WORLD H E A L T H ORGANISATION
ORGANIZATION M O N D I A L E D E L A SANTÉ
VIR/RC/74.13
(Arbo)
ENGLISH ONLY
MEETING OF DIRECTORS OF WHO REFERENCE CENTRES FOR ARBOVIRUSES, CHLAMYDIAE AND RICKETTSIAE Geneva, 1-5 A p r i l 1974
YELLOW FEVER INFECTION IN EAST AFRICA by Dr p. M. T u k e i , D i r e c t o r , E a s t A f r i c a n V i r u s R e s e a r c h E a s t A f r i c a n Community, Entebbe, Uganda Institute
W h i l e t h e o b j e c t o f t h i s w o r k i n g paper i s t o t r y and b r i n g out t h e p r e s e n t s i t u a t i o n r e g a r d i n g y e l l o w f e v e r i n f e c t i o n i n E a s t A f r i c a , i t i s i n e v i t a b l e t h a t we have t o l i n k t h e p r e s e n t s e t up i n t i m a t e l y w i t h i n v e s t i g a t i o n s t h a t have t a k e n p l a c e b e f o r e . We r e c a l l t h a t i n v e s t i g a t i o n s on y e l l o w f e v e r i n f e c t i o n i n a r e a s such as South A m e r i c a , C a r i b b e a n I s l a n d s , C e n t r a l A m e r i c a and t r o p i c a l West A f r i c a were prompted and encouraged by the s e r i o u s e p i d e m i c s t h a t used t o a f f e c t many o f t h e a r e a s i n t h e s e c o u n t r i e s between t h e s e v e n t e e n t h and t h e b e g i n n i n g o f t h e p r e s e n t century,-^ Work i n E a s t A f r i c a , however, was i n i t i a t e d as a r e s u l t o f t h e I n t e r n a t i o n a l H e a l t h D i v i s i o n o f t h e R o c k e f e l l e r F o u n d a t i o n t r y i n g t o i n v e s t i g a t e t h e g e o g r a p h i c a l d i s t r i b u t i o n o f y e l l o w f e v e r immunity i n man. No o u t b r e a k o r i s o l a t e d c a s e s o f y e l l o w f e v e r had been r e p o r t e d from C e n t r a l A f r i c a and t h e p r i n c i p a l o b j e c t i v e s o f t h e s u r v e y were t o d e f i n e t h e a r e a s o f t h e w o r l d i n w h i c h y e l l o w f e v e r had r e c e n t l y been p r e s e n t and might s t i l l e x i s t , and t h u s t o c o n t r i b u t e t o t h e knowledge o f i t s epidemiology.^ The f i n d i n g s o f t h i s y e l l o w f e v e r s u r v e y i n C e n t r a l A f r i c a ( i n c l u d i n g East A f r i c a ) c a r r i e d out by Sawyer and Whitman have been r e v i e w e d on s e v e r a l o c c a s i o n s and need n o t be r e p e a t e d here. I t i s , however, i m p o r t a n t t o remember t h a t t h e s u r v e y r e v e a l e d a wide d i s t r i b u t i o n o f immunity i n t h i s a r e a w i t h t h e w e s t e r n and n o r t h - w e s t e r n p a r t s o f Uganda f a l l i n g w i t h i n t h e y e l l o w f e v e r - i n f e c t e d a r e a w h i l e Kenya and T a n z a n i a were o u t s i d e the i n f e c t e d area. I t was t h e almost complete absence o f r e p o r t e d c a s e s o f y e l l o w f e v e r d i s e a s e i n E a s t A f r i c a , d e s p i t e an e q u i v o c a l e v i d e n c e o f i n f e c t i o n i n p a r t s o f Uganda, t h a t prompted t h e o p e n i n g o f t h e V i r u s R e s e a r c h I n s t i t u t e a t Entebbe, i n t h e hope t h a t answers might be p r o v i d e d t o some o f t h e q u e s t i o n s r a i s e d by t h e r e s u l t s o f t h e immunity s u r v e y . It i s g r a t i f y i n g t o note that current i n f o r m a t i o n , together w i t h r e s u l t s obtained over t h e past 38 y e a r s s i n c e work on y e l l o w f e v e r was s t a r t e d i n E a s t A f r i c a , has gone a l o n g way towards e x p l a i n i n g why t h e y e l l o w f e v e r s i t u a t i o n i n E a s t A f r i c a i s t h e way i t i s ; i . e . t h e r e i s evidence o f y e l l o w fever i n f e c t i o n i n p a r t s of East A f r i c a w i t h evidence of endemicity i n some p a r t s , an abundance o f known y e l l o w f e v e r v i r u s v e c t o r s , and r e s e r v o i r s a r e p r e s e n t i n many p a r t s , y e t very few human y e l l o w f e v e r c a s e s have been r e c o r d e d and no y e l l o w f e v e r e p i d e m i c has e v e r been w i t n e s s e d i n E a s t A f r i c a . The p r e s e n t communication t r i e s t o b r i n g t o g e t h e r to explain t h i s s i t u a t i o n . t h e arguments w h i c h a r e b e i n g projected
