aventis pasteur sa inactivated pollomyelltls vaccine a 1

Aventis Pasteur SA INACTIVATED POLlOMYELlTlS VACCINE A 1 059 1 IVBI 1 07.03 1 01 .O
l n a c t i v a t e d P o l i o m y e l i t i s v a c c i n e
P A R T IV
CLlNlCAL DOCUMENTATION
STUDY 1. INACTIVATED POLIOVIRUS VACCINE CLlNlCAL EXPERTISE
This information is the property of Aventis Pasteur SA
IVB1~Tnall~Ju12003 doc - O-
PASTEUR MERIEUX Sérums & Vaccins
INACTIVATED POLIO VACCINE A 1059 1 714 1 IV B1 1 12.92a
Study 1
lnvestigators : Grenier B.
THIS INFORMATION IS THE PROPERTY OF PASTEUR MERIEUX Sérums & Vaccins
PASTEUR MERIEUX Sérums 81 Vaccins
IMOVAX POLIO A 059 IVB1/12.92a
Clinical documentation
Name of finished ~ roduc t : Poliomyelitis lnactivated Vaccine
Name of active inaredients : lnactivated Poliovirus type 1, 2 and 3
Individual study table referring to Part IV
of the Dossier
( Title of the study : -
INACTIVATED POLIOVIRUS VACCINE, CLlNlCAL EXPERTISE. I lnvestigators : GRENIER B., Paediatric Hospital, CHR Tours, FRANCE.
HAMZA B., National Institute of Children Health, Tunis, TUNISIA.
Infants were recruited in iwo centres : - Paediatric Hospital, CHR Tours, FRANCE. - National lnstitute of Children Health, Tunis, TUNISIA.
Publication (ref) : GRENIER B., HAMZA B., BIRON G., XUEREF C., VIARME F., ROUMIANTZEFF M. SEROIMMUNITY FOLLOWING VACCINATION IN INFANTS BY AN INACTIVATED POLIOVIRUS VACCINE PREPARED ON VER0 CELLS. Rev. Infect. Dis. 1984 ; 6 (S2) : S545-547. GRENIER B., VIARME F., ROUMIANTZEFF M., XUEREF C., DEMONT F. VACCINATION ANTlPOLlOMYELlTlQUE DE JEUNES ENFANTS PAR UN NOUVEAU VACCIN INACTIVE. Arch. Fr. Pediatr. 1985 ; 42 : 321 -323.
Objectives : Evaluation of the reactogenicity of the IPV vaccine. Evaluation of the antibody response to poliomyelitis components of the IPV vaccine during and after the primary series of immunisation.
Study period : April - July 1981
1 Methodology : Multicentric, open, non-controlled study. I
Clinical phase : II
Number of subjects : 56 infants. (total and for each 36 were included in FRANCE. treatment) 20 were included in TUNISIA.
Diagnosis and criteria for inclusion :
Healthy 2 to 12 montt, old infants of both sexes.
Test Product, dose, IPV vaccine : lot no 3063. mode of administration, Each 0.5 ml dose contains : batch no : - lnactivated poliovirus type 1 : 1 immunising dose*
- lnactivated poliovirus type 2 : 1 immunising dose* - lnactivated poliovirus type 3 : 1 immunising dose* - 2-phenoxyethanol : maximum 0.005 ml - Formaldehyde : maximum 0.1 mg * The immunising dose of inactivated poliovirus vaccine for type 1,2 and 3 corresponds to the quantity of antigens which satisfies the norms of the antigenicity test described in the French and European Pharmacopoeia. IPV vaccine was injected intramuscularly.
I t
Name of finished ~roduct : Poliomyelitis lnactivated Vaccine
Name of active inaredients : lnactivated Poliovirus type 1, 2 and 3
Individual study table referring to Part I V
of the Dossier
Duration of treatment : 3 injections at one month interval.
Criteria : - Occurrence of local and systemic reactions for 48 hours following each vaccine injection. - Poliovirus type 1, 2 and 3 neutralising antibody titres before the first injection, one month after the second injection and one month after the third injection.
Statistical methods : Results are described without statistical analysis.
Summary : Clinical safety :
* For infants recruited in FRANCE : - 6 presented local reactions after vaccination (108 injections) : induration or erythema. - 5 presented general reactions atler vaccination (1 08 injections) : fever which lasted 12 to 48 hours, anorexia or diarrhoea. All these children received the same day DTP vaccine. * For infants recruited in TUNISIA, none of them presented reactions.
lmmunoaenicitv of the IPV vaccine :
Only sera from infants recruited in FRANCE were analysed. Neutralising antibody titres against poliomyelitis antigens
When analysis is made taking into account the age group at the beginning of vaccination (2 to 6 months or 7 to 11 months), results confirm the excellent immunogenicity of IPV in both groups.
Conclusions : This study confirrns good safety of this vaccine and the excellent irnmunogenicity of this product after the second injection which is reinforced after the third.
Before vaccination
35 71.4 %
Nb of subjects % of seroposlie (2 114) GMT
Nb of subjects % of seropositie (1 114) GMT
IMOVAX POLIO A 059 IVB1-1/12.92a
S T U D Y R E P O R T
I M O V A X P O L I O
Inactivated pol iomyel itis vaccine
Vero ce11 line
- Clinical Expertise -
I M O V A X P O L I O
Inactivated poliomyelitis vaccine
Bi ogenerator
CLINICAL EXPERTISE
1 Expertize declaration from Professeur GRENIER, Expert clinicien agrée. Page
II 1 ntroducti on Page
I I I Plan of the cl inical expertize : Page
A ) Expert and place of study (Decl aration of the cl inical expertize and conclusions of the cl inical expert).
0 ) Subjects
E ) Results :
2 ) Serological results.
1 - DECLARATION OF EXPERTIZE
Expert clinicien en date du 2 août 1979. B.O.M.S. du 1$ septembre 1979,
Déclare avoir procédt P l'expériaenwtian cliafqus & nouveau vaccin pol icinyelit ique inact ivt produit sur li@ cellulaire VCro en MogMra- teur.
Cette exptrimentation a ttt rtalisée A la d d e & l'institut WUEüX,
17, rue .hurgelat, 69002 LYON.
Elle a 6th enregistree au Ministere de la SantC sous le nunéro 3712.
Le lot soumis à l'expertise fut le nC S 1063.
.4u prhalable, nous avons eu co~aissance du dossier du fabricant et des
conclusions des Experts : CD
- hnsieur le Professeur RENOüX, de la Facultt de Médecine de IUiJRS (Laboratoire d' lmnunologie)
Expert analyste,
Expert toxicophannacologue.
Professeur CIRPIIER Expert clinicien agrCC .
1. the undersigned. Docteur GRENIER, Professeur agrege at the
Hdpi ta1 BRETONNEAU 1 n TOURS, ' 1
Expert clinicien fran 2nd August 1979, B.0.Y S. from 15th September 1979.
Declare having carried out the clinicol experimentation of the new
inactivated polimyelitis vaccine. on Vero cell line in biogenerator.
This experlmentation was performed at the request of the
Institut HERIEUX. 17 rue Bougelat. 69002 LYON.
It has been recorded by the Hinistére de la Santé under the number 3712.
The lot sutunitted to expertize was No 5 1063.
As a preliminary. we have consulted the manufacturer's file and the
results of the experts :
- Monsieur le Professeur RCNOUX. frmi the Faculte de Médecine in TOURS (Laboratoire d' lmnunologie)
Expert analyste
- Monsieur le Professeur OUOAR from the Ecole Nationale de LYON
Expert toxicophannacologue.
INTRODUCTION
Po l iomye l i t i s , an en te r i c i l l n e s s of v i r a l o r i g i n , i s due t o three
pathogenic types 1, II, and III. This s t r i c t l y human disease sometimes
at tacks the an te r i o r horn o f the spinal cord, i n some cases leading to
a p a r a l y t i c syndrome. It i s a c h i l d i s h i l l n e s s o f the f i r s t two years
o f 1 i f e .
This disease i s world-wide and when faced w i t h the powerlessness o f
medicines, the importance o f prophylaxis i s undeniable.
Two vaccine presentat ions are on the market : an o ra l attenuated form
and an inac t i va ted form. These two vaccines have been used i n d i f f e r e n t l y ,
some countr ies using on ly the l i v e attenuated form and others the i nac t i va t
form, whi le other countr ies use both. Epidemical r e s u l t s i n countr ies
where vaccine coverage i s p r a c t i c a l l y complete show the almost t o t a l
e l im ina t ion o f the i l l ness , although a ' s t r e e t c i r c u l a t i o n ' o f v i r u s
pers is ts . These resu l t s are those o f countr ies w i t h a wel l -developed
medical service.
