Acellular Pertussis Vaccines Developed in Japan and Their Application for Disease Control

Transcription

1 S264 Acellular Pertussis Vaccines Develped in Japan and Their Applicatin fr Disease Cntrl Tatsu Ayama Pediatric Departments, Kawasaki Municipal Hspital, Kawasaki, and Schl fmedicine, Kei University, Tky, Japan Acellular pertussis vaccines, cmprising mainly pertussis txin and filamentus hemagglutinin (FHA) and used successfully in Japan since 1981, were evaluated. Anti-pertussis txin antibdy respnses in children immunized with acellular pertussis vaccines were cmparable r higher than in cnvalescent-stage patients with pertussis, while thse fr anti-fha were far higher. Reactgenicity was much less than with whle cell pertussis vaccines: Fever?38 C ccurred in 2%-4% f vaccinees; there was little redness? 5 em in diameter at the vaccinatin site with the first dse but ccurred in 7%-8% f vaccinees with subsequent dses. The estimated efficacy f acellular pertussis vaccine in children ages 2-8 years was 84% (95% cnfidence interval, 71%-91%). Since vaccineinduced immunity weakens after 6-10 years, adults are nw a majr surce f pertussis transmissin. The surce f infectin was an adult in 11.2% (10/89) f cases, and the secndary attack rate was 10.3% (19/185). mmunizatin with acellular pertussis vaccines fr bth adults and children is recmmended fr disease cntrl. There is n dubt abut the efficacy f diphtheria-tetanus txid-whle cell pertussis (DTPw) vaccine in Japan; hwever, 2 fatalities ccurred amng children vaccinated with the same lt f DTPw in 1974 and The Japanese Ministry f Health and Welfare halted DTPw vaccinatin immediately after the 1975 death. DTPw vaccinatin was restarted 2 mnths later, but the participatin rate drpped frm 77.8% in 1974 t 22.1% in 1975 and 13.6% in Despite a rise in the vaccinatin rate t 41.5% in 1977 and 64.4% in 1978, the incidence f pertussis increased markedly during this perid (figure 1). The infectin caused by Brdetella pertussis is believed t have tw stages, respiratry clnizatin and txin-mediated disease, with varius txins and virulent factrs fb. pertussis invlved in these stages. t is nw clear that the prtective antigens against pertussis infectin are pertussis txin (PT), filamentus hemagglutinin (FHA), pertactin (a 69-kDa uter membrane prtein [amp]), and fimbriae (agglutingens). Hwever, because f the demand fr a new vaccine with minimal adverse reactins, the use fthe Japanese DT -acellular pertussis (DTPa) vaccine became widespread befre the pertussis antigens in the vaccine were cmpletely characterized. At the time fits intrductin, the nly efficacy requirement fr DTPa was its ptency, determined using the muse intracerebral prtectin test [1]. With the advent f imprved techniques fr antigen characterizatin, it has becme clear that the antigenic cnstituents f the Japanese DTPa vary by manufacturer, althugh all cntain at least PT and FHA antigens [2]. Reprints r crrespndence: Dr. Tatsu Ayama, c/ Pediatric Dept., Kawasaki Municipal Hspital, 12-1 Shinkawadri, Kawasaki-ku, Kawasaki-shi, 210, Japan. The Jurnal f nfectius Diseases 1996; 174(8uppl 3): by The University f Chicag. All rights reserved /96/ $01.00 The Vaccinatin Research Grup f Kei University (Diph grup) has played a leading rle in the intrductin and assessment f DTPa. Clinical trials with the vaccine and research int pertussis by the grup have evaluated adverse reactins and antibdy respnses [3], clinical vaccine efficacy, and pertussis in adults. Adverse Reactins and Antibdy Respnses t DTPa Vaccine T assess safety and antibdy respnses t DTPa, 350 healthy children ages 3 mnths t 2 years wh were based in a special residential facility were enrlled in the study. Subjects received three primary dses fdtpa at mnthly intervals and a bster dse 1 year later. Each dse had 0.5 ml f vaccine and was administered by deep subcutaneus injectin in the deltid regin. Tw batches f cmmercially available DTPa frm each f three manufacturers were used (table 1). The DTPa made by Biken and Takeda (bth Osaka, Japan) were licensed by the US Fd and Drug Administratin and are nw available fr use as a bster dse in the United States. Biken batches 11 and 17 cntained 5-6 J-lg f prtein nitrgen (PN)/mL PT and FHA but nt pertactin r fimbriae. Takeda lts 15 and 20 cntained J-lg fpn/ml PT and J-lg fpn/ml FHA and als cntained bth pertactin and fimbriae. Kitasat (Tky) lts 17 and 20 cntained J-lg f PN/mL PT and J-lg f PN/mL FHA. Their pertactin and fimbriae cntents were nt tested. All f the DTPa vaccines tested in this study cntained aluminum as an adjuvant. Adverse reactins. Adverse reactins t the DTPa vaccines were evaluated by examining patients fr systemic fever, lcal reactins at the injectin site, and serius systemic reactins. The incidence f fever 38 C within 48 h f DTP immunizatin was 2.5% (7/274) fr Biken vaccines, 4.5% (14/316) fr