Vectors: R i g h t from t h e b e g i n n i n g o f y e l l o w f e v e r s t u d i e s i n E a s t A f r i c a t h e v e c t o r s i n c r i m i n a t e d f o r t r a n s m i t t i n g y e l l o w f e v e r v i r u s were Aedes ( S t e g o m y i a ) a f r i c a n u s . Aedes ( S ) s i m p s o n i , and Aedes ( S ) a e g y p t i . Y e l l o w f e v e r v i r u s was i s o l a t e d from one l o t o f s a n d f l i e s 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. Il ne doit faire l'objet d'aucun compte rendu ou résumé ni d'aucune citation sans l'autorisation de l'Organisation fi^ondiale de la Santé. Les opinions exprimées dans les articles signés n'engagent que leurs auteurs.
VIR/RC/74.13 p.age 2
(Arbo)
3 (Phlebotomus) i n 1948, could in a l s o act as a v e c t o r (personal found yellow during fever In 1949 Garnham e t a l . suggested t h a t Aedes might be (S) d e b o e r i Metselaar the y e l l o w Edwards et al. vector was for fever f o r yellow f e v e r i n East A f r i c a . ^ t h a t Aedes d e n t a t u s Recently,
c o m m u n i c a t i o n ) (1970) s u g g e s t e d frontier district The when 50 coquillettidia
the n o r t h e r n i n 1967. the 1971
of Kenya, where a h i g h y e l l o w of t h e s e
f e v e r immunity i n humans a candidate of y e l l o w lated).^
f u s c o p e n n a t a mosquito r e c e n t l y emerged as mosquitos y i e l d e d a s t r a i n Zika forest No (mentioned yellow
fever transmission yellow isolates
fever v i r u s A l l yellow been isolated
f e v e r e p i z o o t i c i n the i n e i t h e r Kenya or
from v e c t o r s
have been from Uganda. Tanzania.
f e v e r v i r u s has
from v e c t o r s
collected
Most of the m o s q u i t o s mentioned distribution being two i n East Africa. But One as i n f e c t e d by the y e l l o w the
above have a v e r y wide f o r e s t that
and/or
peridomestic opportunity the observed that to of have was infection (1972)^ this appears yellow
would t h e r e f o r e expect f a r back as 1951^ Aedes
i f given
the was and
f e v e r v i r u s these
m o s q u i t o s would e a s i l y
spread
to the human p o p u l a t i o n s . populations, observed
(S) s i m p s o n i Recently,
h u m a n - b i t i n g and
the n o n - h u m a n - b i t i n g .
Mukwaya
t h a t t h e n o n - h u m a n - b i t i n g p o p u l a t i o n was linked. n o n - a n t h r o p o p h i l i c and
also non-primatophi1ic play any part
genetically fever
Over much of i t s range i n Uganda the Aedes s i m p s o n i hence would not
species
almost w h o l l y
as a v e c t o r o f
epidemics. C o m b i n i n g the n o n - a n t h r o p o p h i l i c and non-primatophilic characters, the e n d - r e s u l t f e v e r and much of and to i n many p a r t s o f biting appears the East
to c o n t r i b u t e c o n s i d e r a b l y low in The yellow Africa. Aedes a e g y p t i
to the
almost c o m p l e t e absence of human y e l l o w such as monkeys, o b s e r v e d preference f o r man a very and slight over
f e v e r immunity r a t e s i n p r i m a t e s , shows o n l y population i n the where i t i s e s s e n t i a l l y
i t s range activities more by But The day essentiall occurs t o be
East A f r i c a
exophilic in oviposition, phenomenon have i n r e c e n t canopy and The may the f o r e s t be due
resting years
non-anthropophilic than has floor
been found
widespread on in the
been b e l i e v e d p r e v i o u s l y . forest and at t h e forest edge.
