Clinical and epidemiological evaluation of

Transcription

1 Clinicl nd epidemiologicl evlution of live, cold-dpted influenz vccine for yer-olds L.G. Rudenko,1 N.I. Lonsky,2 A.I. Klimov,3 R.I. Vsiliev,4 & A. Rmirez5 Reported is study of live, cold-dpted (CA) ressortnt mono-, di-, nd trivlent influenz type A nd B vccines in series of controlled clinicl nd epidemiologicl investigtions involving nerly 13 children ged 3-15 yers. The results of clinicl, immunologicl, nd morbidity investigtions of the vccinees nd control group over 6-months' follow-up indicted tht the vccines were completely ttenuted by the children. Trnsient febrile rections occurred in < 1% of the children fter vccintion, including double seronegtive individuls with low ntibody titres. The type A reisoltes exmined were geneticlly stble. The ressortnts did not suppress ech other fter simultneous inocultion of children nd stimulted ntibody response to influenz virus strins Al, A3, nd B. The incidence of influenz-like diseses ws pproximtely 3-4% lower mong the vccinted group thn mong the control group. The study demonstrtes, for the first time, the efficcy of CA vccine ginst infections cused by influenz B virus. Introduction In recent yers gret progress ws mde in the development of live, ttenuted influenz vccines. Gretest ttention hs been given to the development of cold-dpted (CA), ttenuted ressortnt vccines, which re widely used in the Russin Federtion for the immuniztion of children. The ressortnt CA serotype A vccines, developed t the Virology Deprtment of the Institute of Experimentl Medicine, St. Petersburg, nd intended for the vccintion of children, use the donor strin A/Leningrd/134/47/57 (H2N2). This strin ws prepred fter 47 pssges t 25 C nd hs muttions in the PB2, PB, PA, NP, M2 nd NS2 genes (1). Ressortnt strins for use s vccines contin not less thn five genes from the CA donor strin tht code for nonglycosylted proteins nd include ll the genes with is muttions nd genes tht code for the HA nd NA genes of the wild-type I Hed, Lbortory of Immunology nd Prophylxis, Virus Infections, Deprtment of Virology, Institute of Experimentl Medicine, Acdemicin Pvlov 12, St. Petersburg , Russin Federtion. Requests for reprints should be sent to this uthor. 2 Hed, Lbortory of Influenz, Stte Control Institute, Moscow, Russin Federtion. 3 Hed, RNA Viruses Lbortory, Institute for Virl Preprtion, Moscow, Russin Federtion. 4 Senior Scientist, Institute of Influenz, St. Petersburg, Russin Federtion. 5 Hed, Lbortory of Influenz, Ntionl Center of Biotechnology, Hvn, Cub. Reprint No epidemic viruses (2). The sme principle ws used to obtin influenz B virus ressortnts using the CA donor strin B/USSRI69/6. Before the vccines could be pproved for generl use, series of controlled clinicl nd epidemiologicl investigtions were crried out to study ny rections s well s the immunologicl nd protective responses to them in children nd in vrious towns of the former USSR s well s in Hvn, Cub (3). The results of these studies re reported here. Mterils nd methods Study popultion, study design nd vccines Evlution studies were crried out in four stges using the following commercilly vilble live influenz vccines: monovlent type A vccine; divlent vccine (type A (HlNl) nd (H2N2)); divlent vccine (type A (HlNl) nd type B); trivlent vccine (type A (HlNl), type A (H3N2) nd type B). A smple of children ged 3-15 yers from schools nd kindergrtens in St. Petersburg, Kliningrd, Alm- At (now Almty), nd Hvn ws vccinted. A totl of children prticipted in the study, s shown in Tble 1. Before the children were vccinted, their prents were dvised bout ech study nd their consent ws required before ny child ws enrolled. The children selected hd no contrindictions to vccintion nd were chosen from previously prepred school nd kindergrten enrolment lists. Children from ech school or kinder- Bulletin of the World Helth Orgniztion, 1996, 74 (1): Word Helth Orgniztion