But the p o s i t i o n i s t o t a l l y d i f f e r e n t i n developing countr ies, where the
i l l n e s s represents a heavy burden t o the populat ion because o f the
handicapped v ict ims.
Campaigns f o r mass vaccinat ion are organised , using, most f requent ly
the o r a l form o f vaccine which i s more p rac t i ca l and economical.
But ce r t a i n f a i l u r e s have appeared due t o :
1) the o r a l form demands a heal thy i n t e s t i n e for v i r a l
implantat ion. Thus, i n some countr ies, d iges t i ve i l l nesses i r r i t a t i n g
the i n t e s t i n a l mucous membranes, are factors i n the f a i l u r e of vaccine
t a k i ng .
The number o f doses must then be increased. Certain c l i n i c a l studies
show the insu f f i c iency o f three doses and i t i s only a f t e r 5 o ra l
doses t h a t the cor rect r a t e o f seroconversion i s obtained.
2 ) This o ra l form i s r e l a t i v e l y unstable and demands
c e r t a i n conservation ob l igat ions which are d i f f i c u l t t o apply i n ce r t a i n
regions o f the globe.
3 ) The l i v e v i rus , when i t mu l t i p l i es , can i n f e c t
non-immunized contacts o r fami l y members. Thus, f o r example, i n the
U.S.A. the ra re cases o f po l i omye l i t i s ex i s t i ng are found i n contacts.
4 ) This vaccine i s , o f course, contra-indicated i n
imnuno-deficiency, which i s sometimes d i f f i c u l t t o detect, due t o the
subjects ' young age.
5 ) L ive vaccine v i r u s can mutate and may ( r a re l y ) r e tu rn
t o neuro virulence.
On the o ther hand, k i l l e d vaccines i n t h e i r present form also have
some inconveniences :
1) They are given a t a l a t e r age due t o the presence o f
materna1 antibodies.
2) They are more expensive than 1 i v e vaccines.
3 ) Their production needs a greater number o f monkoy kidney
c e l l s .
4) They requ i re co r rec t v i r a l i nac t i va t ion .
A l 1 these r ap id l y discussed problems have l e d t o research i n t o the
improvement o f the products. I n t h i s way, thanks t o the impulsion o f
- Mr SALK, interest in a new inactivated vaccine was aroused.
A Dutch team from the RIJKS institute developed a technique for the massive culture of pol iomyel i t i s virus. This technique uses monkey primary kidney cells in suspension on micro-beads as a way of obtaining concentrated vaccines, standardised on the D antigen content. Clinical studies were then carried o u t which demonstrated t h a t the antigen concentration meant better imunization and possibly a reduction in the vaccination doses.
Following these conclusions, i t was possible t o envisage a product which could be manufactured on a large scale (leading t o a lowering of
costs) and would give a simplified vaccination schema which could be used in an expanded vaccination programne.
So, the Mérieux Institute turned t o this new development, so as t o define a concentrated, inactivated product which woul d avoid the previousl y
mentioned draw-backs.
Inactivated concentrated vaccines have already been widely used (studies in Finland, Israel). These studies have made i t possible t o define :
1) The concentration in D antigen units defined as 40 units for type 1, 8 units for type 2 and 32 units for type 3.
2 ) The qua1 i ty of the anti body response
3) The tolerance t o the product.
The vaccine used in this clinical study i s a t the same concentration as tha' defined in the f i r s t studies. The vaccine differs from the other studies by the ce11 substratum, which i s not constituted by monkey kidney primary
ce1 l s , b u t by Vero cells from monkeys, in a continuous 1 ine.
- The c l i n i c a l t r i a l descr i bed shoul d demonstrate the serol ogical
e f f i c i ency w i t h regard t o the 3 types o f pol iomyel i t i s and the
c l i n i c a l safety o f the vaccine.
III PLAN OF CLINICAL EXPERTIZE
The r e c r u i t i n g o f the ch i ld ren was car r ied ou t on one hand a t the
Centre de Péd ia t r ie de Clochev i l le i n Tours, and, on the other hand,
a t the I n s t i t u t National de l 'Enfance i n Tunis.
The c l i n i c a l expert responsible f o r t h i s c l i n i c a l study was the
Professeur GRENIER, Expert c l i n i c ien , from 2nd August, 1979, B.O.M.S.
from 15th September, 1979.
Under h i s r espons ib i l i t y , the expert izes were ca r r i ed ou t :
1) A t the Centre de Pédia t r ie de C lochev i l l e i n Tours,
expert ize declared on 23rd March, 1981
2) A t l ' I n s t i t u t National de l 'Enfance i n Tunis (Tunis ia)
by Docteur BECHIR HAMZA, exper t ize declared on May 27th 1981.
INSTITUT MERIEUX fond4 m 1ml
Minist&re de la a n t e et de la Sécurltê k h l e Direction de l a Pharmacie et du M6dimmeiit Bureau PH. 13 9 avenue de Lowendal 75700 PARIS Lyon, 23 mirs 1981
Messieurs.
Conformement A l'article R. 5126 du Code de la &nt4 Pubilque, DOUS avons l'honneur de porter A votre conn8Issance 1. mfre en route d'une etride cllnlque concernant :
VACCIN POLIOM'YELITIQUE INACTIVE prCpnr4 sur lignée6 cellulaires VCro en bigCnCrrteur -
Cet essal rera effectuC s o u la responsabillt4 du Professeur B. GRENIER - experî cllniclen pir arrCtC du 2 août 1979 A 1'Hùplîal Bretonneau de Toura. et aura pour but ia propbylulc de la pollomy6lil.e.
Le Dr WJAN - mCdecin pédiatre A finatltut ~ ~ r i t u x - coll8i?orerr aussi P cette Ctude.
Nous voua prion# de blen vouloir accepter, Hessieurr. l 'usunooc de notre conrldCration dirtiiyu6e. 1
C. CiiARBONNIER Directeur
Hinis tère de la Sante e t de l a Sécurité Sociale
Di rect lon de l a Pharmacie e t du Medicament
Bureau PH.13 1
Dear Sirs.
I n accordance w i t h A r t i c l e R 5126 o f the Code de l a Santé Publique.
we beg to 1nfor-m you that a c l i n i c a l study has been star ted concerninq
INACTIVATED POLIOMYELITIS VACCINE
prepared on Vero ce11 l ines i n bioyenerator
This t r i a l w i l l be carr ied out under the respons ib i l i t y of
Professeur B. Grenier - expert c l i n i c i e n by order o f 2nd August. 19/9.
a t the hûpi ta l Bretonneau i n Tours. and w i l l Iiave as aini. the
prophylaxis o f P o l i m y e l i t i s .
Dr AJJAN. a pediat r ic ian a t I n s t i t u t Merieux. w i i l d lso Cake par t i r i t h i s
s tudy.
Yours f a i t h f u l l y ,
- Ministère de la Santé et de la Sécurité Sociale
Direction de la Pharmacie et du Médicament
Bureau PH.13
Dear Si rs,
In accordance with Article R 5126 of the Code de la Santé Publique, we beg to i n f o m you that a clinical study has been started concerning :
INACTIVATED POLIOMYELITIS VACCINE
This trial will be carried out under the responsibility of
Professeur B. Grenier - expert clinicien by order of 2nd August, 1979, at the hôpital Bretonneau in Tours, and will have as airn, the
prophylaxis of Poliomyelitis.
Dr AJJAN, a pediatrician at Institut Mérieux, will also take part in this
s tudy .