Aedes a f r i c a n u s which i s known t o be f l o o r may a l s o b i t e man africanus. an outbreak. s c a t t e r e d immunity i n humans w h i c h t o b i t e s by A. alone maintain
a monkey-to-monkey v e c t o r forest areas where A. simpsoni
does not vector and has
a t t a c k man system t h a t yet
this
i s such an and that
inefficient
i t cannot
significance Africa
o f Aedes d e b o e r i of P h l e b o t o m i i
Aedes d e n t a t u s
as v e c t o r s o f y e l l o w
fever v i r u s i n East
t o be e l u c i d a t e d . i n the past have r e v e a l e d have not t h a t monkeys o f The r e a s o n s why been c l e a r . different immunity Present be the experimental with greater Zika informatio of yellow 1971, rates
Reservoirs : s p e c i e s are among t h e s e
Surveys c a r r i e d
out
important
r e s e r v o i r s f o r yellow us with two
f e v e r i n Uganda. to area Firstly,
a n i m a l s showed v a r i a t i o n s from a r e a i n other places.
information provides
p o s s i b l e reasons. Secondly,
m o s q u i t o s a r e known t o f e v e r c y c l e and (1970)^ showed Zika) i n t e r f e r e s rates
strongly non-primatophilic that c e r t a i n out was that fever 40% i n 1968
T h i s b r e a k s the y e l l o w Henderson e t a l ,
would-be r e s e r v o i r s remain non-immune. Group B a r b o v i r u s showed a v e r y by low immunity and yellow subsequent y e l l o w than 40% virus reported fever viraemia
( e s p e c i a l l y W e s s e l b r o n and
immunity.
S e r o l o g i c a l s t u d i e s of w i l d mammals c a r r i e d compared w i t h i n d i c a t e d that y e l l o w from f e v e r immunity high
f e v e r immunity r a t e of 3% The 1968 survey,
Haddow e t a l . (1951)^ when i t was than 8 8 % . I t during two
widespread
among Uganda p r i m a t e s .
however, showed a v e r y
immunity g r e a t e r immunity. indicating
i s t h e r e f o r e suggested
the e x p e r i m e n t a l Zika forest
i t i s the extensive
Z i k a immunity t h a t may the y e l l o w
c o n t r i b u t e h e a v i l y t o the r e d u c t i o n f e v e r and none had Zika
In f a c t , that the
f e v e r e p i z o o t i c i n the hardly
during
o f the monkey s e r a t e s t e d were immune t o y e l l o w infections can
antibodies,
further
c o - e x i s t i n the
same e c o s y s t e m .
In 1952 monekys, may surveys with yet negative
Haddow s u g g e s t e d be out
that on
i n Kenya and
the d r i e r fever.^
p a r t s of Uganda, g a l a g o s Since t h a t time (the dry of t h i s Karamoja area
and of
not Uganda) fever not of
t h e main mammalian h o s t s galagos In 1969
of y e l l o w
serological
have been c a r r i e d results.
s e r a from Kenya and
g a l a g o s e r a from Amani, T a n z a n i a one i s forced to q u e s t i o n
were t e s t e d f o r y e l l o w significance
neutralizing
a n t i b o d y and 22%
were found p o s i t i v e . T h e
significance
f i n d i n g has
been f o l l o w e d up.