2 JD 1996; 174 (Suppl 3) Acellular Pertussis Vaccines and Disease Cntrl S265,000 (/) c:: 10,000 "0 c:: Q) '0 1,000 z Start f whle-cell pertussis vaccinatin! 1960 Temprary discntinuatin f whle-cell DTP ntrductin f acellular DTP +----_ """T'" Year! Figure 1. ncidence fpertussis in Japan by ntificatins t Ministry f Health and Welfare. DTP, diphtheria-tetanus txid-pertussis vaccine. Takeda vaccines, and 2.7% (14/513) fr Kitasat vaccines. There were n statistically significant differences in fever incidence by batch r manufacturer. The verall incidence f fever 38 C was 3.2% ( ), which is much lwer than seen with whle cell vaccines. The remarkably lw incidence f febrile reactins with DTPa is prbably due t remval f the endtxin, a pyrgenic cnstituent f B. pertussis. The incidence f areas f lcal redness 5 em in diameter was negligible after the first dse and 8.9% (171190) fr the Biken vaccines, 8.3% (17/205) fr the Takeda vaccines, and 7.8% (28/358) fr the Kitasat vaccines after the secnd, third, and bster dses. The nset f lcal reactins ccurred 7 days after the first injectin and within 48 h f all ther DTP injectins. The incidence was higher after the secnd, third, and bster shts than after the first injectin fr all DTPa batches tested. All lcal reactins subsided withut sequelae within a few days. Severe lcal reactins were bserved in 4 patients but subsided within a few days withut therapy r sequelae. Several reprts indicate that lcal reactins are severe and cause either frearm swelling r blisters in 1 patient in every few hundred DTPa injectins. Althugh n serius systemic reactins were bserved, severe adverse reactins t DTPa cannt be adequately assessed in clinical fllw-up studies because the incidence is s lw. Hwever, data n severe adverse reactins are available by analyzing claims submitted t the natinal cmpensatin system fr injuries allegedly resulting frm mandatry vaccinatin [4] (table 2). Frm , when DTPw was used, f 19.8 millin dses, there were 8 severe adverse reactins with sequelae, including 3 deaths, a rate f dses. Between 1981 and 1984, when DTPa was in use, the rate decreased t 5 cases and 2 deaths in 20.4 millin dses (0.25 severe reactinsl1 0 6 dses). Althugh n fficial data n the incidence f severe reactins frm 1985 t the present are available, the incidence appears t be lwer than during Cmpensatin is usually awarded t patients with sequelae cnsidered pssibly caused by pertussis vaccine unless prven therwise. t is difficult t exclude the vaccine as a causal factr, even when ther etilgies are suspected, particularly when the adverse events ccur in clse tempral prximity t vaccinatin. Overall, there are few severe adverse reactins with DTPa. Antibdy respnses. Serlgic studies were dne fr 149 children enrlled in the study. Bld was drawn by venipuncture befre the first immunizatin and befre the bster. Bld was als btained 4 weeks after the last primary series immunizatin and the bster. Anti-PT and anti-fha antibdy titers were measured using a glass bead ELSA develped in ur labratry [5]. Agglutinin titer was measured by the micragglutinatin test using the sertype 1.3 strain; in Japan, 90% f pertussis strains islated are f this sertype [6]. Satisfactry serum gg antibdy respnses t PT and FHA were bserved after three primary dses and a bster dse f the Biken vaccine 11 [5]. The patterns f antibdy changes bserved after the ther five lts f acellular vaccines were similar. n patients with pertussis, anti-pt and anti-fha antibdies reach peak levels 6-10 weeks after disease nset. Therefre, antibdy levels in vaccinees 4 weeks after the primary vaccinatin series were cmpared with thse f pertussis patients 6- Table 1. Cntent f diphtheria-tetanus txid- acellular pertussis vaccines by manufacturer. Manufacturer, Pertussis antigen PT FHA Fimbriae Other Aluminum Diphtheria Tetanus batch n. (Jig f PN/mL) (Jig f PN/mL) (fj.g f PN/mL) (f.lg f PN/mL) (Jig f PN/mL) (mg/ml) (Lf/mL) (Lf/mL) Biken, Takeda, Kitasat, NT NT NOTE. Data are frm manufacturers and were reprted in [3]. PN, prtein nitrgen; PT, pertussis txin; FHA, filamentus hemagglutinin; NT, nt tested.