2 L.G. Rudenko et l. Tble 1: Scheme for the clinicl nd epidemiologicl investigtions of live, cold-dpted influenz vccine Type of Children's No. of Plce of study, yer vccine ge (yers) vccinees Kliningrd, 1986 A(H1 N1) Alm-At, 1987 A(H1Ni) + A(H3N2) Alm-At, 1989 A(H1N1) + A(H3N2) Hvn, 199 A(H1N1) + B Hvn, 1991 A(H1N1) + A(H3N2) + B Totl Vccine grten were rndomly divided into groups to receive either influenz vccine or plcebo. The vccine or plcebo (physiologicl solution) ws dministered intrnslly using spry device; two doses were given (totl volume.5 ml) t n intervl of dys between doses. Clinicl nd lbortory studies Groups of 1 children who hd received vccine or plcebo were exmined cliniclly ech dy for 7 dys by peditricins, who recorded their tempertures nd exmined their skin, eyes nd nsophrynx. In order to determine whether the vccine ws innocuous, we crried out hemtologicl (full clinicl blood nlysis, including counts for thrombocytes nd lymphocytes), biochemicl (estimtes of serum C-rective protein, s well s protein frctions, nd neurminic cid nd blood ure levels), nd urine nlyses on 2 children from ech group s follows: before vccintion; 3 dys fter the first dose; 1 month fter the first dose; 3 dys fter the second dose; nd 1 month fter the second dose. The IgE concentrtion in the blood serum of children ws determined using rdioimmunologicl method (Phdebs test) in order to investigte ny llergic rections. Lymphocyte function ws mesured using n ntigen-conditioned blst-trnsformtion. Hemgglutinin-inhibition (HI) tests were crried out to identify ny chnges in ntibody titre. Tests for vccine immunogenicity were performed using pired smples collected from subgroups who hd been immunized before the min vccintion progrmme begn. The ntigens used were those contined in the vccine. Stndrd methods for HI tests were used, including tretment of serum specimens with receptor-destroying enzymes (4). Epidemiologicl methods were lso used to estimte the sfety of the vccines, bsed on the nlysis of somtic nd infectious diseses (other thn influenz nd cute respirtory diseses) mong the vccinted nd unvccinted children up to 6 months fter the immuniztions occurred. Report of IUIS/WHO working group: use nd buse of lbortory tests in clinicl immunology. Criticl considertion of eight widely used dignostic procedures. WHO unpublished document, WHO Bulletin OMS. Vol

3 Evlution of live, cold-dpted influenz vccine Surveillnce of influenz outbrek nd dt collection Strting in mid-october, nurse in ech prticipting school nd kindergrten begn to record detils of cute respirtory diseses on medicl certifictes. A series of specific dignoses were used. When cute respirtory disese incresed, virologicl surveillnce (pre- nd post-illness blood nd nsl swbs) ws strted to identify influenz viruses. The effectiveness of the vccines ws estimted by compring the incidences of influenz nd cute respirtory diseses with those mong the plcebo group, tking into ccount clinicl dignoses mde on children vccinted during influenz epidemics. These dt were used to clculte the index nd coefficient of effectiveness; 95% confidence intervls were lso determined. Results nd discussion Sfety Clinicl exmintion of the children who received monovlent, di-, or trivlent vccines indicted tht they were well tolerted nd tht there were no serious rections. Where rections did occur, their incidence ws low nd the rectogenicity index ws <.8. Most rections consisted of minor fever, which ppered 2-4 dys fter vccintion nd ws usully of 1-2 dys' durtion. No rise in systemic ctrrhl or