R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 2 9 ( 5 ) : 4 9 7 - 5 0 1 , s e t - o u t , 1 9 9 6 .
SA FETY EVALUATION O F SPf66 MALARIA
VACCINE IN BRAZIL
M. Urdaneta, A- Prata, C.J. Struchiner, C.E. Tosta, P. Tauil and M. Boulos
The f re q u e n c y a n d des crip t io n o f s id e effect s s e co n d a iy to the s u b c u t a n e o u s ap p licat io n o f S P f6 6 m ala ria v a c cine a n d p la ce b o a re rep o rt ed f o r e a c h do s e o f ap p licat io n in t he p art icip an t s o f t he v a c c in e efficacy t rial in B raz il. Side effect s e v a lu at e d tw o ho u rs a ft e r e a c h app licat io n w ere d et e ct e d in 8 .0 % , 3 0 .2 % a n d 8 .8 % , f o r t he I s', a n d 3" ' do s e, respectiv ely , in t he S P f6 6 g ro u p , a n d in 7.0% , 8 .5 % a n d 2 .9 % in t he p la c e b o g ro u p . L o cal re act io ns s u c h a s m ild inflam m at io n, n o d u le a n d p a i n o r ery t hem a fre q u e n t l y a c c o m p a n ie d by p ru rit u s w ere t he m o s t co m m o n reac t io ns d et e ct e d in bo th g ro up s (3- 8% , 2 9 .1 % a n d 8 .5 % in t he S P f6 6 g ro u p a n d 4 .0 % , 7 .6 % a n d 2 .5 % in t he p la c e b o g ro u p ). A m o n g v accinees , lo cal s id e effects a ft e r t he 2 “' do s e w ere m o re f re q u e n t in fe m a le s . Sy s t em ic s id e effect s w ere e x p re s s ed m ainly t h ro ugh g e n e ra l s y m pt o m s re f e rre d by the p art icip an t s a n d w ere m o st f re q u e n t aft er t he 1st do s e in bo th g ro u p s (4 .3 % in t he S P f6 6 g ro u p a n d 3 - 0 % in the p la ce b o g ro u p ). M us cle a ch e s a n d f e v e r w ere refew red b y f e w p art icip ant s . N o s ev e re adv e rs e re act io ns w ere d et e ct e d f o r
eit h er do s e o f ap p licat io n o r gro up .
K ey - w o rds : M a laria v ac cine . V accine safety . S P f6 6 effic acy trial.
Th e sy nthetic m alaria v ac c in e ag ainst the ase x u al fo rm s o f P l a s m o d i u m f a l c i p a ru m (SPf6 6 ) has recently b ein g tested in p o p u latio ns o f e n d e m ic a r e a s o f C o lo m b ia , Ec u a d o r, V enez u ela, Tanz ania and G am b ia1 2 31 5 6 7 8 10. T h e se stu d ies hav e p ro v id ed ev id en c e that the v ac c in e is safe fo r u se in ch ild ren as w ell as in ad ults. V ac c ine ap p lic atio n w as resp o nsib le m ainly fo r lo c al m ino r effects, the m o st freq u ent o f w h ic h w ere the ind u ratio n o f the site o f ap p licatio n, p ain, p ruritus and ery them a. Few c ases o f hy p ersensitiv ity w ere d escrib ed . The p resen t p ap er rep o rts o n the find ing s o f the
Escola N acional de Saúde Pública, Fundação O sw aldo Cruz, Rio de Janeiro, RJ; Faculdade de M edicina do Triângulo M ineiro, U beraba, M G; Laboratório de M alária, N úcleo de M edicina Tropical e N utrição e D epartam ento de Saúde Coletiva, U niversidade de Brasília, D F; D epartam ento de D oenças Infecciosas e Parasitárias, Faculdade de M edicina e Instituto de M edicina Tropical, U niversidade de São Paulo. São Paulo, SP
This trial w as approved b y the ethic com m ittees from the involved institutions. Sources o f support: N ational Health Foundation, M inistry o f H ealth, Brazil (g ran t:008/ 91); Pan-A m erican H ealth O rganization/W orld H ealth O rganization (grants: 0 0 9 / 9 1 , 1 6 7 / 9 1 and H D P/H D R/RG /BRA /119); and, Brazilian Reasearch C ouncil (CN Pq).