Nonetheless,
s t r o n g l y the
VIR/RC/74.13
(Arbo
page 3 a i l the y e l l o w f e v e r immune g a l a g o s o b s e r v e d over t h e y e a r s . Nobody has y e t shown how these a n i m a l s a c q u i r e t h e i r immunity; nobody knows what v e c t o r i s r e s p o n s i b l e f o r t h e g a l a g o - t o galago yellow fever v i r u s t r a n s m i s s i o n . It i s , therefore, impossible at present to assert any s u g g e s t i o n t h a t g a l a g o s a c t as a s o u r c e o f human y e l l o w f e v e r i n f e c t i o n . Other animals such as the hedgehog and t h e P o t t o which have been shown t o be s u s c e p t i b l e t o y e l l o w f e v e r a r e n e v e r found i n g r e a t numbers i n E a s t A f r i c a and a r e n o t l i k e l y t o be i m p o r t a n t f o r human infection. Human y e l l o w f e v e r immunity
Y e l l o w f e v e r immune r a t e s i n the human p o p u l a t i o n i n E a s t A f r i c a have c o n t i n u e d t o remain low i n most p a r t s . The o v e r a l l i n c i d e n c e of y e l l o w f e v e r immunity i n 1967 was 1.3% and a l l were a d u l t s w i t h e x c e p t i o n of one c h i l d from Z a i r e who was found i n K i g e z i . Of p a r t i c u l a r i n t e r e s t was the t o t a l absence o f y e l l o w f e v e r immunity i n c h i l d r e n i n Bwamba. • ' • ^ Bwamba has been known over the y e a r s as the pocket o f y e l l o w f e v e r e n d e m i c i t y i n E a s t A f r i c a . I t was t h e r e f o r e i m p e r a t i v e t h a t a s e r o l o g i c a l s u r v e y among t h e monkey p o p u l a t i o n s h o u l d be c a r r i e d out w i t h o u t d e l a y . Out of t h e 22 monkeys c o l l e c t e d i n t h e a r e a , 48% were found t o be immune; an i n d i c a t i o n t h a t t h e i n f e c t i o n was s t i l l v e r y much p r e s e n t among the monkey p o p u l a t i o n . S i n c e a l l c o n d i t i o n s were v e r y f a v o u r a b l e f o r y e l l o w f e v e r v i r u s t r a n s m i s s i o n t o humans, and f e a r i n g t h a t t h e i n f e c t i o n c o u l d e a s i l y s p i l l over i n t o t h e non-immune human p o p u l a t i o n , the Uganda Government was a d v i s e d t o r e p e a t the mass y e l l o w f e v e r v a c c i n a t i o n campaign c a r r i e d out i n a s i m i l a r s i t u a t i o n 33 y e a r s a g c ^ ^ By 1973 over 32 700 p e o p l e i n T o r o D i s t r i c t , i n c l u d i n g the Bwamba a r e a , had been v a c c i n a t e d . In 1972 t h e y e l l o w f e v e r e p i z o o t i c at Z i k a f o r e s t (mentioned l a t e r ) p r o v i d e d an o p p o r t u n i t y t o c o l l e c t as many as 2200 human s e r a from a l l age-groups i n and around E n t e b b e . When t h e s e s e r a were t e s t e d f o r y e l l o w f e v e r n e u t r a l i z i n g a n t i b o d i e s o n l y s i x were p o s i t i v e d e s p i t e the h i g h v i r u s a c t i v i t y t h a t was g o i n g on i n t h e f o r e s t . Even b e f o r e the s e r o l o g y r e s u l t s were a v a i l a b l e , t h e Government was a g a i n a d v i s e d t o p r o t e c t t h e human p o p u l a t i o n around t h e Z i k a f o r e s t and n e i g h b o u r i n g a r e a s a g a i n s t any p o s s i b i l i t y of t h e e p i z o o t i c s p i l l i n g over. Over 10 000 p e o p l e were v a c c i n a t e d a g a i n s t y e l l o w f e v e r i n a p e r i o d of two weeks. The v e r y s e r i o u s e p i d e m i c o f y e l l o w