Yours faithfully,
C. Charbonnier
Di rector
Development and Vi sas
M l n l s t ~ r e de l a Santé e t de l a Securite Sociale
Dlrectlon de l a P h a ~ c l e e t du Hedicament
Bureau PH. 13 ' 1
9 avenue de Lowendal
75700 PARIS Lyon. 27th May 1981
Direction de la Ph rauc le et du H6dhmcn t Bureau PH. 13 9 avenue de Lowendal 75700 PARIS Lyon. 27 Ma1 1981
Suite A notre d&claratlon dlexpertlre cllnlque du 23 auri dernler et conform6ment A I'artlcle R. 5126 du Code de la &nîé Publique, nous avoris I1homeur de porter A votre connalarance la mlre en route d'une etude clinlque concernant :
Dear Sirs,
Following our declaration of a c l in ica l study on March 3rd. i n
accordance with Ar t ic le R 5126 of the Code de l a Santé Publ ique. we beg
to infonn you that a c l i n i ca l study has been started concerning :
VACCIN POLIOMYELITIQUE LNACTIVE prCprrC sur llgnéer cellulalre8 Varo en blogédmteur
Cet esse1 sera effectu6 h 1 ' I ~ t i t u t Natloml de I1Enfince, Phce Bab-Fuboin A Tunlr par le Docteur BCcblr M H Z A et mou8 la reipon- sabllite de notre expert cllnlclen le Prdereeur B. GRENIER - expert - cllnlclen par arretC du 2 aoPt 1979. le but de cette Ctude Ctint la propbylaxle de l a poliomyCllte.
Inactivated Po l imye l i t i s vaccine
prepared on Vero ce1 l 1 ines i n biogenerator
This t r i a l w i l l be carried out a t the Ins t i tu t National de l'Enfance.
Place Bab-Faaboin. i n Tunis by Dr Bechir Hamza and under the responsibi l i ty
o f our c l i n i ca l expert Professeur B. GRENIER - expert c l i n i c i en by order
of 2nd August 1979 - the aim o f t h i s study being the prophylaxis of
pol iomyeli t is.
Noue v w r prlona de bien voulolr accepter, Meri leuri, l 'ar8ura~ce de notre oomIdCratlon dlrtlnguCe.
C. CHARBONNIER Directeur
Yours f a i t h fu l l y .
C. Charbonnier
Oeveiopnecit and V isds
- Min is tere de l a Santé e t de l a Sécurité Sociale D i rec t ion de l a Pharmacie e t du Médicament
Bureau PH. 13
Dear Sirs,
Fol lowing Our dec la ra t ion o f a c l i n i c a l study on March 3rd, i n
accordance w i t h A r t i c l e R 5126 o f the Code de l a Santé Publique, we beg
t o inform you t h a t a c l i n i c a l study has been s ta r ted concerning :
Inact ivated Po l i omye l i t i s vaccine
prepared on Vero ce11 l i n e s i n biogenerator
This t r i a l w i l l be ca r r i ed ou t a t the I n s t i t u t National de l 'Enfance,
Place Bab-Faaboin, i n Tunis by D r Béchir Hamza and under the r e s p o n s i b i l i t y
of Our c l i n i c a l expert Professeur B. GRENIER - expert c l i n i c i e n by order
o f 2nd August 1979 - the aim of t h i s study being the prophylaxis o f
pol iomyel i ti S.
Yours f a i t h f u l l y ,
C. Charbonnier
Development and Visas
CONCLUSIONS
We have car r ied out, on I n s t i t u t Merieux's request, a c l i n i c a l
experimentation using a new inact ivated po l i omye l i t i s vaccine : new by
i t s production which takes place i n biogenerator and using a new ce11
substratum, and new i n i t s antigen expression, t h i s vaccine being much more
concentrated than present preparations.
This c l i n i c a l study i s aimed a t ve r i f y ing , on the one hand, the
s a f e t y o f the product, and, on the other, i t s e f f ic iency.
This c l i n i c a l study lias been car r ied out i n 2 populations o f chi ldren, one i
the Centre de Péd r i a t r i e de Clochev i l le i n Tours and the other a t the
I n s t i t u t National de l 'Enfance i n Tunis.
The c l i n i c a l follow-up o f the vaccinat ing scheme o f three vaccine
in jec t ions , a t one monthly in te rva ls , showed :
1) The s a f e t y o f the product :
36 ch i ld ren i n Tours received 3 i n j ec t i ons o f vaccine.
- 3 ch i l d ren presented an indurat ion a t the i n j e c t i o n s i t e
- 3 o ther ch i ld ren presented erythema a t the i n j e c t i o n s i t e .
These l oca l react ions were present f o r one i n j ec t i on , but d i d not reoccur
on fu r ther in jec t ions .
General Reactions :
- 3 ch i ld ren presented fever i n the evening o f the i n j ec t i on , which d i d
not exceed 48 hours, and
- 1 c h i l d presented anorexia a t i t s f i r s t i n j e c t i o n and rh ino-
pharangi t is w i t h d iarrhea a t the t h i r d .
I t should be noted that these reactions were present when the children - received the DT Coq the same day. When the children received a further injection of polio vaccine alone, none had any hyperthermic reacti,:n.
The tolerance of this product thus appears excellent.
2 ) Efficiency of th is vaccine :
After 2 , and more so after 3 vaccinations, al1 the children presented protective antibody formation, in spite of the presence of materna1 anti bodies.
Tours, 15th March, 1982
Expert clinicien agrée.
B ) The ------- subiects ---- -
I n order t o study sero-conversion following an injection of trivalent poliomyelitis vaccine, the population studied must include very young children whose minimum age i s 2 months and maximum age one year.
The number of children must be of a minimum of 30 subjects.
Our population comes from :
1) Children from the Centre de Pédriatrie de Clocheville i n Tours, having been vaccinated. A clinical tolerance and serological study was carried o u t .
2 ) Children from the Inst i tut National de 1 'Enfance in Tunis, having received th is vaccine. A cl inical tolerance study was carried out.
C ) The descrietion of the eroduct : ---------- ------------ ------ A polyvalent inactivated vaccine of 0.5 ml prepared from 3 ~ t r a i n s of polio virus :
Mahoney strain fo r type 1
MEFl strain for type 2
Saukett s train for type 3
The viruses are cultivated on a Vero ce11 line.
The culture of the ce l l s and virus i s carried o u t in tanks (biogenerators)
usi ng the microcarrier method. The viral suspensions are concentrated by u l t r a f i l tration, purified by molecular sieving (gel f i l t r a t ion) and
by chromatography .
. Viral inactivation is done by heat and formaldehyde. - The antigen composition of each vaccination dose is based on the antigen D content, fixed at :
40 D units for type 1 8 D units for type 2 32 D units for type 3
wi th added phenol red 10 pg
preservatives 2 phenoxyethanol 0.5 % V/V 2.5 p l ethanol 0.5 % V/V 2.5 pl formaldehyde 12.5 pg.
The antibiotics used during preparation are :
streptomycin
neomyc i n
polymyxine B sulphate.
These antibiotics are no longer dosable in the final product because
of the high purification.
r Blood samples were taken and a minimal quantity of 2 ml of
complete blood were harvested on DO, D + 60 and D + 90.
The blood is centrifuged so as to obtain the serum which is immediately
frozen at - 20°C.
Each tube harvested was coded differently for each sampling and each
child, decoding taking place after the ti tering of the anti bodies.
+ ~ h e titering of the antibodies was carried out by the laboratories of Institut Mérieux in Mrs Xueref's department : they are expressed
in 2 modalities : .
- the seroneutralisation test against the 3 types. Technique in microcupules on Hep 2 cells.
Dilution from 2 to 2, from 1/4 to 8192 and from 1/6 to 6144.
- conversion into international units established according to WHO standards.
The titerings were carried out in 3 series on 22/10/81, 3/12/81,
and 17/12/81.
This study is aimed at creating imnunity to the poliomyelitis virus by means of the vaccine above described.
1) Product employed :
Poliomyelitis vaccine in a 0.5 ml solution L o t S 1063.
Concentration of the types :
Type 1 79 D units
Type 2 9 D units
Type 3 34 D units.
2) Methods : each child receives 3 doses o f vaccine at one
monthly intervals.
D + 60 Blood sampling
The vaccine injections were al1 carried out intrarnuscularly
into the deltoid region in children in good health.
The clinical follow-up was carried out in the 48 hours following
the injection : local tolerance (erythema-induration-pain) as well
as possible general reactions (indisposition, fever) were noted. This information is noted on the clinical form, drawn up for each child.
PROTOCOL FOR THE CLIN ICAL STUDY OF THE INACTIVATED POLIOMY ELITIS ' VACCINE PREPARED AT INSTITUT MERIEUX ON VER0 CELL LINES IN BIOGENERATORS.
Expert clinicien : Professeur B. Grenier (kcreeof 2nd August 1979)
No of experimental lot : S 1063
Beginning of clinical study : 1st April 1981
Planned end of study : 15th July 1981.
Experimentation aim : to study sero-conversion in children of one month minimum and one year maximum, vaccinated by the new inactivated poliomyelitis vaccine prepared on Vero ce11 lines, by Institut Mérieux, Lyon.