A d dres s to: Prof. A luizio Prata. M edicina Tropical/FM TM . C a i x a P o s ta l : 1 1 8 , 3 8 0 0 1 - 9 7 0 U b e ra b a , M G , B ras il . Fax: 5 5 - 3 4 - 3 1 2 7 7 2 2 ,ram al 1279.
Receb id o p ara p ub licação em 2 9 / 0 7 / 9 6 .
B r a z il ia n tria l re g a r d in g th e s a f e ty o f th e v ac cin e.
S t u d y p o p u l a t io n a n d p ro c e d u re s . Th e Bra z ilia n trial c o n s is te d o f a ran d o m iz e d , d o u b le-b lind ed , p lac e b o -c o n tro lled , effic ac y trial9. Eig ht hu nd red v o lu nteers, m ale and fem ale, ag ing 7 to 60 y ears, resid ing in the rural settlem ents o f the M u nicip ality o f C o sta M arq ues, Ro nd o nia, and w h o fu lfilled the se lec tio n criteria w ere rand o m ly allo c ated to rec eiv e three d o ses o f the v ac c in e o r p lac e b o . W ritten c o n se n t w as o b tain e d fro m all p articip ants o r tuto rs, in c ase o f c h ild ren .
U r d a n e t a M , P r a t a A , S t m c h i n e r CJ, T o s ta CE, T a u i l P, B o u l o s M . S a f e t y e v a l u a t i o n o f S P J 6 6 m a l a r i a v a c c i n e i n B r a z i l . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 2 9 : 4 9 7 - 5 0 1 , s e t - o u t , 1 9 9 6 .
w ith th e letters L and S in C o lo m b ia. Th e p rep aratio ns w ere se n t “read y fo r u se ” w ith a m em b er o f the lab o rato ry , w h o su p erv ised their ap p lic atio n d uring the first d ay s o f e ac h p ro g ram m ed v ac cin atio n . N o info rm atio n is av ailab le fo r eith er th e b atc h n u m b er o r fo rm u latio n lo t o f SPf66 v ac c in e p rep aratio ns o r the tetanu s to x o id u sed in this trial.
V accinatio n sc h ed u le w as d efined as the su b c u taneo u s ap p licatio n o f 0 .5m l c o ntaining 2m g o f the v ac c in e and lm g o f alu m inu m hy d ro xid e, o n d ays 0, 30 and 180’ . To facilitate the d etec tio n o f lo c al reactio ns, the 1M and 3rd d o ses w ere ap p lied o n the d elto id reg io n o f th e r ig h t a rm a n d th e 2 nd o n th e l e f t. A su rv eillance sy stem fo r d etec tin g any ad v erse reac tio n s w as set u p d uring ev ery p lann ed v ac c in atio n . A ll p artic ip an ts w e re c lo se ly m o nito red d u ring the first 30 m inu tes after v ac c in e ap p lic atio n b y the m ed ical inv estig ato r in charg e o f v accinatio n. Em erg ency eq u ip m ent an d th e rap e u tic p ro c e d u re s w e re read ily av ailab le. Inq u iries fo r p o ssib le sy m p to m s and id entificatio n o f lo c al reactio ns w ere p erfo rm ed tw o ho u rs after e ac h ap p licatio n, as w ell as fo u r w e e k s after th e 1st d o se and tw o w ee k s after the 2“ 1 and 3rd d o ses. Particip ants w ere ad v ised to c o n tac t the m ed ical inv estig ato r in c ase o f p o ssib le sev ere sig ns and sy m p to m s seco nd ary to v ac cin atio n .