f e v e r t h a t a f f e c t e d E t h i o p i a (1960-1962) prompted y e l l o w f e v e r immunity s u r v e y s i n N o r t h e r n Kenya and i n Karamoja ( n o r t h e r n p a r t of Uganda), two a r e a s which b o r d e r the p a r t of E t h i o p i a a f f e c t e d d u r i n g 1966-1967. No y e l l o w f e v e r immune s e r a were d e t e c t e d among t h e 245 s e r a from Karamoja sampled d u r i n g t h e s u r v e y . Of g r e a t i n t e r e s t however was t h a t y e l l o w f e v e r immune s e r a were found i n t h e n o r t h e r n f r o n t i e r d i s t r i c t o f Kenya w i t h the h i g h e s t r a t e s (14.8%) e v e r r e c o r d e d i n Kenya. Some of t h e s e immune s e r a were from c h i l d r e n , i n d i c a t i n g t h a t y e l l o w f e v e r i n f e c t i o n had o c c u r r e d r e c e n t l y , s i n c e no v a c c i n a t i o n had e v e r been c a r r i e d out t h e r e , • ' • ^ These r e s u l t s have n o t y e t been interpreted. One h y p o t h e s i s i s t h a t the immunity must have come i n t o t h i s r e g i o n o f Kenya as an e x t e n s i o n of the E t h i o p i a n y e l l o w f e v e r e p i d e m i c . A second h y p o t h e s i s i s t h a t some o f t h o s e found t o be immune were i n f e c t e d i n E t h i o p i a b e f o r e moving i n t o Kenya, s i n c e t h e r e i s a f r e e t r a f f i c between the two c o u n t r i e s . Yet a n o t h e r p o s s i b i l i t y i s t h a t most of the y e l l o w f e v e r immunity was a c q u i r e d i n Kenya i t s e l f . To t r y and e l u c i d a t e the e p i d e m i o l o g y of t h i s h i g h y e l l o w f e v e r immunity l e v e l i n the n o r t h e r n f r o n t i e r d i s t r i c t o f Kenya, i n t e n s i v e e n t o m o l o g i c a l and s e r o l o g i c a l s u r v e y s were conducted i n t h e a r e a . None of the u s u a l l y known y e l l o w f e v e r v e c t o r s has e v e r been found i n t h e s e a r e a s and no y e l l o w f e v e r v i r u s has been i s o l a t e d from m o s q u i t o s so f a r c o l l e c t e d . The y e l l o w f e v e r e p i d e m i o l o g y , t h e r e f o r e , s t i l l remains o b s c u r e .
VIR/RC/74,13
(Arbo)
p.age 4 Hurnan i n f e c t i o n ; S i n c e t h e s t u d y of y e l l o w f e v e r was s t a r t e d i n E a s t A f r i c a t h e r e have been o n l y f i v e human c a s e s of y e l l o w f e v e r d i s e a s e documented. Y e l l o w f e v e r v i r u s was i s o l a t e d from o n l y two of t h e s e c a s e s . The o t h e r c a s e s were j u s t c i r c u m s t a n t i a l . The y e l l o w f e v e r e p i z o o t i c i n Z i k a f o r e s t , Uganda
The f i r s t e v i d e n c e o f y e l l o w f e v e r v i r u s a c t i v i t y i n t h i s f o r e s t was i n 1 9 4 6 when two monkeys shot i n t h e f o r e s t ( b o t h C e r c o p i t h e c u s n i c t i t u s mpange) were found t o be immune t o yellow fever. A y e a r l a t e r ( 1 9 4 7 ) one s e n t i n e l r h e s u s monkey became y e l l o w f e v e r immune a f t e r a s u b c l i n i c a l i n f e c t i o n . O n b o t h o c c a s i o n s i n t e n s i v e m o s q u i t o c a t c h e s were c a r r i e d out but no v i r u s was i s o l a t e d . These two o b s e r v a t i o n s o b v i o u s l y s i g n i f i e d t h a t y e l l o w f e v e r v i r u s was a c t i v e i n t h e Z i k a f o r e s t and was b e i n g t r a n s m i t t e d t o monkeys. S i n c e 1 9 6 0 r o u t i n e s u n