WORLD H E A L T H ORGANIZATION
VIR/YF /71.16
ORGANISATION M O N D I A L E D E L A SANTÉ EXPERT COMMITTEE ON YELLOW FEVER
E n t e b b e , 9-15 March 1971 INDEXED
IMMUNOLOGY Antibody responses a f t e r n a t u r a l i n f e c t i o n and a f t e r v a c c i n a t i o n by
W i l b u r G. Downs, M.D. Department o f E p i d e m i o l o g y and P u b l i c H e a l t h Yale U n i v e r s i t y School of Medicine
N a t u r a l i n f e c t i o n w i t h y e l l o w f e v e r v i r u s i s f o l l o w e d by appearance o f complement f i x i n g (CF), h a e m a g g l u t i n - i n h i b i t i n g (HI) and n e u t r a l i z i n g (N) a n t i b o d y . There i s a l a c k o f i n formatiçn c o n c e r n i n g t h e p r e c i s e t i m i n g o f appearance o f such a n t i b o d i e s and t h e c o m p o s i t i o n o f such a n t i b o d i e s i n t h e human h o s t , b u t by i n f e r e n c e from s t u d i e s i n a n i m a l s i t c a n be assumed t h a t N and HI a n t i b o d i e s appear w i t h i n a few days o f i n f e c t i o n f o l l o w e d s h o r t l y by a p p e a r a n c e o f CF a n t i b o d i e s . N e u t r a l i z i n g a n t i b o d y i s f i r s t d e m o n s t r a b l e on t h e f o u r t h o r f i f t h day a f t e r o n s e t o f i l l n e s s and t h e peak l e v e l may n o t be reached u n t i l t h e f o u r t h week or l a t e r . B e r r y e t a l . (1931) i n a study o f l a b o r a t o r y a c q u i r e d i n f e c t i o n s , m e n t i o n a case i n w h i c h b o t h v i r u s and N a n t i b o d y were s i m u l t a n e o u s l y p r e s e n t i n t h e b l o o d on t h e f o u r t h and f i f t h day o f d i s e a s e . Downs e t a l . (1955) r e p o r t a case where a v i r u s was i s o l a t e d on t h e e l e v e n t h day o f i l l n e s s , a t w h i c h t i m e , and a l s o l a t e r , a low l e v e l o f N a n t i b o d y was p r e s e n t . The a n t i b o d y l e v e l was so low t h a t i t prompted t h e statement " i f v i r u s had n o t been i s o l a t e d , t h e d i a g n o s i s o f y e l l o w f e v e r c o u l d n o t have been made on t h e b a s i s o f t h e s e n e u t r a l i z a t i o n tests". The N (and H I ) a n t i b o d i e s produced f o l l o w i n g i n f e c t i o n p e r s i s t f o r l o n g p e r i o d s o f t i m e , a l t h o u g h t h e r e may be some d r o p i n a n t i b o d y l e v e l s over a p e r i o d o f y e a r s . The i n d i v i d u a l a p p e a r s a l s o t o have a l i f e - l o n g immunity t o YF v i r u s . I t has been p o s t u l a t e d t h a t t h e l o n g p e r s i s t e n c e o f a n t i b o d i e s may r e s u l t from a p e r s i s t i n g v i r u s i n f e c t i o n . T h i s h a s n o t been proven. T h e i l e r and C a s a l s (1954) p r e s e n t a d e t a i l e d study o f H I , CF and N t e s t r e a c t i o n s i n y e l l o w f e v e r c a s e s ( a l l d i a g n o s e d by v i r u s i s o l a t i o n ) o r i g i n a t i n g i n T r i n i d a d and B r a z i l . In p r i m a r y i n f e c t i o n s ( i . e . i n i n f e c t i o n s i n i n d i v i d u a l s who had no d e t e c t a b l e group B a n t i b o d i e s i n t h e a c u t e phase serum specimen), t h e HI response i n a l l c a s e s was h i g h e r f o r a YF a n t i g e n t h a n f o r a n t i g e n s o f s e v e r a l o t h e r v i r u s e s o f group B a l t h o u g h c r o s s i n g a n t i b o d y was d e t e c t a b l e i n most of the cases s t u d i e d . A s i m i l a r s i t u a t i o n o b t a i n e d f o r t h e CF a n t i b o d y , a l t h o u g h t h e r e was c o n s i d e r a b l y l e s s c r o s s - r e a c t i v i t y seen. I n N t e s t , t h e c r o s s - r e a c t i v i t y w i t h DI, D2 and I l h e u s was e i t h e r m i n i m a l o r n o n - e x i s t e n t , whereas t h e r e was d i s t i n c t YF n e u t r a l i z a t i o n i n a l l serum specimens t a k e n more than t h r e e d a y s a f t e r o n s e t o f d i s e a s e . In secondary