T h e f r e q u e n c y , in te n s ity , d u ra tio n an d d e s c rip tio n o f an y a d v e rse e f f e c ts w e re s y s te m a tic a lly r e c o r d e d a c c o r d in g to th e fo llo w in g criteria: m ild o r m o d erate lo cal
inflam m atio n (p re se n c e o f ed em a, p ain and ery them a < 5m m o r > 5m m , resp ectiv ely ), iso lated ery them a o r p ain, p ruritus, no d u le (ind u ratio n), sig ns o f hy p ersensitiv ity and g e n e ral sy m p to m s as d e sc rib e d b y e ac h p articip ant.
St at ist ical analy s is . Th e freq u en c ies o f sid e effec ts w ere c o m p ared fo r the v ac c in e and p lac e b o g ro u p s and fo r e ac h d o se ap p lic atio n stratified b y se x and ag e, and fo r the to tal stu d y p o p u latio n. C o rrected x ’ tests o r tw o - tailed Fish er’s e x ac t tests at a sig n ific an c e lev el o f 0.05 w ere u sed to c o m p are p ro p o rtio ns u nd er the null hy p o thesis o f ho m o g eneity (n o d ifferen ces in the p ro p o rtio n o f ind iv id uals w ith sid e effec ts in the v ac c in e and p lac e b o g ro u p s o r b e tw e e n d o ses).
RESULTS
Sid e effec ts ev alu ated tw o ho u rs after eac h ap p licatio n w ere d e tec ted in 8 .0 % , 30.2% and 8.8 % o f the p articip ants o f the SPf66 g ro u p fo r the 1st, 2nd and 3rd d o ses, resp ectiv ely . In the p lac e b o g ro u p they w ere d e tec ted in 7.0% . 8.5% and 2.9% . Lo cal reac tio ns at the site o f ap p lic atio n o f the p rep aratio ns w ere th e m o st freq u en t sid e effec ts d etec ted and / o r referred b y the p articip ants at the three d o ses o f eith er the v ac c in e o r p lac e b o p rep aratio ns (Tab les 1 an d 2). Sy stem ic reac tio ns w e re m o re freq u ent d uring the 1st d o se and co n sisted o f sy m p to m s referred b y the p articip ants w ith the ex c e p tio n o f the b lo o d p ressu re alteratio ns. N o sev ere ad v erse reactio ns w ere d etec ted d u ring the
Table 1 - Frequency o f side effects observ ed tiuo ho urs after the application o f each v accine and placebo dose.
D o se
1st 2 nd 3rd
Sid e e ffe c t SPf66 T.T*. P SPf6 6 A K O H ) ,' P SPf66 A L(OH)j P n - 40 0 n - 40 0 n - 361 n = 354 n - 2 8 3 n - 2 7 9 Lo cal (to tal) 1 5(3.8) 16(4.0) 1 05(29.1) 2 7 ( 7 .6 ) < 0 .0001 2 4 ( 8 .5 ) 7 ( 2 .5 ) 0 .0035
iso late d p ain o r e ry th em a 8 ( 2 .0 ) 8( 2 .0 ) 0 .8 5 ( 1.4) 3 ( 0.8) 0.7 3(1-1) 3 ( 1.1)