PROTOCOL
- D O Bl ood sampl i ng 1st injection of vaccine
- D 30 2nd vaccine injection - D 60 Blood sampl ing
3rd vaccine injection
- D 90 Blood sampling
Whenever possible and if the children can be found, on D 365 a new
blood sampling and booster i n j e c t i o n w i l l be ca r r ied out, and on
D 395 a f i n a l blood sampling, destined t o estimate the e f f e c t o f the
- boos te r .
I f , f o r reasons o f operational d i f f i c u l t i e s o r fami ly problems,
the blood sampl i ng on D 60 cannot be car r ied out i n a l1 subjects,
the ch i ld ren w i l l nevertheless be included i n the study. On the other
hand, the blood samplings on D O and D 90 are imperative.
Number o f ch i ld ren : minimum o f 30 chi ldren. This f i gu re may be
increased, i f t h i s i s poss ib le w i t h i n the l i m i t s set, up t o
50 chi ldren.
Place o f tes ts : Hosp i ta l i sa t ion and Consultation serv ice a t
C.H.U. Bretonneau,
Consul tat ion des nourrissons de P.M. 1. i n
Indre-et-Loire.
P rac t i ca l Modal i t i e s : a minimal quan t i t y o f 2 m l o f blood w i l l
be taken from each ch i l d . A f t e r r es t i ng a few hours a t room temperature,
the blood thus co l l ec ted w i l l be centr i fuged u n t i l a p e r f e c t l y c lea r
serum i s obtained. This w i l l be frozen immediately a t -20° C.
The sera w i l l be kept a t t h i s temperature and given a code number
enabl ing the sera from the same c h i l d a t d i f f e r e n t examination times
t o be found eas i ly .
A t the end o f the study, I n s t i t u t Merieux w i l l take the sera i n charge
a t Tours and w i l l have them transported t o the Control department
i n Marcy 1 ' E t o i l e i n isothermic boxes.
D r Nicolas (7) 887 81 81 and D r B i ron ( 7 ) 838 06 10, both from
I n s t i t u t Mérieux, are a t the disposa1 o f Professeur Grenier and the
c l i n i c i a n s from h i s team, t o provide any informat ion t h a t might be
needed.
Tubes intended f o r c o l l e c t i n g and conserving blood, may be sent - t o Professeur Grenier 's department on h i s request.
F i l e f o r Marketing author isat ion : Professeur Grenier has received
copies o f the reports from the ana ly t i ca l expert (Prof. G. Renoux)
and the toxico-pharmacologist (Prof. J. Oudar) author is ing the
beginning o f human c l i n i c a l tes t ing.
Docteur A j jan o f I n s t i t u t Mérieux, Paris, may, i f the e f f ec t i ves
are i n s u f f i c i e n t , pa r t i c i pa te i n t h i s tes t , under the d i r e c t
responsi b i 1 i t y o f Prof. Grenier.
Fees : These have been f ixed by agreement a t F per c l i n i c a l f i l e - s t a t i s t i c a l l y exp lo i tab le and w i l l be sent a t the end o f the study
t o the bank account t h a t Prof. Grenier indicates.
Lyon, 27th March, 1981
P r . B. Grenier D r G. B i ron
CLINICAL FORM - INACTIVATED BI0 POLIO VACCINE
INSTITUTION : HOPITAL BRETONNEAU - TOURS
NAME ................... FIRST NAME ........... AGE .......... - SEX ..........
CLINICAL HISTORY OF THE CHILD .................................. ................................................................ VACCINE : LOT S 1063 ....... DATES OF VACCINATION 1
2 ....... 3 .......
SITE OF VACCINATION : DELTOID 0 SUPRA OR SUB SPINAL FOSSA u OTHER 0
REACTIONS ATTRIBUTABLE TO THE VACCINATION
-
2 u 6 . V)C> r > - 3 . cc 3 U - O - -
$ : 2 - a . m U
b C - Q: 0
24H Erythema at 48H
24H Induration at 48H *
24H Pain at 48H
Others (To be precised)
VACCINE 3
... yes t l naX1 ength. .. yest ina7 length. .
.. yes0noFlength. . .. y e s g n a l e n g t h . .
... y e s m n o z l ength. .. yesmnoalength. .
.. yeslJna1ength.. y e s d n-1 ength. ...
- .. y e s ~ n ~ l ength..
y e s ~ n o g l e n g t h . . ..
VACCINE 1
... yesUnotJ l ength. .. yesmnoaength . .
... yes t lno i l i eng th . .. yesanon leng th . .
... yest]notfl ength. .. y e s O n a l e n g t h . .
.. y e s O n o i e n g t h . . y e s n n o ç j l - ength.. ..
. yesDnoDlength. . y e s ~ n o ~ l e n g t h . . .
VACCINE 2
. yesUno01ength.. . yesano,IJlength..
. yestlnocl length.. . yesnnoalength. .
.. yes l l lno01 eng th. . y e s o n ~ l e n g t h . .
. y e a n m l ength.. y e ~ n a 1 ength.. .
. y e d l n a length.. y e ~ n ~ l e n g t h . . .
E) Resul t s -----..- - 1") Sampl ing :
- 36 ch i ld ren aged 2 t o 11 months were followed.
Average age : 4 months.
13 g i r l s 13 boys.
20 ch i ld ren from Tunis i n whom tolerance alone was observed.
2") C l i n i c a l tolerance : (see a t t a c h e n t 2) - 36 ch i ld ren from Tours received three in jec t ions e i t he r i n the d e l t o i d region, o r i n the supra o r sub spinal fossa.
- Local react ions :
3 ch i ld ren presented a t the i n j e c t i o n po in t 1 durat ion
3 other ch i ld ren presented a t the i n j e c t i o n po in t 1 erythema.
- Generalised react ions :
3 ch i ld ren presented fever i n the evening o f the vaccination, which las ted 12 t o 48 hours.
1 c h i l d presented anorexia a t the 1 s t vaccination and rhino-pharyngi t is w i t h d iarrhea f o r the 3rd vaccination.
But the ch i l d ren presenting hyperthennia o r anorexia, a l 1 received the same day a vaccinat ion w i t h associated DT Coq. .
I n addit ion, when these same ch i l d ren received the po l iomyel i t i s vaccine alone, they had no general i sed react ion.
It can be deduced t h a t these general ised reactions are l i n ked t o the i n j e c t i o n o f DT Coq.
+20 ch i ld ren frorn Tunis received 3 i n j e c t i o n s o f vaccine and none presented any i ntolerance react ions. (See 1 e t t e r from D r Bechi r H A M A ) .
Professeur Béchir HAMZA Directeur de 1 ' I n s t i t u t National de Santé de l 'Enfance, Membre de 1 ' Académie Françai se de Médecine.
Tunis, 18th February 1982
CERTIFICATE
1, the undersigned, Professeur Bechir HAMZA, Professeur de Ped ia t r ie a t the Faculté de Médecine i n Tunis and Di rector o f the I n s t i t u t National de Santé de 1 'Enfance, c e r t i f y t h a t the admin is t ra t ion o f the inact iva ted b i o p o l i o vaccine, Lot S 1063, from I n s t i t u t Mérieux, was fo l lowed by no secondary reactions.
Professeur B. Hamza.
3") Serological resul t s : Only the sera o f the ch i ld ren from Tours were t i te red . From the 36 ch i ld ren observed we have
- obtained : 30 t r i p l e sera 36 double sera 35 s ing le san~plings.
The resu l t s are evaluated according t o the antibody t i t e r s obtained a f t e r the f i r s t two i n j ec t i ons and a f t e r the t h i r d i n j e c t i o n o f vaccine.
Bearing i n mind the m d a i i t i e s o f the seroneutral isat ion, a subject i s considered as non-imnune when h i s serum presents no discernable antibodies i n 114 d i l u t i o n , the f i r s t d i l u t i o n c o n t r o l l ed.
The demonstration o f the ef fect iveness o f vaccination can be expressed i n d i f f e r e n t ways :
3 - 1) Percentage o f imnunity f o r each type (see tables 1, 2 and 3 )
Table 1 concerns the c h i l d populat ion as a whole. The percentage o f immune ch i ld ren i s la rge f o r the 3 types before vaccination. This i s due t o maternal antibodies, f o r the average age o f t h i s populat ion i s very low (4 months). Seroconversion a f t e r 2 vaccinations i s exce l len t since 100 % o f the subjects are imnune w i t h regard t o the three types.