nsophryngel rections ws noted in vccinted children, reltive to those mong the plcebo group. Children who were vccinted in three successive yers with live ttenuted influenz vccines were followed up closely. As shown in Tble 2, no serious rections occurred over the 3-yer follow-up period. The incidence of upper respirtory trct, ctrrhl, nd systemic rections ws no greter mong the children vccinted in three successive yers, compred with children who were vccinted only once. The low vccine rectogenicity ws lso confirmed independently by polyclinic physicins who were involved in the study. Children who received influenz vccine did not suffer ny more frequently from diseses thn those who received plcebo; the rectogenicity index ws 4.% for children who received vccine nd 7.3% for those who received plcebo. In ddition to clinicl exmintions, the results of lbortory tests reveled no hemtologicl bnormlities mong children who received vccines compred with those who received plcebo. In rre instnces where bnormlities were detected, repet mesurements were lwys norml. Biochemicl tests reveled the presence of C- rective protein in two vccinted children nd two children who received plcebo. Anlysis of serum lbumin levels in ll the groups of children indicted smll but significnt increses in the levels of 1 nd C2 globulins nd flls t different times of the study. However, the differences were not significnt between the vccinted nd plcebo groups. In ddition, the observed chnge vried gretly mong individul children nd could not be regrded s stble chrcteristic. The ure, neurminic cid nd lnine-minotrnsferse concentrtions in serum Tble 2: Frequency of febrile rections mong the study children who received live, cold-dpted influenz vccine or plcebo in three successive yers Annul Children's No. of febrile rections: immuniztion ge Preprtion Rectogenicity perio (yers) receive n C C 38.6 C index First 3-6 Vccine (8.4) 2 (1.54) (8.3) 1 (.76).78 Vccine (5.4) 1 (.6) (9.5).6 Second 3-6 Vccine (15.4) 5 (1.) Vccine (15.7) 9 (1.5) 3-6 Vccine 68 7 (1.3) 1 (1.5) Third 61 4 (6.6) 1 (1.6) 2 (3.3) Vccine 48 7 (14.6) 49 5 (1.2) 1 (2.) Figures in prentheses re percentges. WHO Bulletin OMS. Vol

4 L.G. Rudenko et l. smples were constnt during the entire period of the study, indicting tht the vccine hd no detectble effects on heptic or renl function. Urine tests were crried out on the children t the sme time s the blood exmintions, nd the results gin were norml. Occsionlly fter vccintion there were trces of protein nd single leukocytes present but their incidence in vccinted groups ws identicl to tht of the plcebo group. These bnormlities lwys returned to norml fter retesting. Humorl responses to the following other ntigens were lso determined serologiclly during the study: prinfluenz viruses tht were not present in the vccine; nd IgM nd IgA in ser nd nsl wshings. No decline in titres to prinfluenz viruses occurred in children dministered mono- or divlent vccine. Of 12 children of preschool ge who received monovlent influenz A vccine, six exhibited incresed ntibodies to prinfluenz viruses, which were probbly cused by intercurrent infections. Also, there were no significnt chnges in the immunoglobulin concentrtions of serum nd nsl wshings. There ws no evidence of ny overll decline in the locl or generl immune responsiveness of children following dministrtion of the live, ttenuted influenz vccines. To investigte ny llergies induced in the children by the vccines, we determined the ntibody levels to chicken embryo protein in both the vccinted nd unvccinted children, since chicken embryos were used to grow the vccine viruses. No chnges were detected for children who received mono-, di-, or trivlent vccines or for those who received plcebo. Increses