m ild in flam m atio n 2 ( 0 .5 ) 2 ( 0.5) 85 ( 2 3 .5 ) 12(3.4) < 0 .0 0 0 1 15(5.3) 2 ( 0 .7 ) 0 .0 0 3 4 m o d e rate in flam m atio n 1(0.2)
n o d u le 5 ( 1 .3 ) 5 ( 1.3) 0.7 15(4.1) 12(3-4) 0 .8 2( 0.7) 1(0.4)
p ain in arm 1(0.3) 1(0.4)
p aresth esia
su b c u tan e o u s em p h y se m a
2( 0.7) 1(0.3)
Sy stem ic (to tal) 1 7 (4.3) 1 2( 3.0) 0 .4 4 ( 1 .1 ) 3 ( 0 .8 ) 1( 0.3) 1( 0 .4 ) h e ad ac h e 13(3.3) 10(2.5) 0 .7 3 ( 0 .8 ) 2 ( 0 .6 ) 1(0.3) 1(0.4) b lo o d p ressu re alte ratio n s 2 ( 0.5) 1(0.2)
u n sp e c ific g astric sy m p to m s 2 ( 0.5) 1(0.2) 1(0.3)
m u sc le p ain 1(0.3)
To tal 3 2 ( 8 .0 ) 2 8 ( 7 .0 ) 0.7 109 ( 3 0 .2 ) 30 ( 8 .5 ) < 0.0001 2 5 ( 8 .8 ) 8 ( 2 .9 ) 0.0 0 4 7 *T.T. - T etan u s to x o id ; f A J(O H )^ - A lu m in u m h y d ro x id e
U r d a n e t a M , P r a t a A , S t r u c h i n e r CJ, T o s ta CE, T a u i l P, B o u l o s M . S a f e t y e v a l u a t i o n o f S P f 6 6 m a l a r i a v a c c i n e i n B r a z i l . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 2 9 : 4 9 7 - 5 0 1 , s e t - o u t , 1 9 9 6 .
\
Table 2 - Frequency o f side effects referred by the participants 2 w eeks after the application o f each v accine an d placebo dose D o se
jSt 2n d 3rd
Sid e e f f e c t SPf66 n = 361
T.T*. n = 3 5 6
P SPf66 n - 361
A l(O H )3* n - 354
P SPf66 n - 210
A L(O H )a n - 201
P
Lo c al ( to tal) 3 1 ( 8 .6 ) 5 7 ( 1 6 .0 ) 0 .0035 1 22(33.8) 4 5 ( 1 2 .7 ) < 0.0001 42 ( 2 0 .0 ) 2 4 ( 1 1 .9 ) 0.0 3 6 6 iso late d p ain o r e ry th em a 9 ( 2 .5 ) 10( 2 .8) 0.9 5 ( 1 .4 ) 9 ( 2 .5 ) 0.4 12(5-7) 7(3-5) 0.3 9 m ild in flam m atio n 10( 2 .8) 10( 2 .8) 0.8 99 ( 2 7 .4 ) 2 3 ( 6 .5 ) < 0.0001 16(7.6) 7(3-5) 0.11
m o d e rate in flam m atio n 1( 0 .3 ) 6 ( 1 .7 ) 0.0 7 1(0.3) 1(0.3) 2 ( 0.9) 2( 1 .0 ) n o d u le 11( 3.0) 3 1 ( 8 ,7 ) 0.0021 1 7 (4.7) 12(3-4) 0.5 9 ( 4 .3 ) 7 ( 3 .5 ) 0.9
p am in arm 2( 0 .9 ) 1(0.5)
p are sth e sia 1(0.5)
Sy stem ic (to tal) 2 4 ( 6 .6 ) 1 2 (3.4) . 0.0 7 4 ( 1 .1 ) 3 ( 0.8) 3( 1 .4 ) 3(1-5)
headache 15( 4.1) 10( 2 .8) 0.4 4 ( 1 .1 ) 2 ( 0 .6 ) 0 .7 1(0.5) 1(0.5)
u n sp e c ific g astric sy m p to m s 2 ( 0 .5 ) 2 ( 0.9) 2( 1 .0 ) m u sc le p ain 5 ( 1 .4 ) KO -3) 0 .2 1 ( 0.3)
f e v e r ICO.3) 1 ( 0.3)
d iz z in ess 1 ( 0.3)
To tal 5 5 ( 1 5 .2 ) 6 9 ( 1 9 .4 ) 0.2 126(34.9) 4 8 ( 1 3 .6 ) <0.0001 4 5 ( 2 1 .4 ) 2 7 ( 1 3 .4 ) 0 .0 4 5 3
N u m b e r (% ) o f p artic ip an ts re fe rrin g sid e e ffe c ts.
ap p lic atio n o f any o f th e th ree d o ses o n eith er g ro up .