3 S266 Ayama JD 1996; 174 (Suppl 3) Table 2. Severe adverse reactins after pertussis vaccinatin. Vaccine dses in millins Severe reactins with sequelae (deaths) ncidence/n" dses (deaths) NOTE. Data are frm [4] , , whle cell acellular vaccine vaccine (3) 5 (2) 0.4 (0.15) 0.25 (0.10) 10 weeks after disease nset [3]. n vaccinees, the anti-pt antibdy respnse t DTPa was equal t r greater than thse in patients with pertussis at the cnvalescent stage (figure 2A). The anti-fha antibdy respnses were significantly higher in children vaccinated with DTPa than in pertussis patients (figure 2B). As fr antibdy respnses against fur pertussis-specific antigens, all three vaccines prduced bth anti-pt and anti-fha antibdies equivalent t r higher than thse in cnvalescentstage patients. DTP vaccines manufactured by Takeda prduced bth pertactin and fimbriae antibdies, and the Kitasat DTP vaccines prduced pertactin antibdy. The immungenicity fdtpa in children f different ages was als investigated. Anti-PT and anti-fha antibdy respnses were cmpared 4 weeks after the third dse f DTPa (Kitasat batch 17), accrding t the child's age when the first dse was given. The immungenicity fthis OTPa vaccine in children ages 3-6 mnths and 2 years did nt differ [3] (figure 3). children immunized with DTPw and DTPa did nt differ. n unimmunized children ages 2-8 years, the attack rate was 50 (58.8%) f 85, which was higher at a 1% significance level, than that in any fully immunized grup. The estimated efficacy fdtpa in children ages 2-8 years was 84% (95% cnfidence interval re], 71%-91%; table 3). Because the cntent f DTPa varies by manufacturer, the secndary attack rates fr the vaccines were calculated by manufacturer as fllws: f 8 fr Biken, 3 f 38 fr Takeda, and 1 f 17 fr Kitasat. The number f children fully immunized with each vaccine was small, s vaccine efficacies culd nt be calculated. Hwever, OTPa prduced by all three manufacturers appeared t be similarly effective. Prtectin fyung infants [8]. Data n vaccine efficacy in children 1 year ld culd nt be determined in the husehld cntact study. Frtunately, we were able t cnduct a prspective study f a pertussis utbreak in a residential facility husing 19 children 2 years ld. Ten fthe children had nt been immunized and 9 had been immunized with OTPa. Of the 10 nnimmunized children, 7 acquired labratry-cnfirmed pertussis (4-fld titer rise, psitive culture, r bth) and 6 fthe A 50.A.... T- t 'c.. t.i- :::J --.- «10 en :::J w 5 -. Clinical Efficacy f DTPa and DTPw Vaccines Prtectin f husehlds [3, 7]. Since ur knwledge f the prtective immune respnses against B. pertussis is incmplete, prf f prtectin against the disease is at present the nly acceptable measure f vaccine efficacy. Therefre, we assessed the prtective efficacy f DTPa by cmparing the secndary attack rates in husehld cntacts fchildren immunized with DTPa, DTPw, r bth and thse nt immunized. n ttal, 546 patients with pertussis wh attended Kei University Hspital and its affiliated hspitals in the Tky metrplitan area frm 1981 t the present were entered int the study. Of these 546 index cases, 247 (45.2%) were cnfirmed by culture. The husehld cntacts f each patient were surveyed in the clinic r by telephne, and symptms, vaccinatin status f all children in the husehld, and the ccurrence f any primary r secndary cases were ascertained. This survey identified 557 children wh were husehld cntacts. n fully immunized children C?<3 dses fdtp) ages 2-8 years, the secndary attack rate was 12 (9.6%) f 125 after DTPa injectin, 7 (13.5%) f 52 after DTPw, and 5 (13.5%) f 37 in thse wh received bth vaccines. The attack rates in B Biken Takeda Kitasat Patients* (n=32) (n=48) (n=69) (n=20)... t.. t 50 i T 'c :::J «en :::::i w L 5 - Biken (n=32) Takeda (n=48) Kitasat (n=69) Patients* (n:20) Figure 2. Antibdies induced by acellular diphtheria-tetanus txid - pertussis vaccine by manufacturer. A, Anti - pertussis txin antibdy. B, Anti - filamentus hemagglutinin antibdy. Cnvalescent stage.