in the levels of ntibodies to chicken proteins vried from 25% to 39%; the proportion of children who exhibited increses in their level of ntibodies to the vccine vried from 56.5% to 66.7%. A significnt increse in ntibody to chicken embryo proteins occurred 28 dys fter immuniztion mong children who received divlent vccine. Previous studies hve shown tht such n increse is of short durtion nd tht subsequently no child exhibited llergic rections following consumption of eggs or egg products. Further evidence for the bsence of llergic rections to immuniztion ws provided by estimtes of the IgE levels of children who received divlent vccine or plcebo. The verge levels of IgE in the ser exmined were in ccordnce with the norml physiologicl rnge (Tble 3). Virus, non-specific, cell-medited immune responses to immuniztion were mesured by blst trnsformtion (Tble 4). Specific rises in blst trnsformtion ctivity occurred on the 7th nd 21st dys fter the initil vccintion nd on the 21st dy fter revccintion. To study the effect of the influenz vccine on the functionl ctivity of polymorphonucler leukocytes, we mesured the following: the migrtory ctivity of stimulted leukocytes in cpillry tubes; the cpcity of such cells to bsorb tetrzolium slts; nd the fermenttive cpcity of ctionic lysosoml proteins in stimulted leukocytes. All these studies were crried out on blood collected from preschool-ge children who hd been immunized with the divlent vccine or plcebo. On the 7th dy fter vccintion, inhibition of leukocyte migrtion ws the sme mong vccinted nd unvccinted children. In ddition, diformzn stining indicted tht the cell-count of immunized children hd incresed by 17-24% compred with 1-15% in helthy unimmunized controls. These prmeters remined the sme 28 dys fter immuniztion. Also there were no significnt chnges in the concentrtion of ctionic lysosoml proteins on the 7th or 28th dys fter immuniztion. The dt in Tble 5 show tht the incidences of common diseses mong the vccinted children were comprble with those who received plcebo. Tble 3: Concentrtion of IgE in the ser of children vccinted with live, cold-dpted influenz vccines Concentrtion of IgE (IU) Age of Before 28 dys fter Vccine children (yers) n vccintion vccintion Monovlent ± 35.9 A(H1N1) ± ± 27.9 Bivlent ± 62.7 A(H1N1) + A(H3N2) ± ± ± WHO Bulletin OMS. Vol

5 Evlution of live, cold-dpted influenz vccine Tble 4: Effect on the functionl ction of lymphocytes of immunizing preschool children with live, cold-dpted influenz vccines Stimultion index for period: Antigen Preprtion A B C D Vccine.86 t ± ± ±.29 A(H1N1) 1.27 ± ± ± ±.12 A(H3N2) Vccine 1.6 ± ± ± ± ± ± ±.5 A = before vccintion; B = 7 dys fter vccintion; C = 21 dys fter vccintion; nd D = 7 dys fter revccintion. Tble 5: Incidence of somtic nd infectious diseses mong children up to 6 months fter immuniztion with live, cold-dpted influenz vccines First yer of vccintion: Second yer of vccintion: No. in vccine No. in plcebo No. in vccine No. in plcebo group group group group Disese (n = 1 224) (n = 1 191) (n = 22) (n = 195) Tonsillitis 8 (.7)b 2 (1.7) 1 (.45) Phlegmon, bscess () 1 (.1) Furuncles 1 (.1) 1 (.1) Acute intestinl infections 4 (.3) 3 (.3) 1 (.45) Hert diseses 1 (.1) Pneumoni 8 (.6) 9 (.7) Bronchitis 49 (4.) 66 (5.5) 5 (2.3) 6 (3.1) Allergy 11 (1.) 12 (1.) 2 (.9) 1 (.5) Phryngitis, lryngitis 38 (3.1) 46 (3.9) 5 (2.3) 4 (2.1) Kidney diseses 3 (.2) 1 (.1) 2 (.9) Diseses of the nervous system 1 (.1) Conjunctivitis 6 (.5) 6 (.5) 2 (.9) 1 (.5) Other diseses 12 (1.) 