T h e m o st freq u en t lo c al reac tio ns d etec ted in b o th v ac c in e and p lac e b o g ro u p s after the three d o ses w e re m ild inflam m atio n, no d u le an d iso lated p ain o r ery them a, freq u ently a c c o m p an ie d b y p ru ritu s at th e site o f ap p lic atio n (T ab le 1). T h e se lo c al reac tio ns d id n o t d iffer b e tw e e n g ro u p s after the 1st d o se (3-8% in SPf6 6 and 4.0% in p lac e b o ), b u t in c re a s e d sig n if ic a n tly in v a c c in e e s ( 29 .1 % ; p < 0 .0 0 0 1 ) and slig htly , in the p lac e b o g ro u p (7.6% ; p = 0.047) after th e 2nd d o se. Fo llo w ing th e 3rd d o se, th e n u m b er o f lo c al sid e effects d ec reased sig nificantly in b o th g ro u p s ( 8 .5 % fo r SPf66 and 2.5% fo r p lac e b o ; p < 0.01). Few p articip ants referred p ain that c o m p ro m ised the w h o le arm , p aresth esia in the arm w h ere th e v ac c in e w as ap p lied , and o n e v ac c in e e had su b c u taneo u s em p hy sem a p ro b ab ly d u e to im p ro p er ap p licatio n techniq u e.
H e ad ach e w as th e m o s t f req u en t sy stem ic re actio n in b o th g ro u p s at e a ch d o s e . B l o o d p re s s u re alteratio n s o ccu rre d o n ly af ter th e ap p l icatio n o f th e P' d o s e in 0 .5 % o f th e v accin e e s an d 0 .2 % o f th e p l ace b o g ro u p . O th e r rare m an if estatio n s in clu d ed u n sp ecif ic g as tric s y m p to m s, m u s cl e p ain s, f e v e r an d d iz z in ess at v e ry l o w f req u en cies.
Sid e effec ts w e re m o re freq u en t in fem ales in b o th g ro u p s (Tab le 3). In the v ac c in ees, lo c al reactio ns w ere sig nificantly m o re freq u ent in fem ale s after the 2nd and 3rtl d o ses, sp ecially in p artic ip an ts o v er 15 y ears o f ag e. In the
p lac e b o g ro u p , fem ales had m o re sy stem ic reac tio ns after th e 1st d o se (Fisher; p = 0.007), w hile c hild ren sh o w ed m o re ad v erse reactio ns fo r th e th ree d o ses.
Sid e effec ts p ersisted fo r a c o m p arab le p e rio d in b o th g ro u p s. Is o la te d p ain an d ery them a g enerally d isap p eared w ithin the first 24 ho u rs. Inflam m atio n g enerally p ersisted fo r 24 to 72 ho u rs and n o d u les d isap p eared in 48 ho u rs, b u t p ersisted in so m e c ases f o r 15 d ays, as d etec ted in the tw o w e e k s lo c al ev alu atio n after the 2nd d o se. M u scle ac h es and fev er, as referred b y so m e p articip ants (1.7% in tho se v ac c in ate d ), lasted a few d ays (1 to 5 d ay s). N o c o n c o m itan t p arasitem ia w as d etec ted in these ind iv id uals. A ll o th er sy stem ic sid e effec ts w ere transito ry , lasting o n ly a few m inu tes.