c a s e s ( i . e . c a s e s i n w h i c h group B a n t i b o d y was p r e s e n t i n t h e a c u t e phase specimens) t h e s e r o l o g i c a l response was d i s t i n c t l y d i f f e r e n t . A h i g h l e v e l o f HI and CF a n t i b o d y was seen e a r l y , and c r o s s i n g a n t i b o d y t o o t h e r group B v i r u s e s a l s o appeared e a r l y , and a t t a i n e d l e v e l s t o c e r t a i n o f t h e v i r u s e s a t t i m e s s u r p a s s i n g t h e c o r r e s p o n d i n g YF a n t i b o d y level. I n such c a s e s , i d e n t i f i c a t i o n o f t h e i n f e c t i o n by HI o r CF r e a c t i o n , i n absence o f v i r u s i s o l a t i o n , might be i m p o s s i b l e . T h i s i s t h e f a m i l i a r "anamnestic r e s p o n s e " w h i c h has The issue of this document d o e s not constitute publication. It should not be reviewed, C e document ne constitue pas une publication, II ne formal
doit
faire l'objet d 'aucun compte
abstracted or quoted without the agreement of the World Health are Organization. Authors alone
r é s u m é ni d 'aucune citation l'Organisation
rendu ou sans l'autorisation de Mondiale de la S a n t é . Les opinions n'engagent
responsible for views expressed in signed
e x p r i m é e s dans les articles s i g n é s que leurs auteurs.
articles.
VIR/YF/71.16
page been of not
2 frequently noted antibody the so clear, in various D2 a group B v i r u s i n f e c t i o n s . was observed. the The A significant respect degree of to was Ilheus with development virus Ilheus was virus,
cross-N
t o DI a n d of
position with
p o s s i b l y b e c a u s e most o f possibility
p r e - e x i s t i n g group B experience
precluding
"conversion". two yellow fever and cases CF. in prior I n one g r o u p B immunes, b o t h studied i n NT, YF the l o g s more o f solidly virus showing conthan 1.3 in
Spence et valescent did both the
a l , (1961) d e s c r i b e of day) 1.6 (40
a marke,d d e v e l o p m e n t acute (five SLE and
g r o u p B c r o s s i n g i n HI specimen. l o g s more o f
case
sei-um s p e c i m e n
d a y s p o s t - i n f e c t i o n ) n e u t r a l i z e d 2.8 However, t h e ILH. The convalescent individual was
specimen a l s o n e u t r a l i z e d immune t o d e n g u e
l o g s more o f
specimens. The antibody response by by following yellow by s c r a t c h has Smith that fever immunization with by by the a 17D s e r i e s of ed., both the French neurotropic by subnumber
(FN)" s t r a i n cutaneous of as the years. of FN
of vaccine The chapter was of by
administered
s c r a t c h , and been s t u d i e d Fever" the the antibody use
vaccine 1951)
administered summarizes
i n o c u l a t i o n or I t was
l a b o r a t o r i e s over a
i n "Yellow t h a n was
(Strode,
the p o s i t i o n with The
that date. vaccine entirely frequency
apparent
response of the FN
following immunization immunization. has l e d to vaccine
more p r o n o u n c e d complications the 17D vaccine.
response
f o l l o w i n g 17D
higher almost A
f o l l o w i n g the
replacement
number o f m o r e r e c e n t of the N test, the 17D JSS the the use t h o s e who from from the the Using of
s t u d i e s have an HI
shown t h a t w i t h can be
the
n e w e r HI
tests, Lobo
and
with
modiout,
fications 100%, of in prepared prepared can a be
p o s t - v a c c i n a l immunity of the as of test, A the very to
demonstrated using higher
in a proportion
approaching antigen
have r e c e i v e d strain strain 17D
adequate dose of
viable vaccine.
(1958) p o i n t s of positive antigen
connexion with
importance of significantly the t e s t s run This
a haemagglutinating proportion has u s i n g an
itself. yellow
r e a c t o r s were thus d e t e c t e d , confirmed.
contrasted
in parallel
fever. observed, as
important
observation studies of
been and
repeatedly N test individuals, considered
haemagglutinin, survival using the 100%
a very
c l o s e c o r r e s p o n d e n c e b e t w e e n HI i n the
achieved.