14 (1.2) 12 (5.5) 16 (8.2) Totl 151 (12.3) 184 (15.4) 3 (13.6) 28 (14.4) Other thn cute respirtory diseses. b Figures in prentheses re percentges. Follow-up of the children for 6 months fter vccintion showed tht the indices of those diseses were the sme for both observtion groups. The incidences of liver nd kidney diseses nd of cses of pneumoni were not significntly different in the vccinted nd control groups. No llergic diseses could be detected in the vccinted children. These studies, therefore, indicte tht the vccines used were sfe nd produced no detectble side-effects. Cpcity of the vccine viruses to spred Nsl swbs were obtined from 22 vccinted children nd 18 children who hd received plcebo on the first, second, third, seventh, nd eighth dy fter the first dose. A totl of 24 swbs were lso obtined on dys 2 nd 3 fter the second dose. All children were ttending kindergrten. Altogether, 11 strins were isolted from the 22 children who hd received live vccine. The vccine virus ws not isolted from ny children in the plcebo group, indicting tht it hd not spred to susceptible contcts. Genetic stbility of the vccine strins A totl of 8 isoltes from vccinted children immunized with different CA ressortnt vccines were studied; 52 virus isoltes were obtined 1-4 dys WHO Bulletin OMS. Vol

6 L.G. Rudenko et l. fter vccintion, 16 isoltes fter 5-7 dys, nd 12 isoltes fter 8-9 dys. All the isolted viruses hd identicl surfce ntigens to those present in the strins used to prepre monovlent vccines, nd ll the isoltes retined both the CA nd TS phenotypes. Recombintion nlysis showed tht the number of TS muttions in the virus isoltes vried ccording to the time fter vccintion. Viruses isolted from the children in the first few dys fter immuniztion retined the number of TS muttions tht were present in the originl vccine viruses. To obtin more precise estimte of the genetic stbility of influenz A(H1N1) nd A(H3N2) ressortnts, we used the polymerse chin rection (PCR) to study the muttions in ll the nonsurfce ntigen genes of 11 isoltes obtined from children on dys 2, 5, nd 8 fter vccintion. Amplifiction ws crried out on the c-dna copies of those prts of the RNA genome contining muttions ssocited with ttenution. The results showed tht ll muttions ssocited with ttenution were retined fter growth of the vccine ressortnt in the respirtory trct of children nd subsequent growth in chicken embryos. The vccine ressortnts therefore, pper to be geneticlly highly stble. Antigenic ctivity Children immunized with the live ttenuted influenz vccines hd dequte titres of hemgglutintion-inhibition ntibody (Tble 6). The immunogenicity of the HlNl nd H3N2 components in tri- nd monovlent vccines were the sme (seroconversions: % for H1N1; % for H3N2). The immunogenicity of monovlent influenz B vccine ws slightly higher thn for the influenz B component of trivlent vccine (54.5% versus 43.7%). Immuniztion of children using live, ttenuted influenz vccine therefore induced stisfctory protective levels of ntibody when the component viruses were dministered s prt of mono-, di-, or trivlent preprtion. Prophylctic efficcy of vccintion Influenz vccine efficcy ws studied over three epidemic sesons in Alm-At. During the seson divlent vccine ws used contining the HlNl influenz virus surfce ntigens of the A/Brzil/1/79 strin nd the H3N2 surfce ntigens of the A/Philippines/1/82 strin. The study ws crried out during n epidemic of HlNl virus A/Tiwn/1/86 strin; the epidemic begn on 17 November 1986 nd continued for 5 weeks until 21 December The mximum bsenteeism mong the school nd preschool children occurred between 24 November nd 7 December The epidemic commenced unexpectedly erly in the seson, coinciding with the time when the second dose of vccine ws dministered. The incidence of influenz nd cute respirtory dis- Tble 6: Immunogenicity of live, ttenuted mono- nd polyvlent cold-dpted influenz vccines in children ged 5-14 yers with initil titres of hemgglutintion-inhibition (HI) ntibody <1:2 Geometric men HI No. of children titre (GMT) with nti- No. of No. who Rtio body titres Antigen Preprtion children seroconverted II of GMTs >1:4 Monovlent (61.)b (51.2) A(H1 N1) A/Tiwn/i 1/86 Polyvlent (63.3) (71.4) (H1N1) vccine 45 2 (4.4) (2.2) Monovlent (73.3) (77.8) A(H3N2) A/Zkhrptie/354/89 Polyvlent 43 3 (69.8) (83.7) (H3N2) vccine 37 2 (5.4) (1.8) Monovlent (54.5) (77.3) B B/USSR/3/87 Polyvlent (43.7) (68.7) vccine 25 2 (8.) (2.) = initil titre; II = titre 3 weeks fter vccintion. 82 WHO Bulletin OMS. Vol