D ISCUSSIO N
T h e v a c c in e w as w e ll to le ra te d b y th e p articip ants, and m o st sid e effects w ere d etected m ainly at the site o f ap p licatio n. Freq u en c y o f sid e effec ts w as sim ilar fo r SPf66 v ac c in e and tetanu s to xo id w ith the e x c e p tio n o f p ersisting no d u les and m o d erate inflam m atio n, w h ic h w e r e m o r e f r e q u e n t in th e l a tte r . M ild inflam m atio n at the site o f ap p lic atio n w as co nsid erab ly m o re freq u en t in the p articip ants w h o re c e iv e d SPf66 th an in th o se w h o rec eiv ed o nly alu m inu m h y d ro xid e. Freq u en c y o f to tal sid e effec ts w as g reater fo r the first tw o d o ses than th o se rep o rted in o th er trials.
U r d a n e t a M , P r a t a A , S t r u c h i n e r CJ, T o s ta CE, T a u i l P, B o u l o s M . S a f e t y e v a l u a t i o n o f S P f 6 6 m a l a r i a v a c c i n e i n B r a z i l . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 2 9 : 4 9 7 - 5 0 1 , s e t - o u t , 1 9 9 6 .
Table 3 - Frequency o f o bsew ed side effects acco rding to sex, age and do se o f application. Sideeffect/ V ac c in e
P lac e b o
ag e(y rs) m ales fem ale s P m ales fem ales D 1st d o se
Lo cal 7/ 247 ( 2 .8 ) 8/ 153 ( 5 .2 ) 0.34 8/ 245 ( 3 .3 ) 8/ 155 ( 5 .2 ) 0.5 0 15 4/ 76 ( 5 .3 ) 2/ 65 (3-1) 0.69 5/ 86 ( 5 .8 ) 5/ 66 ( 7 .6 ) 0.75 > 15 3/ 171 ( 1 .7 ) 6/ 88 ( 6 .8 ) 0.06 3/ 159 ( 1 .9 ) 3/ 89 ( 3 .4 ) 0.6 7 Sy stem ic 7/ 247 ( 2 .8 ) 10/ 153 ( 6 .5 ) 0.01 2/ 245 ( 0 .8 ) 10/ 155 ( 6 .4 ) 0 .0 0 2 15 5/ 76 ( 6 .6 ) 3/ 65 ( 4 .6 ) 0.7 2 1 / 8 6 ( 1 .2 ) 6/ 66 ( 9 .1 ) 0.0 4 > 15 2/ 171 ( 1 .2 ) 7/ 88 ( 8 .0 ) 0.008 1/ 159 ( 0 .6 ) 4/ 89 ( 4 .5 ) 0.0 6 To tal
2nc' d o se
14/ 247 ( 5 .7 ) 18/ 153 ( 1 1-8) 0.046 10/ 245 ( 4 .1 ) 18/ 155 ( 1 1 .6 ) 0 .007
Lo cal 44/ 221 ( 1 9 .9 ) 61/ 140 ( 4 3 .6 ) < 0.0001 9/ 215 ( 4 .2 ) 12/ 139 ( 8 .6 ) 0.1 3 15 14/ 70 ( 2 0 .0 ) 23/ 61 ( 3 7 .7 ) 0.04 3/ 82 ( 3 .6 ) 6/ 59 ( 1 0 .2 ) 0 .1 6 > 15 30/ 151 ( 1 9 .9 ) 38/ 79 ( 4 8 .1 ) < 0.0001 6/ 133 ( 7 .5 ) 6/ 80 ( 7 .5 ) 0.3 7 Sy stem ic 1/ 221 ( 0 .4 ) 3/ 140 ( 2 .1 ) 0.30 0/ 215 ( 0 .0 ) 3 / 1 3 9 ( 2 .1 )
15 0/ 70 ( 0 .0 ) 0/ 61 ( 0 .0 ) 0/ 82 ( 0 .0 ) 2/ 59 (3- 4 ) > 15 1/ 151 ( 0 .7 ) 3/ 79 (3-8) 0.12 0/ 133 ( 0 .0 ) 1/ 80 ( 1 .2 ) To tal
3rd d o se
45/ 221 ( 2 0 .4 ) 64/ 140 ( 4 5 .7 ) < 0.0001 9/ 215 ( 4 .2 ) 1 5 / 1 3 9 ( 1 0 .8 ) 0.0 3