4 JD 1996; 174 (Suppl 3) Acellular Pertussis Vaccines and Disease Cntrl S267 i: %- -.i -t- T T 1 '2:..... r ::::l <C en 10 ::J w 5 Age (mnths) Figure 3. Antibdy respnses t pertussis txin (left) and filamentus hemagglutinin (right) 4 weeks after 3 dses f acellular diphtheria- tetanus txid-pertussis vaccine. 7 develped typical symptms. Ofthe 9 immunized children, 8 became infected (cnfirmed by labratry tests), but nly develped typical symptms. Six f the 9 immunized children received their first DTP dse at age 6 mnths. Althugh n difference in the pertussis infectin rate was nted between the nnimmunized and immunized grups (7/10 vs. 8/9), the attack rate was 6 f loin nnimmunized children and 1 f 6 in immunized children wh received their first DTP immunizatin at age 3-6 mnths. This finding and the results fthe immungenicity study f DTPa by age suggest strngly that the Japanese DTPa vaccine is equally effective in children ages 3-6 mnths r 2 years. The antibdy respnses t PT after vaccinatin in the typically symptmatic case were cmparable with thse in the ther 8 immunized children (figure 4A). The PT antibdy level in the sera f 9 immunized children btained just befre the pertussis utbreak was lwest in the typically symptmatic case. The interval between the last vaccinatin and utbreak f pertussis was 25 mnths in the typically symptmatic case and 6-10 mnths in the ther 8 immunized children. Therefre, the lw PT antibdy level bserved befre the pertussis utbreak in the typical case can be explained by the lng interval (25 mnths) between vaccinatin and disease expsure. The antibdy respnses t FHA after vaccinatin and just befre the pertussis utbreak were similar t the respnses t PT (figure 4B). Neither leukcytsis nr lymphcytsis were bserved in immunized children with pertussis. mmunized children als had less severe disease than did nnimmunized children with pertussis. n this utbreak, the islatin rate f B. pertussis in the frmer was als lwer than in the latter (2/9 vs. 6/1 0). Furthermre, the develpment f symptms after expsure t pertussis ccurred later in vaccinated children than in symptmatic unvaccinated children (38 vs. 28 days in this utbreak), similar t that bserved in a Swedish trial [9]. These findings suggest that the effect f the vaccine weakens a few years after vaccinatin, althugh disease severity and lymphcytsis are still mdified in immunized children. Several grups have described a decline in whle cell vaccine-vinduced immunity [10, 11], including my grup [12], which reprted an utbreak f pertussis in highly immunized adlescents and secndary spread t their families. mmunity induced by DTPw r DTPa vaccines weakens cnsiderably 6 10 years after vaccinatin. Althugh the effect f vaccinatin may be maintained by natural expsure t the disease, the likelihd f this ccurring is very lw because f the lw incidence f pertussis. Therefre, bster immunizatins are needed t maintain the prtective effect f the vaccine. Pertussis in Adults My clleagues and surveyed 89 husehlds in which persn with culture-cnfirmed pertussis was detected [13]. n 10 husehlds (11.2%), the surce f infectin was an adult; the secndary attack rate was 19 (10.3%) f 185. Furthermre, a labratry study disclsed 17 adults with subclinical pertussis (subclinical infectin rate, 17 [25%] f 68). T cmpare pertussis in adults and children by clinical and hematlgic features, 14 adults and 50 children with culture- NOTE. Data are n.lttal r %. AC, acellular pertussis vaccine; we, whle cell pertussis vaccine; bth, immunized partially with we and partially with AC.

