f e v e r , occurs among adolescents o r a d u l t workers going i n t o o r c l o s e t o the f o r e s t where the v i r u s i s c i r c u l a t i n g . In A f r i c a , n a t u r a l immunity may appear i n very young c h i l d r e n (Brès, 1965). Non r e s i d e n t s o r immigrants, are o f exceptional i n t e r e s t and they may be considered as s e n t i n e l s f o r the d e t e c t i o n of the v i r u s . Thus, according t o the circumstances, the s e r o l o g i c a l survey i s based e i t h e r on a representative sampling of the whole population or on a purposive sampling. The e v a l u a t i o n of the population a t r i s k considers the negative r e s u l t s «md mainly t h e i r prevalence In d i f f e r e n t age groups. D i f f e r e n t s i t u a t i o n s a t higsh r i s k and low r i s k may be c h a r a c t e r i z e d by the survey. I t has been s a i d that the r i s k of epidemic transmission disappears i n a population when 80 per cent are immune. I n yellow fever such a f i g u r e Is c e r t a i n l y dependent, on the density of the c i r c u l a t i o n of the v i r u s , and on the p o s s i b i l i t i e s of transmission by l o c a l vectors. No p r e c i s e f i g u r e can be given f o r a l l The issue of 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, II ne doit faire l'objet d'aucun compte rendu ou résumé ni d'aucune citation sans l'autorisation de l'Organisation fvlondiale de la Santé. Les opinions exprimées dans les articles signés n'engagent que leurs auteurs.
VIR/YF /71.22 page 2
s i t u a t i o n s , but an epidemic outbreak occurred i n Senegal (Brès I966) where 40 per cent o f the population were not protected by v a c c i n a t i o n . S u r v e i l l a n c e of the epidemic r i s k i s of s p e c i a l i n t e r e s t In h e a v i l y populated areas i n the endemic zone, or close to I t , and t h i s consideration would J u s t i f y a p r i o r i t y i n planning a country-wide programme of surveys. A s e r o l o g i c a l survey a f t e r a mass campaign w i l l appreciate the e f f e c t i v e n e s s of the v a c c i n a t i o n {% of coverage). F a i l u r e s i n v a c c i n a t i o n may be relevant from d i f f e r e n t possible causes - i n s u f f i c i e n t proportion of the population being reached; defective i n o c u l a t i o n or bad q u a l i t y vaccine at the time of i n o c u l a t i o n . The two last causes w i l l appear i n the percentage of p o s i t i v e s among the "vaccinated" group. The prevalence of protected people may be followed up p e r i o d i c a l l y or estimated i n the future by e x t r a p o l a t i o n from the growth rate of the population. Generally, a sample s i z e of around 100 sera w i l l provide a s a t i s f a c t o r y degree of p r e c i s i o n , but t h i s number must be increased should the frequency of p o s i t i v e sera be very low. P r a c t i c a l experience i n d i c a t e s that 25 sera per age group ( 0 - 1 0 ; 1 1 - 2 0 ; 20-40 and above) are frequently convenient. " I t i s the usual experience to f i n d that the percentage of immune persons r i s e s with age i n endemic areas, and the minimum number of t e s t s which would g i v e dependable negative r e s u l t s would therefore need to be l a r g e r i n the case of c h i l d r e n than i n that of a d u l t s " (Sawyer 1 9 5 6 ) . I f the rates are to be compared between two d i f f e r e n t populations, or two d i f f e r e n t i n t e r v a l s , the sampling must be convenient f o r a s t a t i s t i c a l l y significant comparison. L o n g i t u d i n a l surveys imply a good i d e n t i f i c a t i o n of donors s e l e c t e d f o r t h e i r easy c o l l e c t i n g . Schools are a very convenient source of such sera. S e r o l o g i c a l s u r v e i l l a n c e of yellow fever i s accomplished at lower cost and l e s s d i f f i c u l t i e s i n p a r t i c i p a t i n g to a multipurpose s e r o l o g i c a l survey. These surveys u s u a l l y cover a too Important number of sera f o r the s i n g l e purpose of s u r v e i l l a n c e of yellow fever and I t i s necessary to s e l e c t subsamples. In t h i s , one w i l l look f o r a f a i r representation of the d i f f e r e n t s t r a t a i n which the v i r u s could c i r c u l a t e . Multipurpose surveys, w i t h c o l l a b o r a t i o n of WHO Serum Reference Banks w i l l make a v a i l a b l e " p o s t e r i t y samples" f o r r e t r o s p e c t i v e s t u d i e s . 2. C o l l e c t i o n of sera
In multipurpose and i n l o n g i t u d i n a l surveys, blood must be c o l l e c t e d by venepuncture. Children under three years of age need to be punctured i n the femoral v e i n . This procedure i s sometimes badly considered by the population, but more e a s i l y accepted i n epidemics. When the survey i s d i r e c t e d to yellow fever, f i n g e r p r i c k puncture w i l l give 0.25 to 0.50 serum, or sometimes more, which Is convenient f o r several reactions by microtechniques. F i n g e r p r i c k p r a c t i c e i s generally w e l l accepted by the population, even i n young c h i l d r e n . The bleeding i s more important during the warmer hours of the day than e a r l y i n the morning. A s u r v e i l l a n c e survey J u s t i f i e s a minimum f i e l d laboratory equipment to separate sera from c l o t s under good aseptic c o n d i t i o n s . Good conditions must be a v a i l a b l e f o r the t r a n s p o r t a t i o n of sera under r e f r i g e r a t i o n . J. Serological tests
The choice of reactions must f i t a l s o with the two aims of the survey: d e t e c t i o n of the c i r c u l a t i o n of the v i r u s and e v a l u a t i o n of the population at r i s k . Three t e s t s are c u r r e n t l y used: haemagglutination I n h i b i t i o n ( H i ) , complement f i x a t i o n (CF) and n e u t r a l i z a t i o n (N). Other methods may prove of value f o r s u r v e i l l a n c e but they have not yet been assessed.