7 Evlution of live, cold-dpted influenz vccine Tble 7: Efficcy of live, cold-dpted influenz vccine mong children ged 3-15 yers, Alm-At Yers Type of vccine A(H1N1) + A(H3N2) A(H1N1) + A(H3N2) A(H1N1) + A(H3N2) A(H1N1) + A(H3N2) Figures in prentheses re percentges. Children's ge (yers) No. of vccinees No. of ptients with influenzlike diseses (24.) (33.9) 37 (15.9) 513 (22.2) 254 (31.3) 3564 (47.4) 469 (18.9) 7296 (29.9) Index (coefficient) of efficcy 1.4 (28.6) 1.4 (28.6) 1.6 (36.3) 1.6 (36.3) ese mong the 3-6-yer-old vccines ws 24.% nd 33.9% mong those receiving plcebo. The prophylctic efficcy index for the vccine ws 1.41 (lower limit, 1.4). The sme dt were obtined for yer-olds (Tble 7). A second vccintion study ws crried out in Alm-At during the seson where n epidemic ws cused by both influenz A/Tiwn/1/86 nd B/Victori/1/87. This epidemic ws chrcterized by verge rtes of illness, nd ffected mostly -14-yer-olds mong whom the ttck rte ws 6.%. The epidemic begn on 26 Mrch 1989 nd continued for 9 weeks, with the pek incidence occurring during the 4th week fter onset. Although the epidemic ws cused by two viruses, nd the vccine did not contin influenz B virus; good rtes of protection were chieved for both preschool nd school children (see Tble 7). Finlly the prophylctic efficcy of three monovlent nd three trivlent influenz vccines in yer-old children in Hvn, Cub, ws studied. Ressortnt CA vccine strins were prepred with the surfce ntigens of A/Tiwn/1/86 (HlNi) strin, A/Zkrptie/354/89 (H3N2) strin, vrint of A/Shnghi/1/89 nd B/USSR/3/87 strin, nd vrint of the B/Victori/3/87 strin. Children were immunized in November 199 nd study to record clinicl cses of influenz nd of cute respirtory disese ws crried out from 1 December 199 to 31 December Episodes of cute respirtory disese occurred in Cub in Jnury-Februry nd My-June 1991; third episode begn in September 1991, reched its mximum in October-November, nd continued until the end of Cses of influenz nd of cute respirtory disese were frequent nd some children experienced severl episodes of illness. These periods of cute respirtory disese WHO Bulletin OMS. Vol were chrcterized by the simultneous ppernce of more thn one influenz serotype in the test popultion. Qurterly serologicl records showed tht the incidence of seroconversion to influenz A H3N2 nd HlNl serotypes in the period Jnury-Mrch 1991 ws 22.7% nd 2.4%, respectively; for April- June, 1.% nd 15.1%, respectively; for July-September 22.8% nd 11.4%, respectively; nd for October-December, 5.3% nd 3.%, respectively. Therefore, prt from the period July-September, the incidence of both serotypes of influenz virus A ws similr. Over the corresponding periods the incidence of influenz B virus ws 4.5%, 2.5%, %, nd 1.7%. Monthly nlysis of the incidence of influenz nd of cute respirtory disese mong vccinted children ged 5-14 yers (Tble 8) showed tht the number of children who were ill in the vccinted group ws lower thn tht in the control group nd tht the totl number of diseses in the vccinted group ws lso lower thn in the plcebo group (r =.1). In the control group, the totl incidence of influenz nd cute respirtory disese ws 49.5%, while in the group dministered monovlent HlNl vccine it ws 34.2%; for the groups vccinted with monovlent influenz A(H3N2) or influenz B vccine the corresponding incidences were 32% nd 28.3%. For the trivlent vccine, the incidence of influenz nd cute respirtory diseses ws 31.5%. The coefficient of efficcy ws 31.