Tables 2 and 3 ind ica te respec t i ve ly the resul t s f o r the age groups 2 t o 6 months and 7 t o 11 months. As i s natural , i t i s the 2 t o 6 month group which contains the most subjects imnune before vaccination, an imnuni t y corresponding t o maternal a n t i bodies.
The 7 t o 11 month group o f ch i l d ren which i s very small (N = 6 ) has a low percentage o f niembers immune before vaccination, whatever the type, i t being o f 16.6 % f o r the types 1, 2, 3. The seroconversion confirms the exce l len t resu l ts, a l 1 subjects being immune a f t e r the f i r s t two in jec t ions .
3 - 2) Evolut ion o f the geometrical average o f the l eve l o f a n t i bodies expressed :
a) i n d i l u t i o n ( tab le 4) b) i n i n t e rna t i ona l u n i t s ( t ab le 5)
I n the populat ion as a whole, the average o f antibodies o f a naterna1 o r i g i n i s low f o r the three types, being respect ive ly f o r types 1, 2, and 3 o f 8,15 and 8 (expressed i n inverse o f d i l u t i o n ) and of 0.20, 1.96 and 0.36 (expressed i n i n t e rna t i ona l un i t s ) .
Af ter the f i r s t two vaccine in jec t ions , the r i s e i n ant ibodies i s considerable f o r a l 1 three types. The t h i r d i n j e c t i o n leads t o a r i s e i n antibodies o f type 1 and above a l 1 type 2.
3 - 3) Expression in cumulated percentages of the distribution of the antibodies (table 6 - figures 1, 2 , 3 . ) -
3 - 4) Response of the triple and double negatives (tables 7 and 8)
In Our child population, 9 belong t o this category. Seroconversion after the f i r s t two injections and more so after the three injections, leads t o 100 % seroconversion with high-level t i ters .
3 - 5 ) Presence of maternal antibodies :
Most of the children in Our sampling present, due t o their young age, antibodies of a maternal origin, which may reach high t i ters as with the child No 3 (see l i s t of serological results). The high antigenicity of the vaccine makes i t possible t o overcome this obstacle and t o create immunity by vaccination, whatever the type.
CONCLUS ION
This sero log ica l study shows the e x c e l l e n t e f f i c i e n c y o f t h i s vaccine, which makes i t possible w i t h 2 i n j e c t i o n s t o i m u n i z e completely Our population o f c h i l d r e n from the age o f 2 months, i n s p i t e of the presence o f materna1 antibodies.
B I B L I O G R A P H Y
BEALE A. J . Killed and Live Poliovirus Vaccines. Rev. Inf. Dis., - 2, (6), 960-961, 1980.
- F I W C., BM3.J C., MEïMA M., sCKL+UMBERGER M., GUERIN N. Clinical trial of concentrated inactivated polio vaccine in a simplified
inmnmization program.
NLGINITI V.A. The Problems of $oliovinrs Imunization.
h p . Pract., - 53, 61-67, 1980.
COLDBLLM N., M - û z Z., and !XAKïZ T. .
Antibodt to polioviw in older children and young adults in Israel
and the use of poliovaccines for the iaaunizatim of the seronegatives. Develop. biol. Stand., - 43, 173-177, 1979.
HESS P. Doit-on remettre en question le vaccin buccal de la polielite ?
Med. en marche. - 25, 1607-1608, 1981.
MUNICX J.L. Ccnnbined use of live and killed vaccines to control polianyelitis in tropical areas.
Develap. biol. Stand., - 47, 265-273, 1981.
hWW3ûN B.J., FAN= B and NICOLAS A.J. The large-scaïe cultivation of vero cells in micro-carrier culture for virus
vaccine production preliminary results for killed poliovins vaccine.
Develop. biol. Stand., 2, 55-64, 1981.
bDNïAC;NON B.J., NICOLAS A., FANGET B. and PEYRON L. Camparison of sensitivity of ver0 ceil line versus primary monkey kidney
cells in the detection of residual live polio vins during and after inactivatior Develop. biol. Stand., 47, 151-1 55, 1981.
REY M. Le vaccin polio buccal doit-il être rémis en question ?
Cah. M., - 6, (15) , 957-959, 1981.
SABIN A.B.,
- vacc h t ion against poliomyelit is in economically underdeveloped countr ies . Bull. Wld Hlth Org., - 58, (l), 141-157, 1980.
SALK D.M.D. Eradication of poliomyelitis in the united States : 1. Changing Ratio of Live Virus Vaccines-Associated and Wild Poliovirus Disease. 2. Experience
with Killed Poliovirus Vaccines. 3. Practical Considerations. Rev. Inf. Dis., 1980.
SALK D.M.D. Herd effect and virus eradication with use of killed poliovirus vaccine. Develop. biol. Stand., 47, 247-255, 1981.
SAlX J. Interview du Dr J . SALK M. e t ïiyg. 1981.
SALK J. M.D. Inmnmization against polianyelitis : Risk/benefit/cost in a changing context. Develop. biol. Stand. 2, 151-157, 1979.
SALK J. Polio vaccines and polioviruses.
Brit. med. J. (6089) , 765, 1977.
SALK J . , LAPINLElMI K. , VAN WEZEL A. L . , STOECKEL P. Srwnary of results of inactivatecl poliovinis vaccines study un Finland. 1981.
SALK J., COHEN H., F I L i S î R E C. and coll. Killed poliovirus antigen titration in humans.
Develop. biol. Stand., - 41, 119-132, 1978.
SALK J. and coll.
Theoret ical and pract ical cons iderat ions in the application of killed
poliovirus vaccine for the control of paralytic poliomyelitis.
Develop. biol. Stand., 181-198, 1981.
SALK J..and SALK D a Control of Influenza and Policmyelitis with Killed Virus Vaccines. Science, - 195, (4281), 834-847, 1977.
SALK J. and SALK D. Vaccination against polianyelitis.
üniv. Park Press, - 64, 117-153, 1978.
SALK J. and SALK D. Rinciples of Vaccinology in the Control .of Virus Diseases : Policmyelitis. in "Proc. Third Internat. Conf . Ca~parative Virology, Mnt Gabriel, Mai 197: Kurstak E. , Maramorosch K. , éci. Acamedic Press New York, San Francisco, Londc
451-496. 1978
SALK J. and coll.
Antigen Content of inactivated poliovirus vaccine for use in a one or two dose
regimen.
Foundation - for the Advancement of Irmninization Research (F.A.I.R.) Paris.
SK)ECKEL Ph. , SALIOU P. , SCHLüMBERGER M. La vaccination des enfants africains : un programne élargi simplifié ; bases
théoriques et pratiques.
2- Semaine Internationale sur les vaccinations en Afrique, BAMAKu, fév. 1981.
W T Z T .A. and coll . A controlled trial with inactivated poliovaccine. Develop. biol. Stand., - 47, 199-206, 1981.
T R W R. and coll. Le renoweau du poliovaccin inactivé. Pédiatrie, -' XXXV (5) , 439-449, 1980.
WUEL A.L. van and coll.
New approach to the production of concentrated and purified inactivated polio and rabies tissue culture vaccines.
Develop. biol. Stand., fi, 159-168, 1978.
GENERAL CONCLUS IONS
- The inact iva ted po l i omye l i t i s vaccines a t present avai lable t o the population, have made i t possible i n ce r ta in countr ies (such as Scandinavia) t o jugulate and e l iminate t h i s i l l ness .
The new vaccine used i n t h i s c l i n i c a l study should make i t possible t o replace the present inact iva ted preparations, f o r i t presents c e r t a i n advantages :
1) To e l iminate the dependance on monkeys which are now r a r e animais and d i f f i c u l t t o rear, by using as a ce11 substrata, continuous l i n e ce l l s .
2 ) To increase the a n t i g e n i c i t y o f the vaccine antigens, the recording o f the imnunity memory making i t possible t o decrease the doses, a considerable advantage f o r the vaccine calendars i n newly developing countr ies. It i s thus possib le t o imnunize ch i ld ren from the age o f 2 months i n s p i t e o f the presence o f maternal antibodies.
3) To lower the cost o f t h i s vaccine by the cu l t u re method which al lows massive i n d u s t r i a l cul ture.
4 ) The erad icat ion o f t h i s exc lus ive ly human i l l ness , e l im ina t ion o f w i l d c i r cu la t i on .