VIRAF /71 .22 page 3 The h i g h number o f s e r a t o d e a l w i t h would s u g g e s t t h e u s e o f t h e H I t e s t as a s c r e e n i n g method f o r n e g a t i v e r e s u l t s . One must remember t h a t a serum may l o o k H I n e g a t i v e b e f o r e t h e apparition of antibodies or after their disparition. I n t h e f i r s t c a s e , t h e CF c a n be found p o s i t i v e and i n t h e l a s t t h e N a n t i b o d i e s may s t i l l p e r s i s t . S p e c i f i c i t y o f t h e p o s i t i v e r e s p o n s e s w i t h t h e y e l l o w f e v e r e i n t i g e n must be a s c e r t a i n e d a s much a s p o s s i b l e . The i n t r o d u c t i o n In t h e HI t e s t o f o t h e r group B a n t i g e n s l o c a l l y p r e v a l e n t w i l l e v i d e n c e a p r i m a r y t y p e r e s p o n s e , w h i c h i s s p e c i f i c , from a secondary t y p e r e s p o n s e w i t h a broad pattern of antibodies. The CF t e s t i s g e n e r a l l y c o n s i d e r e d o f l e s s v a l u e i n s u c h a s u r v e y , b u t i n c e r t a i n c a s e s i t c a n c o n t r i b u t e t o t h e d i s t i n c t i o n between homotyplc and h e t e r o t y p i c a n t i b o d i e s . The N t e s t i n mice h a s been t h e most w i d e l y u s e d , e s p e c i a l l y i n 1932-1950 i n an a t t e m p t t o l o c a t e the American a n d A f r i c a n endemic zones. T h i s t e s t i s more s p e c i f i c t h a n t h e HI t e s t , b u t i t a l s o l e a v e s many s e c o n d a r y t y p e r e s p o n s e s w i t h a doubt on t h e i r a e t i o l o g y ( T h e i l e r , 1958). A s t i l l more s p e c i f i c t e s t i s needed, a s w e l l a s an e f f o r t i n s t a n d a r d i z a t i o n o f t e c h n i q u e s and i n t e r p r e t a t i o n s . The t r e a t m e n t o f s e r a t o e v i d e n c e Igfl a n t i b o d i e s h a s n o t been s u f f i c i e n t l y assessed i n s e r o l o g i c a l surveys. The u s e o f m i c r o t e c h n i q u e s b r i n g s a g r e a t e r f a c i l i t y when a g r e a t number o f t e s t s a r e t o be d e a l t w i t h a s i n l a r g e s u r v e y s . A u t o m a t i o n w i l l a l s o be an advantage. 4. Recording of information
The I m p o r t a n t number o f s e r o l o g i c a l s u r v e y s p e r f o r m e d i n A f r i c a have been r e v i e w e d by B o n e l e t a l (1954) and Brès (1970). D i s p o s i t i o n s s h o u l d be t a k e n a s soon a s p o s s i b l e t o a d a p t t h e n e x t s e r o l o g i c a l s u r v e y s t o t h e c o m p u t e r i z e d s t o r a g e o f d a t a , as t h i s i s b e i n g done w i t h m u l t i p u r p o s e s u r v e y s . REFERENCES B o m e l , P.H. à Deutschman, Z. (1954) B u l l . Wld H l t h O r g . , 11, 325 Brès, P. & B o i r o n , H. (I963) B u l l . S o c . Méd. A f r . n o i r e Langue franç. 10, 412 Brès, P. (1966) Méd. t r o p , 26, 21 Brès. P. (1970) B u l l . Wld H l t h O r g . , 43, 223 Sawyer, W.A. e t a l (1936) T r a n s Roy S o c . T r o p . Med. Hyg., 2^. T h e i l e r . M. à C a s a i s , J . 397
(1958) Amer. J . t r o p . Med. Hyg.. 7, 585