% for A(HlN1) vccine, 35.2% for A(H3N2), 42.8% for B, nd 36.2% for trivlent vccine. The prophylctic efficcy of live, ttenuted influenz vccine, bsed on the incidence of influenz nd cute respirtory disese, therefore indictes the effectiveness of ll four vccines, used either seprtely or in combintion. In ddition, our findings demonstrte, for the first time, tht CA ressortnt 83

8 L.G. Rudenko et l. Tble 8: Epidemiologicl efficcy of live, cold-ttenuted ressortnt monond polyvlent influenz vccines for children ged 5-14 yers Totl morbidity with No. of influenz nd cute Index of Coefficient Vccine children respirtory disese efficcy of efficcy (%) A(H1N1) (34.2) A(H3N2) (32.) B (28.3) Polyvccine (31.5) (49.5) -- Figures in prentheses re percentges. vccine is effective ginst infection cused by influenz B virus. The efficcy of the live influenz vccines in the study ly in the rnge %. This is lower thn hs been reported elsewhere (5). Perhps, the differences rose becuse of n ntigenic distinction between vccine nd epidemic strins s well s di- or trivlent vccine. Vccine efficcy lso depends on the ttck rtes of influenz, which cn vry from seson to seson. Acknowledgements We thnk the stff of the Centers of Epidemiologicl Surveillnce in Kliningrd nd Alm-At for their help in orgnizing the study. Resume Evlution clinique et epidemiologique d'un vccin ntigrippl vivnt dpte u froid pour les enfnts de 3 14 ns Cet rticle rend compte d'une s6rie d'etudes cliniques et 6pidemiologiques contr6lees effectu6es sur pres de 13 enfnts de 3 15 ns et portnt sur des vccins ntigrippux types A et B,-mono-, di- et trivlents vivnts, dptes u froid et obtenus pr genie g6n6tique. Les 6tudes cliniques et immunologiques, insi que les enquetes de morbidit6 effectu6es pendnt six mois sur les enfnts vccines et sur un groupe t6moin, ont conclu une ttenution complete du vccin. Des r6ctions f6briles trnsitoires ont ete not6es chez moins de 1% des enfnts, prmi lesquels se trouvient des sujets doublement s6ron6gtifs vec des titres d'nticorps tres bs. Les souches de type A isolees pres vccintion se sont montr6es genetiquement stbles. Les vccins ne se sont ps nnul6s r6ciproquement pres inocultion simultnee et stimulient l reponse en nticorps ux souches Al, A3 et B. L'incidence des mnifesttions gripples u sein du groupe vccine 6t6 environ 3 4% plus fible que dns le groupe temoin. Cette 6tude d6montre pour l premiere fois l'efficcit6 d'un vccin dpte u froid contre les infections dues u virus de l grippe de type B. References 1. Alexndrov GI et t. Study of live recombinnt colddpted influenz bivlent vccine of type A for use in children: n epidemiologicl control tril. Vccine, 1986, 4: Klimov Al et l. Genetic stbility of cold-dpted A/ Len/137/47/57 (H2N2) influenz virus: sequence nlysis of live cold-dpted ressortnt vccine strins before nd fter repliction in children. Journl of generl virology, 1995, 76: Rudenko LG et l. Min chrcteristics of live influenz vccine for children from influenz A virus strins (Hi Ni + H3N2) used seprtely nd in combintion. Voprosy virusologii, 1989, 34: (in Russin). 4. Hrmon MW et l. Antibody response in humns to influenz virus type B host-cell-derived vrints fter vccintion with stndrd (egg-derived) vccine or nturl infection. Journl of clinicl microbiology, 1988, 26: Rudenko LG et l. Efficcy of live ttenuted nd inctivted influenz vccines in schoolchildren nd their unvccinted contcts in Novgorod, Russi, Journl of infectious diseses, 1993, 68: WHO Bulletin OMS. Vol