5) To take the place o f the o ra l vaccine, whose ef fect iveness i s under question i n t r o p i c a l count r ies and which allows, i n count r ies w i t h a developed medical st ructure, a l eve l o f res idua l paralyses t o subsist i n ce r t a i n subjects, and i n non-vacci nated contacts, and a lso the p o s s i b i l i t y o f a r e tu rn t o v i ru lence of attenuated vaccine s t r a i ns i n c i r c u l a t i o n i n nature (water) . E a r l i e r studies ca r r ied ou t i n Finland, Sweden, I s rae l and /. fr ican count r ies have shown, f i r s t l y , t h a t the imnunity created against pol iomyel i t i s i s dependant on the an t igen ic i t y contained i n the vaccines and t o determine the dose o f antigens f i x e d a t :
40 D u n i t s f o r type 1 8 D u n i t s f o r type 2
32 D u n i t s f o r type 3
These studies were ca r r i ed ou t w i t h vaccines c u l t i va ted on the same p r i n c i p l e as the vaccine used fo r Our study but using primary monkey ce1 1 s as a substrata.
Our c l i n i c a l study confirms :
1) The harmlessness o f t h i s vaccine c u l t i v a t e d on Vero ce11 S. No l oca l o r general ised s e n s i t i v i t y phenomena have been noted a f t e r repeated vaccination.
2 ) The e f f i c iency o f the product : Our study was car r ied out i n very young ch i ld ren (average age 4 months) and despi t e the presence of maternal a n t i bodies, the vaccinat ion response
i s excel lent , f o r a f t e r 2 i n jec t ions , 100 % protect ion i s obtained and the antibody average i s (expressed i n inverse o f d i l u t i o n ) :
396 f o r type 1 - 156 f o r type 2 623 f o r type 3
The t h i r d i n j e c t i o n re in forces the immunity obtained a f te r the f i r s t two i n j ec t i ons and i s a t :
572 f o r type 1 353 f o r type 2 604.5 f o r type 3
I n conclusion and bearing i n mind the attached report , we consider as h igh ly desirable the d i f f us i on i n the medical serv ice o f t h i s new inac t i va ted p o l i o vaccine which gives immunization against po l i o m y e l i t i s from a very ea r l y age and we hope t h a t t h i s vaccine obtains the author isat ion f o r marketing given by the D i rec t ion de l a Pharmacie e t du Médicament.
Tours, 15th March, 1982
Professeur GRENIER Expert c l i n i c i e n
IMOVAX POLIO A 059 IVB1-1112.92a
P U B L I C A T I O N
Clinical
documentaiion
Vaccination antipoliomyelitique de jeunes enfants par un nouveau vaccin inactivé
Résultats sérologiques
B. GRENIER. F. VIARME, M. ROUMIANlZEFF, C. XUEREF. F. OEMONT
Rbsud . Un vaccin antipoliomydlitique trivalent inactiv6. PM# sur une l q n h cdlulaim m t i m e d'ongim simienna fcellules VerW a ét6 utilis6 en trois inpctnms inltunuJCUi8im a un mois d'intwalh chez 36 nournmssotu dg& de 2 1 1 1 mois. dont 30 dgds de 2 O 6 mois, daru le but d'dp- sa t o l 6 m et son efficdclCdClt6 annghqu.. La fmcumüon antigdnque de chaque dose &ait mspwmmmt dg& 4 40.8 et 32 unit63 O pour chacun des trots lyprs de poiiovr~s. Co vat* OT cu~uehche 8 cit6 inpd si mu^ ut un 8Um point du c m . Avant la vacwnaüon, Zû mtmts ptwM8iuW des anncwps antipolio w n t n les trois typos; 8 utfrnl6t8ùtü triples négatib, Un mois apds 18 d e u x h m W. IW# IOS enfants avaient un taux sgnmCrbf d'anlfoorps mtm les fro# rypes, titn qui n'a pas et6 s g n i h t i ~ w m t &M un mois aprds la 3'injeum. On obsuw donc qw deux dosa d8 va& O un mis d'intwaIk ont 6t6 sutîbanm pmw imUm une r6ponso immunitaire satisfaiunta qui n'a pu 6H en- v h par la p ~ s ~ pr6alable d'antmrps poik Mrnmis pa? wie transplacmtaire. La tol6ranco ainique 8 6H exç.lknW.
Summy. An inscbY8td triv- p/iawhu. v- p r m on simian l i n u d b (VUQ crlbh h n h m mpcW m 3 d o j . s o n e m o n t h r p M h 3 6 M n b 2 & 11tTmîîwo#(30 o f w h o m r w n 2 t o 6 ~ d d ) t o d . r r m i n i i b t o k n n c i r and antrQcMic e-. EEIch 10. 6 rnd 32 antigenie O unin Ik ih. 3 lyp+i mp#dw& OPT v8&m was injecfad s i w . h moüw pmî d üw body. Belors begimiq Ih, minnuridbn prognm, 30 hfmts h8d signi-t t i tm d .glinrt üw 3 type8 d mWh18: 0 n I y 6 ~ ~ 0 f n p k n a g d h ~ . O m ~ 8 R ~ ( h i w a w r d ~ of vaccine. al1 um inf8nah8dsiqnmcMlihnolMabodi+r against the 3 types; th.j. titm h.H no( k.n sqMc8nîly enhancd one monlt, atïu üm Wrd &se. Tm, &sea of Ih. inactivateâ vaixitm one mCn rpvt IWUW 8 saW.ctrwy
Depuis bientôt 30 ans où k premier vaccin antipolio- my6libiqw inacîiv6 de J. Saik a 614 mis en application (1955), a4 depuia la dittuskm du vaccin atthu6 oral de Sabin (1961), I'effkadt6 de la vaccination antipoliomyé- liüqua r 6t6 si largement démontrée qu'dk peut tenir lieu de modèle dea vaccinations prévmtives modemes (1). En fait, plusiours difficultb restent imparfaitement r hdum (2) : le vaccin p o l i oral (OPV) fait courir le risque, certes excepoocid, d'imidonts paralyhques chez les enfants vaecinéa ou dam leur entourage i m W d : dam les populations dm paya îrovicaux et sub-tmpkaux, il amnait un pourcentage non ndgii- geabk d'&hem (3). 11 est souhaitable que I'antigdniat6 des vaccina inactivés (IPV), pr6ciséfnmt d4finie et centMo, soit s u ~ m e n t 6 1 ~ 6 0 pour induin une répomw immunitaire dèa lm pmmiem mim de b vie. réUr@ k n o m h des injectbm n&esakes la pfifmvicanebioir et mpaar, voim rendra inutiles les in- do rappd (4). 11 est souhaitable enfin que la m d ü p m t h des culbim celhrlaires néwssairw 8 la pcoductkri de vaEçuu sur wllulea primaires de singe puisa B t r s effectuée dodnavant sur des lign60S wllu- la im coritinuea non tumaies et san8 risque d'oncogb nicit6.
A h d'+or une réponse au moins partidle (L ces propositions, un vaccin inaciiv6 forte
amwnmiocr anbghique a pu Btre p- sur une liqw coritinw non t~~moralo de cellules r6naJets de singe (celiulea V m ) . L'ahana de powOir or i coqh et I'efkacit6 anbgbrique d'un W vaccin ont 6t6 largment d&nmr& ch02 l'animai puis chez l'homme adulte (5).
: Travail du Conm de Matf ia C.H.R.U. de Taur. 49, bubvud Wmgu, 37W4 T a n et do I'lnStitUl MWunt. 17. N. 69ûûû
Lyon Cdex 2. aaeptd le 28 mai 1W.
~eauelle3xe gie e enb!i!ler(wo!lod u ~ e ~ np onblq~sA8 enb y-1 luel m e g l o a e l
-e!A rnel ep SIOU oe!ue~d Sel SQP 'quelue seunet Se( z e ~ p enb!wbounuui! f33WpWe uos le e3Ue~9lO1 es reu!jum ep inq rnod ne e enb!u!p psse je3
etait triple ndgatif. Parmi les 6 enfants Agds de 7 a I l mois, un seul avait un titre dtkelable d'anticorps antipolio contre les trois types. Les cinq autres &aient triples n6gatifs.
Avant la t r o l r i ho Injocüon (J60). soit un mois aprds la deuxrbme dose, 36 enfants avaient un titre significatif d'anticorps neutralisants contre les trois serotypes. Les moyennes géom6triques des titres, exprimées en inverse des di lutm. sont reportées dans le tableau 1. La figure 1 montre les pourcentages cumu- latifs des titres contre chacun des trois sérotyp~ qui ont 616 observes respectivement avant la premidre dose (JO), un mois apr6s la deuxième dose (J6û) et un mois aprds la troisième injection (J90). L w titres obterrus aprds deux ou trois doses ne sont pas signifmüvment diff6rents.