5 S268 Ayama JD 1996;174 (Supp3) -'c ::3 <t: Cf') ::::J w A <1 3 PT antibdies in child with pertussis symptms PT antibdies in ther children,.. ",".... ', ''" : Figure 4. 2 Years B 50 FHA antibdies in child with pertussis symptms FHA antibdies in ther children - 'c : ', ::3, Cf'), '.,,, <t: 10 ::::J w <1 Outbreak f 3 2 Outbreak f pertussis Years pertussis Changes in pertussis txin (A) and filamentus hemagglutinin (B) antibdies in immunized children. cnfinued pertussis were selected frm the 89 husehlds. Pertussis in adults was generally less severe than in children. Mst infected adults reprted shrtness fbreath and a tingling sensatin in the thrat, whereas many children with pertussis suffered cugh-induced vmiting, whp, and cyansis, which were rarely bserved in adults. Thirty-tw bld samples frm 14 adults and 120 samples frm 50 children (::::; 1 year ld) with pertussis were examined. Marked leukcytsis and lymphcytsis (leukcyte cunt ;d5,000/mm 3 ) were bserved in the children within 30 days f disease nset, but neither leukcytsis nr lymphcytsis was bserved in the adults. Pertussis used t be mainly a childhd disease, but adults are nw a majr surce fits transmissin. As the incidence f pertussis amng adults has yet t be elucidated, it is difficult t knw whether t advcate pertussis immunizatin fr all adults. Adults wh wrk in clse cntact with children (e.g., in day care centers, schls, and pediatric wards) are mre likely t cntract pertussis, and immunizatin f such individuals may be desirable fr disease cntrl. Summary Clinical trials with DTPa and research int pertussis by the Vaccinatin Research Grup f Kei University yielded the fllwing results. After vaccinatin, the incidence f fever 38 C was 2%-4%. Lcal redness 5 em in diameter was negligible after the first dse and 7%-8% after the secnd, third, and bster dses. Severe lcal reactins were seen ccasinally (incidence f 1 in every few hundred injectins). All lcal reactins subsided withut sequelae. N differences in incidences f fever r ther lcal reactins were bserved amng different vaccine lts r by vaccine manufacturer. Extraplatin f data frm the natinal cmpensatin system shwed an incidence f severe neurlgic reactins with sequelae f 0.2/1 0 6 dses f DTPa. The anti-pt antibdy respnses t the DTPa vaccines were equal t r greater and the anti-fha antibdy respnses were far higher in vaccinees than in cnvalescent patients with pertussis. Althugh there were significant differences in the antibdy respnses against pertactin and fimbriae amng vaccines frm different manufacturers, the DTPa vaccines were equally immungenic in children ages 3-6 mnths and 2 years. DTPa vaccines were as effective as DTPw vaccines with an estimated prtective efficacy f 84% in children ages 2-8 years (95% C, 71%-91%). The vaccines appeared t be equally effective in children ::::;6 mnths ld and in thse 2 years ld. N differences in the efficacies fthe vaccines frm different manufacturers were nted. n additin, DTPa did nt prevent infectin by B. pertussis but mdified the severity f disease. Althugh adult pertussis is usually unrecgnized because its clinical and labratry features differ frm thse in children, it is a significant health threat that necessitates sme diseasecntrl measures. Acknwledgments thank the pediatricians f Kawasaki Municipal Hspital and members f the Vaccinatin Research Grup, Kei University, fr assistance. References 1. Precipitated-purified pertussis vaccine: minimum requirement fr bilgical prducts. Tky: Ministry f Health and Welfare, 1982: Sat Y, Kimura M, Fukumi H. Develpment f a pertussis cmpnent vaccine in Japan. Lancet 1984; 1: Ayama T, Murase Y, Kat M, wai H, wata T. Efficacy and immungenicity f acellular pertussis vaccine by manufacturer and patient age. Am J Dis Child 1989; 143: Nbel GR, Bernier RH, Esber EC, et al. Acellular and whle-cell pertussis vaccines in Japan, reprt f a visit by US scientists. JAMA 1987;257: Ayama T, Hagiwara S, Murase Y, Kat T, wata T. Adverse reactins and antibdy respnses t acellular pertussis vaccine. J Pediatr 1986; 109:

6 JD 1996; 174 (Suppl 3) Acellular Pertussis Vaccines and Disease Cntrl S Watanabe M, Nakase Y, Ayama T, et al. Sertype and drug susceptibility f Brdetella pertussis islated in Japan frm 1975 t Micrbil mmunl 1986; 30: Ayama T, Murase Y, Kat T, wata T. Efficacy f acellular pertussis vaccine in Japan. J Pediatr 1985; 107: Ayama T, wata T, wai H, et al. Efficacy f acellular pertussis vaccine in yung infants. J nfect Dis 1993; 167: Ad hc grup fr the study f pertussis vaccines. Placeb-cntrlled trial f tw acellular vaccines in Sweden-prtective efficacy and adverse events. Lancet 1988; 1: Lambert HJ. Epidemilgy f a small pertussis utbreak in Kent Cunty, Michigan. Public Health Rep 1965;80: Jenkinsn D. Duratin f effectiveness f pertussis vaccine: evidence frm a lo-year cmmunity study. Br Med J 1988;296: Ayama T, Harashima M, Nishimura K, Sait Y. Outbreak f pertussis in highly immunized adlescents and its secndary spread t their families. Acta Paediatr Jpn 1995; 37: Ayama T, Takeuchi Y, Gt A, et al. Pertussis in adults. Am J Dis Child 1992; 146:163-6.