Theiler repeatedly average a test, test
i n a number o f judged by
immunized
prolongation He
t i m e o f mice used as are v i r u s source achieved,
conventional intracerebral strain of yellow fever virus this HI . . . ,
inoculation equivocal. i n monkey test tests. antibody The develops is likely group B
of a d u l t mice developed as
when r e s u l t s
mouse m o r t a l i t y m i g h t be
the A s i b i
serum, and
test this
animal test
i n f a n t mouse i n o c u l a t e d i n t r a p e r i t o n e a l l y . with s e n s i t i v e one
With
conversion also.
rates approaching
close correspondence a l s o w i t h
Incidentally,
i s a very
f o r d e t e c t i n g h e t e r o t y p i c group B
problem of remains. to is a
the With
occasional the
individual of
i n whom no examination and
detectable by a to
antibody with the
response virulent vaccine virus, of i t viruses
impossibility block
challenge of
remain unanswered. f a c t o r w h i c h may
Whether p r e - e x i s t i n g a n t i b o d y infection with
(certain) other
multiplication
virus i s
conjectural. Protection effective in a high the disease found did afforded life of by yellow the fever immunization in a 17 region years strains. is certainly in Brazil earlier. long-lasting, possibly and HI antibodies they also than
f o r the never
span of
individual. living vaccinated other YF
Groot e t a l . (1962) found N In the to N HI
proportion 17D
individuals
where n a t u r a l l y o c c u r r i n g tests, test results
has
been r e c o g n i z e d , prepared
haemagglutinin
gave r e s u l t s more c l o s e l y f r o m two
corresponding
haemagglutinins
VIR/yF/71.16 page 3 I t has been shown t h a t v a c c i n a t i o n w i t h 17D v a c c i n e can i n d u c e a s e r o l o g i c a l r e s p o n s e t o a range of g r o u p B a n t i g e n s , i n i n d i v u d u a l s w i t h p r e - e x i s t i n g group B a n t i b o d i e s , whereas the r e s p o n s e i n group B n e g a t i v e s i s much n a r r o w e r i n range, e s s e n t i a l l y l i m i t e d to YF. Wisseman e t a l . (1962) s t u d i e d the N r e s p o n s e i n Japanese who had had p r i o r JE i n f e c t i o n and showed a broadened r e s p o n s e t o s e v e r a l o t h e r group B v i r u s e s . Pond e t a l , (1967) c a r r i e d out s i m i l a r s t u d i e s i n i n d i v i d u a l s w i t h p a s t h i s t o r y o f SLE o r dengue, h i s t o r y b e i n g s u p p o r t e d by s e r o l o g i c a l f i n d i n g s . These s t u d i e s were l i m i t e d t o HI and CF, and t h e y showed broad h e t e r o t y p i c HI r e s p o n s e s i n t h e p r i o r group B immunes, w i t h p a r a l l e l f i n d i n g s w i t h CF a l t h o u g h a t a lower l e v e l and more v a r i a b l e . They remark t h a t "YF v a c c i n a t i o n i s a p o t e n t t o o l t o r e c a l l p a s t e l e v a t e d HI t i t r e s o f SLE and dengue a n t i b o d i e s f o r e p i d e m i o l o g i c p u r p o s e s i n o r d e r t o d e t e c t p o p u l a t i o n s i n w h i c h o u t b r e a k s o f group B a r b o v i r u s i n f e c t i o n s have p r e v i o u s l y o c c u r r e d and may r e c u r " . Monath (1970) c a r r i e d out d e t a i l e d N t e s t s t u d i e s o f the i m m u n o g l o b u l i n s a p p e a r i n g f o l l o w i n g 17D i m m u n i z a t i o n . IgM a n t i b o d i e s were f i r s t d e t e c t e d on day e i g h t o r n i n e , r o s e t o h i g h t i t r e s between day 14 and 17 and tended t o d e c l i n e g r a d u a l l y t h e r e a f t e r . However, s i g n i f i c a n t amounts were d e t e c t a b l e as l o n g as 82 days f o l l o w i n g p r i m a r y i m m u n i z a t i o n . IgG a n t i b o d i e s a p p e a r e d between 10 and 17 days a f t e r i m m u n i z a t i o n , tended t o r e m a i n s t a b l e or t o r i s e s l i g h t l y t h e r e a f t e r , and d i d not s u r p a s s IgM t i t r e s . Both IgM and IgG a n t i b o d i e s had a h i g h degree of s p e c i f i c i t y f o r c e r t a i n s t r a i n s o f YF. Serum N t i t r e s were h i g h e r f o r FN o r 17D t h a n f o r A s i b i o r Dakar 1279. The a n t i b o d i e s were a l s o h i g h l y s p e c