DISCUSSION
La toldranco cllnlqw de ce vaccin ant ipo l i i i - tique in-6 a 6t6 satisfaisante dans w groupe de 36 noumssons. La réponse s h i o g i i oôservh such quelques commentaires.
L'antig6nicit4 6 l w h a induit une ôofmo dponm immunitaire chez tous les enfanta dana k pr'mior smestm âe la vie malgr6 la pr6sence âe taux significi. tifs d'anticorps antipoliomydlitiques vra&emMsM«mrit d'origine matemdk transmis par voie placent8im. Ce#. réponse immunitaire n'a pas 616 entmv60 par I'injacüon simultanée du vaccin umru d i 6 r i e , t6tanos et aqw- luche. Les taux d'anticorps a n t i p o i i i 6 i i i obtenus aprbs les d m premières doscw du vaccin, injwt6ea & un mois d'intervalle. n'ont pas 6té agMWhm . . ont modifiés par la troisidme injeaion un mois plu8 tord. Ce rewltat autorise d'envisager la pos8ibilit4, g r â a & d. tels vaccins inacthrb I haute antigérWt4, de féduim d. trois deux injedom k pmgmmmo da Ir primo= vaccination antipdiomyélii, préciou amntago en particulier pour Io8 progmmmba vrctinrux +u pays tropicaux et wMiopicaux rt ô88 pays d4favoris6s. D'autres 6tudm (7) ont, pu Wours, motW que les titres d'anücop obtenus rUrit plus 6levés quand I'inkrvdk antre kr doux doses est augment6 de 2 & 4 vdn I 6 mok L'obwvaüorl esî identique pour k a DT, un p u In0inr amduante pour le vaccin M(icoqwkidieux. L ' W do Cohen (7) aux Pa- mîorb m a i n d'mnhagw la primo-vaccinatbn â a mmimom pu k vaccin t6tnv8-
lent OTC polio par deux injections a 4 8 6 mois d'intervalle.
On sait, enfin, qua la vaccination de masse par le vaccin polio inactiv6 peut aboutir 1'6radication du poliovirus sauvage dans la colledivit6 et obtenir un effet de protectiori de mas80 (a herdimmunity =) si 90 % de la population enfantine est immuni* (8). Même après une seule dosa de vaccin OU en I'abSbllCb de nowelles sümulatioru antighiquos par inpctmm de rappel ou par intadon naturelk par le virus sauvage, I'immunit6 vaccinah peut sa traduire par la persistance tr6s prolong60 d'un taux décalable d'anticorps. ou par une protadon li6a P la m6moim immunitaire (9). Cette n o t h doriiw une r6pama au moins sphlative la questioci de k bng6vit6 dm titras d'anticorps obtenus apràa 2 ou 3injacüons. Rien na permet a pmri de p m w q w k dmanena da I'immunit6 humorale sera moiridm quo calk qui &ait o ~ h avec les vaccins antédeun, su# rapFnl anüg6nique, vaccinal ou acci- denW par k poliovifus a t t M ou par le poliovirus SUNagC II appamil ainai qw k produdion et la diffusion d'un
v& uiogol . ' inacbV6 I haut pouvoir antqé- nique a( m ~ f a c b w de simplification des pmgmnwa do primovrccinrtkri dm jewm enfants. A in^ da pwytiqw s'ajoute ia possibiii6 d ' h d h t h du virus pdiomy6i iw au sein d'une popukooii où k ~~ de la protodbn vaccinaie est stmmmmt Wb.
!je&munity Following Vaccination in Infants by an Inactivated Poliovirus occ ci ne Prtpared on Vem CeU
a a ~.mtr , G. B-, c xa-t, F. VI- rad M. RMmlratni!
Fmm the &Yi de M l d t d Hdpitol G. de Ctachrville fowi. F- I ' f ~ t { ~ l Naliond dr %nt( de I'f~fonr*
lLnQ l ù n w and l'Institut M a i m a Lyon, F m w
An inrctivated polioviw vaccine prrpurd from culnrrrr of Vao ce& h u km testeâ on 61 infants fmm twa to II moncbs of q e (man 4.3 rnoaths) for tolerinœ and serologic potency. Three d o l a of vaccine wem gim one moath .put u the lunc timc that diphtheria-t~~~~wpmuuis vaccine w u injmcd u uiocha body site PoiioWuL neutmiizin8 rntibody t i t m w m masurcd kkn the fint a d third injatiooc rnd one month aftcr uch. The titer w u considad porithir wbra tbs dilution wu 31%. The tolennce h u b e a 8006 -oc infrnu wcrr for mhgk cf- ail haâ significanr mlogic rapowr alter OrO injoaiom of POUO vlCCiD4 OI the titer of m a t c d l y t d a e û rntibodia Won the immunitukrir Tbe thid injcc- tion did noc significutly in- rhr rntiboây tiw obrand rfta tho f ' t w dosa
It has bten known for 20 yun that antibodta of high qudity c m be induced with inactivated p o b v inu vaccine (IPY). New dewlopmenu in the rccb- nology of vaccine prcpuuion have brou* qxc- cations of an impnyvement in the q d t y of nc- cina accornpuried by grut rcductioa in thcir cous. This clinid triai wu inteadai to test both the tolenncc of a new IPV prrp.rrd on Vem ceilr anâ its serologic e f fdvcnus in youn~ infanu,
Mrtuiib rad Met-
Vaccin& The I W uscd wu prrpuad from the t h m typa of poliovinrr; v a a b mr producd by culture on Vem ceils in a rnhmnier fyncnr on an industriol scdc ~ p t i o i i r of poiiovinu ruriar, ce11 cultun, and mctâods of purifiution .ad inrc- civarion have ben pubUeâ drcwhm (1-3). The ancigcaic coircnmdoa of ercti &se of w c h vas exprrUdd as Ihndgm du-44 8, and 32 UNU for pdiovinrr typ& 1.2, rad 3, respectiveiy (41.
&tien& 'Ibr fm p u t of this ongoin8 virl comprited 61 iahatr, bon and g&is from two to II month of a= the mcra age wrr 4.3 months Tbenty-fiw childm mrr vaccinated in ninir, iùnisia (B H.) anci 3 6 in Toun, France (B G).
Pmtocoi Thm dose of I W mre i n j d iar
Infonned coavat wu obuiaod from tiw pucw of th mimu
Pleucrddrru~rca~fareprinutoûr. BGnW1,Savkr le PCdiatric Hdpiul a dc Clocùcviiia 49 W. &Mpr, 37 O ioun ceda Fnnce
at onc-moath imavrlr At the tune timc, the chil- d m rrceived an injection of AlunlAIlrrbed diph- t h e r i 8 4 e t a a ~ u i r (m) vaccine (Institut Mtiicux, Lyon, Fnacc) u motha body site Thm blood umpia mrr takw from erch infant: the Tint, befote vsdnaioa; the second, beforc the third injedon, to detemine the p d e n c e and quandty of rntibody afte the fint two doser; and the thlld, 30 â8ys lUrr to de tcdae the e f f ~ of the thM dose on rntibody pmrlence and citer.
W o g & pr#rbun. Saum titen of neutraiiz- in# ratibody wae masurrd by seriai dilutioas. in- cubrtcd for 3 hr u 37 C and then ovemight u 4 C 100 TC1Dw of M&o~w, MET,, uid S a u W ruiiar of poliavinu cultivated on Hep2 c& A refcrro# senun from the Worid Heath Otpnintioa containing type-specific poliovirus aatibody mr iacludai in u c h neuulliution tut. The Ievd of neutmkiq rntibody wu considerrd positive whcn iu &procal dilution w s 34.
-eut of v&e tolemntx Clinid tolerance to the vrccinc w u cvlluted by determina- tioa of local si= u the site of injection and sys- ternic ruaions durb rutsequent dap.