Lo cal 7/ 173 ( 4 .0 ) 1 7 / 1 1 0 ( 1 5 .4 ) 0 .0017 2/ 167 ( 1 .2 ) 5/ 112 ( 4 .5 ) 0.1 2 15 3/ 58 ( 5 .2 ) 6 / 5 4 ( 1 1 .1 ) 0.31 3/ 73 ( 4 .1 ) 4/ 52 ( 7 .7 ) 0 .4 5
> 15 4/ 115 ( 3 .5 ) 11/ 56 (1 9 .6 ) 0.0013 0/ 94 ( 0 .0 ) 1/ 60 ( 1 .7 ) Sy stem ic 0/ 173 ( 0 .0 ) 1/ 110 ( 0 .9 ) 1/ 167 ( 0 .6 ) 0/ 112 ( 0 .0 ) 15 0/ 58 ( 0 .0 ) 0/ 54 ( 0 .0 ) 1/ 73 ( 1 .1 ) 0/ 52 ( 0 .0 ) > 15 0/ 115 ( 0 .0 ) 1/ 56 ( 1 .8 ) 0/ 94 ( 0 .0 ) 0/ 60 ( 0 .0 )
To tal 7/ 173 ( 4 .0 ) 18/ 110 ( 1 6 .4 ) 0 .0 0 0 8 3/ 167 ( 1 .8 ) 5/ 112 ( 4 .5 ) 0.2 7 P ro p o rtio n (% ) o f p artic ip an ts w ith o b se rv e d sid e effe c ts.
b o th g ro u p s as rep o rted in Ec u ad o r’s trial8. Sev eral lo c al sid e effec ts n o t rep o rted in o ther trials w e re d e te c te d , su c h as p a in an d p a re s th e s ia in th e arm ( 0 .3 % an d 0 .7 % , resp ec tiv ely ). N o d u les p ersisted fo r w ee k s in so m e c a s e s an d n o c o n tra la te ra l lo c a l m anifestatio ns w ere d e te c te d as d esc rib ed in so m e trials13. T h e fac t that lo c al sid e effects c au sed b y the rep eated ap p lic atio n o f SPf66 w ere m o re freq u en t in fem ales and w ere ap p arently e n h an c e d b y ag e is n o t clearly u nd ersto o d . Sim ilar resu lts w ere rep o rted b y A m ad o r e t al3. N o y a e t al rep o rted that hyp ersensitiv ity ty p e reactio ns w ere sig nificantiy h ig h er in w o m e n 5.
Sy stem ic reac tio ns w ere m ild and transito ry e x c e p t fo r the referred m u sc le ac h es and fev er, th at c o u ld last fo r d ay s. A lth o u g h no hy p ersensitiv ity reac tio ns w ere d etec ted , no co nclu sio ns can b e d raw n ab o u t their freq u en c y b e c au se o f the in ad eq u ac y o f the sam p le siz e to d e te c t th ese reactio ns.
Th e increased freq u ency o f ad v erse reactio ns fo r b o th p rep aratio ns in c hild ren and fem ales m ig ht lead to d ifferential lo sses to fo llo w -u p in f ie ld tria ls. O f th e in itia l c o h o rt o f 8 0 0 p artic ip ants, 714 rec eiv ed the 2nd d o se and 572 the 3rd. A sep arate analy sis o f lo sses co nsid ering
the freq u en c ies o f sid e effec ts ac c o rd in g to the treatm ent g ro u p , ag e and se x ind ic ated that the p ro p o rtio n o f ind iv id uals lo st to fo llo w -u p w ith seco nd ary reac tio ns w as eq u al in b o th g ro u p s (X 1, p = 0.4) 9.