s e t m o s q u i t o c a t c h e s have been c o n d u c t e d i n the Z i k a f o r e s t . I t was d u r i n g one of t h e s e w e e k l y r o u t i n e s u n s e t m o s q u i t o c a t c h e s t h a t on 1 3 March 1 9 7 2 Aedes a f r i c a n u s m o s q u i t o s (MP 1 1 8 4 0 ) were o b t a i n e d w h i c h y i e l d e d the f i r s t ever y e l l o w f e v e r v i r u s from Z i k a f o r e s t i n c e n t r a l Uganda, Between t h e n and 1 2 June 1 9 7 2 , when t h e l a s t i s o l a t e was o b t a i n e d , 1 8 y e l l o w f e v e r v i r u s s t r a i n s were i s o l a t e d from m o s q u i t o s . A l l i s o l a t e s were from A. a f r i c a n u s m o s q u i t o e x c e p t one, (MP 1 2 1 1 7 ) i s o l a t e d from C o q u i l l e t t i d i a fuscopennata. No human c a s e s were d e t e c t e d d u r i n g t h i s p e r i o d . Twenty-one monkey s e r a were t e s t e d f o r y e l l o w f e v e r n e u t r a l i z i n g a n t i b o d i e s and 4 0 % were p o s i t i v e . ^ In c o n c l u s i o n , i t appears t h a t t h e y e l l o w f e v e r s i t u a t i o n i n E a s t A f r i c a has not changed s i g n i f i c a n t l y from t h a t o b s e r v e d about 4 0 y e a r s ago. (i) S e r o l o g i c a l s u r v e y s b o t h i n humans and a n i m a l s show t h a t t h e r e i s s t i l l of y e l l o w f e v e r v i r u s i n f e c t i o n i n a number of p l a c e s . (ii) (iii) It Very few human c a s e s o f y e l l o w f e v e r d i s e a s e have been r e c o r d e d T h e r e has been no e p i d e m i c o f y e l l o w f e v e r i n E a s t Africa, so f a r . evidence
appears t h a t the f o l l o w i n g f a c t o r s have c o n t r i b u t e d t o t h i s s t a t u s quo: non-anthropophilic
(a) The wide d i s t r i b u t i o n of t h e m o s q u i t o p o p u l a t i o n w h i c h i s b o t h and n o n - p r i m a t o p h i l i c i n many p a r t s of E a s t A f r i c a ;
(b) c r o s s r e a c t i o n o f y e l l o w f e v e r v i r u s w i t h a number of o t h e r group B a r b o v i r u s e s affecting i t s infectivity; (c) good s u r v e i l l a n c e .
VIR/RC/74.13 (Arbo) page 5 REFERENCES 1. 2. 3. Strode, G, K., ed,, (1951) Yellow Fever, New York and London, McGraw-Hill Sawyer, W, A. & Whitman, L, (1936) Trans, roy. Soc, trop. Med. Hyg., 29, 397-412 Smithburn, K. C., Haddow, A. J . & Lumsden, W. H. R. (1949) Ann, trop. Med. P a r a s i t . , 43, 74-89 4. 5. 6. 7. y 8, 9. 10. K i r y a , B. G, et a l . , WHO/V1R/72.7 G i l l e t t , J , D. (1951) Ann, trop. Med, P a r a s i t , , 45, 110-121 Mukwaya, L. G. (1971) Ph,D Thesis Henderson, B. E, et a l . (1970) Amer. J . trop, Med. Hyg., 19, 110-118 Haddow, A, J , et a l . (1951) Trans, roy. Soc, trop. Med. Hyg., 45, 189-224 Henderson, B. E,, Hewitt, L. E. & Lule, M. (1968) East A f r i c a n V i r u s Research I n s t i t u t e Report, No, 18, p, 48 11. 12. 13. Haddow, A, J, (1952) Ann, trop, Med. P a r a s i t . , 46, 135-143 K i r y a , B. G, et a l , (1970) East A f r i c a n Virus Research I n s t i t u t e Report, No. 20, pp. 32-36 Henderson, B. E. et a l . (1968) East A f r i c a n V i r u s Research I n s t i t u t e Annual Report, No, 18, pp, 35-37 14. 15. 16. 17. Haddow, A, J , , G i l l e t t , J , D. & Highton, R. B. (1947) B u l l . Ent. Res,, 37, 301-330 Dick, G. W. A., & Smithburn, K. C. (1949) Amer. J . trop. Med., 29, 57 Henderson, B. E. et a l , (1968) B u l l , Wld H l t h Org., 38, 229-237 Haddow, A. J . (1948) B u l l . Ent, Res. , 39, 185