?olarmcr fu tht .vrx&u Amon8 the 61 infants who &wd r toul of 183 dorer, m observed s u locaiki m o u s a! the site of injection of polio vacciac; t h of th- wec erythemacoui, and thrcc wm tmi to ry induratioru. Thm infants had low-grade f m for 12-48 hr following the
\
Belore cm IPV 2 dom 3 dosa
1 8 3% 572 2 l 5 156 353 3 a 353 604
NOTE. Geomaric mana of oômved titen are apraKd u reciproul dilutionr.
fint, second, and third doses. One infant had anonxia aftcr the fint injection, and one otha had rhinopharyngitis and diarrhea after the third injection. Whether thae systemic rcactions w m produced by IPV or by concurrent MP vaccination is diffxult to assus.
Setwlogic mponrc Thirty-six infanu (from the study in Tours) wem avlilable for estimation of the serologic rrsponse At the s u n of the irnmuni- zation program, 30 of these infanu werc two to six months old; 2S (83%) had detexable leeh of neu- tralizing antibodia aglinst type 1 vinu; 26 (86%) had antibodia against type 2: anà 22 (72%). against type 3. One of the six infaau in the sevca to LI month-ale m u p haâ detecable antibodia against al1 t h m types of polionnu One rnonth after the fint two d o w of the vaccine, ail of the 36 infants had signifiant levcis of ncutrPI'ing antibodia against the t h m serotyper of poüo- virus. The geometric muns of the titar (in &p rocal dilutions) obrcrvcd are rrportai in tabk 1.
Flgm 1. sedogic rrrpoase for erch of thru scmtypa of patbvintc in 35 infuro. Rapoare u aprrued u cumu- lrtiw paccnuga of neutraliting uitibody.
SU infanu had no decccuble specific antibodics a&abt w of the t h m serocypes u the suin of the study. Thrœ additionai infants w«c doubly-nega- tivc, ir , had 8 low aatibody tita against type 1 (oee infant) or type 2 (tm, infants) virus. AU of
Ti& 2. Scrologk mpoavr f o m d d tâird âo6a of haivusd poliovinu vaaine (IPV) in infants having no or low l e d a of uuiôoây agaiaa poüoWur typa 1, 2, and 3.
Sadodc- for iiidk.rl krdodc rrr~oaw to iadkueâ POüOYlrPI type afta 1PV
Age of infant beram IPV 2Qlcr 3 dosa
(montlu) I 2 3 I 2 3 I 2 3
2 16 <4 <4 192 3512 3512 3512 3512 3512 4 c4 16 <4 U,1% 1.536 6.144 S <4 <4 <4 2.048 1,536 1 ,ou 8.192 4.096 . 3.072
. ' 6 <4 16 <4 3.072 5 12 1,536 1.336 256 1,530 7 <4 <4 ~4 IM l a i n 512 512 512 8 <4 <4 <4 1.024 JI2 fa8 384 JI2 2% 9 <4 <4 <4 384 2S6 3512 384 384 384
10 <4 <4 <4 2,048 768 2.048 1,J% 1.536 7b8 I I <4 <4 <4 1.536 768 2% SI2 384 1.536
NOTE. Ceornecric merar of obsaved atm ur ex- u ncipIod dilutham.
thes nine infants showcd a significant serolodc mpom lfta two and thm dosa of vaccine (cab- 2).
The lerch of serologic mporue for each of the thm semtypes arc nponed in figure 1 u cumuh- cive percentaga obKNed beforc the fint injection and aflm the second and third dosu of vaccine No signifiant diffmnce was observed between the titen after the second and third dosa.
The prrliminory mults of thh clinid triai in infants r h d thu IPV pcepucd by cultutes of V m ceih on m i c d n w u mU tolentai. tu potency WPJ detennined on 36 infants, 30 of whom wwe youngu than s u months 016 AU of the vaccines had signifiant mlogic raponsa aftcr two doser of IPV injccted one month rput This mpow bore no rehtioo to the l m l of m~tcrnrlly tnnr- mitted spccific antibodia af the s u r t of the im- muniution procedure The thirû injection did not
significantly incruse the Id of antibodia ob- tain4 afta the fint two monthly injmions for any of the thm serologic typer
1. Mon- BI, Fin(n 8 Niolu AJ. The IirleKJe Eulti- ntioa of MRû c& in mbxanier niltun for v i w ncQiii plroduclioo: p d h a u y multa for killed gobe virui nccior OI* Bld Sund 1%l;ff:JJ44
2. Moa- W. F- 8 Viaceut-Faiqwt JC. Indusrriai sah pioducdoo of Wntd pohmmne prepurd by cuitun of YERO cdb oa mia#uria. Prrgriat p c e m r d Pt tb IntaPldoarl SympoSiulll oa ~ V r l i t i a contrd. Wuhùum, DC: Pan Awrian H U Orluuuuos Murb 1447, 1983
3. V a a w ~ d ~ L , V a n S u P t Q H ~ C A . C o h e a H . N c w rpporchtattnpodunioaofcoocio<ntcdUldpuriried iowdrudpobradnbiridtiurcuftunvwQaaDcv Bbl S(iod l r n I : U 9 U
4. s.Ü 1, SmœU P. Vas Whil AL. W i a k h u K. VUI ~ Q A i i r l g i a ~ d i n v t i v u r d p d i a v i w n c - cinrfaaniaroa8-amodomrrpmcp AnnClin Ra 19Q142m-42
T A B U L A T E D S E R O L O G I C A L
D A T A
L I .
PERCEATAGE OF SUBJECTS WITH ANTIBODIES&1/4 AFTER 2 AND 3 COSES OF VACCIilE 1
- TABLE 1 -
- TABLE 3 -
100 b (30/30)
100 a (36/36)
1 .
2
3
1
2
3
TABLE 4
n = 36
TABLE 5
572
Y, vi
- 0 8 8 .d 4 .CI 4 J U U U U a al 0 c 'ri 'q 'CI E C U .d .rl U
(d
aJ L L L a J a J 0 C> cl '4 " - ' + a J m m a
d i J b .z .% .% U C C y e-4 -4 cP > N m
1 . - . - - _ Gefore vaccination - Af t e r 2 injections
- - - - .If t e r 3 injections
. $ 8
\ 8
. - 3 - -
I I . . a n ;Xgb &( GY 5 9 1 1 A O W II% b u f 30)2 4096 d*9'
LeVel ot antibodies i n inverse of d i lu t ions
CUMULATED PERCENTAGES OF THE DISTRIBUTIOPi OF k i i T 1 - I i
BODIES AFTER 2 DOSES AMD AFTER 3 SES n~ VACCINF l TABLE 6
Level o f ant ibodies inverse o f seroneutral i sat ion
Level o f ant ibodies inverse o f seroneutra l isa t inn
)Y 8
b 16
>, 32 > 64
b 128
>, 256
>/ 512
1024
), .2048
>, 4096
.>/ 8192
Percentages
A f t e r 2 doses 1 A f t e r 3 doses
Percentaqes . A f t e r 2 doses
100 % (36/36)
97,2 % (35/36)
94,4 % (34/36)
91,6 % (33/36)
86,l % (31/36)
80,s % (29/36)
v RESULTS OF VACCINATIOII AFTER 2 AIX 3 DOSES
. I N CHILDRFN TRIPLE AND DOUBLE rJEGbTIvF BEFORE VACC1I:ATION b L
TABLE 7
Before vaccinat ion , I . 35 !
!
A f te r 2 i n j ec t i ons i J S O I o 1 O 1 1 35
Ch i l d reno f 7months Il
/ ~ h i l d r e n of 10 ncnths l ;
1 Chi ldren o f 6 months
1 C h i l d r e n u f Snionths 1 11
I Chiiciren o f 9 nanths
: Chi ldren o f 2 months , 1
Af te r 2 aoses o f vaccine
Before vaccination
o f vaccine !
1 4 4 1 4 4 l
2S6
i Chi ldren o f 8 month. 1 4 4 ( 4 / C 4 1 10241 i l 2 20481 384
Neyative 3 types
i 1 I
512 1
1 5 3 6 1 1.361 256 I
768
512
1136
128
11 4 L 4 c 4 ! I 384 / 6 I
l I
1 6 i < 4 / < 4 i g t i I I I
2048
3072
4 : C 4 L 4 2048 1 /1 i t
16 i 4 :
1 2 384 / 181 / 384 i I
h s l t >,slt 1 ) / s i2 i l II
2512
Ciinical documentation
I N D I V I D U A L D A T A
TABLE 6 (con t . )
ITYPE3( - Level o f antibodies inverse o f seroneutral i sation
8
16
32
64
INACTIVATED POLlOMYELlTlS VACCINE A / 059 / IVB1 / 07.03 / 01 .O

aventis pasteur sa inactivated pollomyelltls vaccine a 1

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