S P f 6 6 h a s n o t b e e n a s s o c i a t e d w ith b io c h e m ic al o r au to im m u ne ab no rm alities, and th e freq u en c y o f hy p ersensitiv ity reactio ns s e e m s l o w a s r e p o r t e d i n p r e v i o u s trials12 3 ’ 5 6 7 8 10. H o w ev er, th e freq u en c y o f th ese ty p es o f reac tio ns c an o n ly b e d eterm ined in larg e field trials. O u r c o n c lu sio n s are restricted to this p articu lar trial in w h ic h SPf66 w as resp o n sib le fo r m ino r lo c al reactio ns.
RESUM O
A f re q ü ê n c i a e d es criçã o do s efeit o s s e cu n d á rio s à ap lica çã o s u b c u t â n e a d a v ac in a a nt í m a lã ri ca S P f6 6 e p la ce b o , s ão no t ificad as p a ra c a d a do s e no s p a rt icip an t es d o es t udo d a e fic á c ia v a c in a i no
B ras il. Efeito s co lat erais av aliado s d u a s ho ra s apó s a a p lic a çã o do s p re p a ra d o s f o ra m det ect ado s em
8 ,0 % , 3 0 ,2 % e 8 ,8 % p a ra a 1* 2 a e 3 a do ses, resp ectiv am ente, no g ru p o d e v acina do s ; e e m 7,0% , 8 ,5 % e 2 ,9 % no gru p o q u e re c e b e u o p la ce b o . R ea çõ es tais co m o infla m a çã o lev e, n ó d ulo e d o r f re q ü e n t e m e n t e a c o m p a n h a d a s d e p ru rid o , f o ra m
U r d a n e t a M , P r a t a A , S t n i c h i n e r CJ, T o s t a CE, T a u i l P, B o u l o s M . S a f e t y e v a l u a t i o n o f S P f S ó m a l a r i a v a c c i n e i n B r a z i l . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 2 9 : 4 9 7 - 5 0 1 , s e t - o u t , 1 9 9 6 .
g ru p o s (3 ,8 % , 2 9 ,1 % e 8 ,5 % n o g m p o v acinado , e
4,0% , 7 ,6 % e 2 ,5 % no g ru p o p la ce b o ). N o g ru p o q u e
re c e b e u a v acina, as reaçõ e s lo cais f o ra m m ais
f re q ü e n t e s em m u lh e re s apó s a 2 S do s e. O s efeito s co la t e ra is s is t êm ico s b a s e a ra m - s e e m s in a is e
s int o m as referido s p elo s p a rt icip ant es . Fo ra m m ais f r e q ü e n t e s a p ó s a a p l i c a ç ã o d a 1 - d o s e e m
a m b o s o s g ru p o s (4 ,3 % , no g ru p o d e v acina do s e,
3 ,0 % , n o g ru p o p la c e b o ) . A lg u n s p a rt icip a n t e s
re fe rira m m ialgias e f e b re . N e n h u m efeit o co lat eral
g ra v e f o i det ect ado em n e n h u m a do s e d e ap lic açã o o u g ru p o .
P alairas - chav es : V acina ant im alãrica. S e g u ra n ça
SP f6 6 . E ns aio d e ca m p o SP f66.
A CK N O W LED G EM EN TS
The au tho rs are g ratefu l to Dr. Patarro yo , L.A . M urillo and M. Ro jas fo r p ro v id ing SPf66 v ac c in e and initial su p erv isio n o f v ac cin e ap p lic atio n s; to th e v o lu n te e rs o f C o sta M arq u es and to the lo c al au tho rities fo r their u n c o n d itio n al help . Sp ec ial thanks to Dr. A g o stinho Cruz M arq u es, Ped ro d e So u z a, H arley A z ev ed o Jr, A irto n M ed eiro s D ias and Shig u eru O fu g i. W e are g ratefu l to the N atio nal H ealth Fo u n d atio n , M inistry o f H ealth o f Braz il, the Pan-A m erican H ealth O rg aniz atio n and the Braz ilian Research C o u ncil - CN Pq fo r financial su p p o rt.
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