i f i c when compared w i t h s e v e r a l h e t e r o l o g o u s group B v i r u s e s . Monath remarks t h a t the p r o l o n g e d s y n t h e s i s of IgM a n t i b o d y s u g g e s t s a p e r s i s t e n c e of a n t i g e n i c s t i m u l a t i o n . Wheelock e t a l . (1969) have d e m o n s t r a t e d t h a t 17D v i r u s i n f e c t s and m u l t i p l i e s i n u n s t i m u l a t e d human monocyte c u l t u r e s and i n human lymphocyte c u l t u r e s s t i m u l a t e d t o b l a s t development by p h y t o h a e m a g g l u t i n i n . U n s t i m u l a t e d monocytes and l y m p h o c y t e s exposed to 17D produced i n t e r f e r o n . In f u r t h e r s t u d i e s Wheelock e t a l . (1970) have d e m o n s t r a t e d t h a t i n i n d i v i d u a l s v a c c i n a t e d w i t h 17D, t h e i r p e r i p h e r a l l y m p h o c y t e s , s t i m u l a t e d by phytohaemagglut i n i n , l o s e t h e i r a b i l i t y t o s u p p o r t growth o f 17D between seven and 14 days f o l l o w i n g v a c c i n a t i o n but r e g a i n t h i s c a p a c i t y by the t w e n t y - f i f t h day p o s t - v a c c i n a t i o n . In one donor, however, the r e f r a c t o r y s t a t e p e r s i s t e d f o r 76 days, but had d i s a p p e a r e d by the two hundred and f o r t y - e i g h t h day a f t e r v a c c i n a t i o n . Wheelock e t a l . (1969) suggest t h a t " f o l l o w i n g i m m u n i z a t i o n , l y m p h o c y t e s i n the l y m p h o r e t i c u l a r t i s s u e s o f immune i n d i v i d u a l s may c o n t a i n 17D v i r u s w h i c h r e m a i n s i n a s l o w l y r e p l i c a t i n g or n o n - r e p l i c a t i n g l a t e n t s t a t e f o r p r o l o n g e d periods of time".
VIR/YF/71.16
page 4 REFERENCES 1. 2. 3. Berry, G.P. & Kitchen, S. F, (1931) Yellow fever a c c i d e n t a l l y contracted i n the laboratory, Am. J . trop. Med., 11, 365-434 Downs, W. G., Anderson, C, R. & . Spence, L. (1955) I s o l a t i o n of yellow fever v i r u s from a human patient on the t w e l f t h day of i l l n e s s , Trans, roy. Soc. Med. Hyg., 49, 557-579 Groot, H. & R i b i e r o , R. B. (1962) N e u t r a l i z i n g and h e m a g g l u t i n a t i o n - i n h i b i t i n g a n t i b o d i e s to yellow fever 17 years a f t e r v a c c i n a t i o n with 17D vaccine. B u l l . Wld H l t h Org., 27, 699-707 Lobo, M. Bruno (1958) Avaliacao da imunidade pos-vacinal, Revista do Service E s p e c i a l de Saude P u b l i c a . 10, 167-175 Monath, T, P. C. N e u t r a l i z i n g antibody responses i n the major immunoglobulin c l a s s e s to yellow fever 17D v a c c i n a t i o n of humans (In press) Pond, W. L. et a l . (1967) Heterotypic s e r o l o g i c responses a f t e r yellow fever v a c c i n a t i o n : detecting of persons with past S t . Louis e n c e p h a l i t i s or dengue, J . Immunol., 98, 673-682 Spence, L. et a l . (1961) D e s c r i p t i o n of human yellow fever cases seen i n T r i n i d a d i n 1959, W. Indian med. J . , 10, 54-58 8. 9. 10. Strode, G. K. (ed.) (1951) Yellow fever, McGraw-Hill, pp. i - x v , 1-710 T h e i l e r , M. & Casals, J . (1958) The s e r o l o g i c a l reactions i n yellow fever. Am. J . t r o p . Med. Hyg., 7, 585-594 Wheelock, E. F. k Edelman, R. (1969) S p e c i f i c r o l e of each human leukocyte type i n v i r a l infections. I I I . 17D yellow fever v i r u s r e p l i c a t i o n and i n t e r f e r o n production i n homogenous leukocyte c u l t u r e s treated with phytohemagglutinin, J . Immunol., 103, 429-436 Wheelock, E. F . , Toy, S . T. & Stjernholm, R. L. (1970) Lymphocytes and yellow fever. I . Transient v i r u s r e f r a c t o r y s t a t e f o l l o w i n g vaccination of man with the 17D s t r a i n , J . Immunol., 105, 1304-1306 Wisseman, C. L., j r . et a l . (1962) Immunological studies with group B arthropod-borne viruses. I . Broadened n e u t r a l i z i n g antibody spectrum induced by s t r a i n 17D yellow fever vaccine i n human subjects previously i n f e c t e d with Japanese e n c e p h a l i t i s v i r u s . Am. J . trop. Med. Hyg. , 11^, 550-561
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