Immunogenicity of a Recombinant Hepatitis B Vaccine (Euvax-B) in Haemodialysis Patients and Staff Author(s): S. A. Teles, R. M. B. Martins, C. L. R. Lopes, M. A.

dos Santos Carneiro, K. P. Souza and C. F. T. Yoshida Source: European Journal of Epidemiology, Vol. 17, No. 2 (2001), pp. 145-149 Published by: Springer Stable URL: http://www.jstor.org/stable/3582642 . Accessed: 14/11/2013 22:59
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Journal 17: 145-149,2001. European of Epidemiology Academic Publishers. Printed in theNetherlands. ? 2001Kluwer

of a recombinant Immunogenicity hepatitisB vaccine(Euvax-B) in haemodialysis patientsand staff

S.A. Teles1'3, R.M.B. Martins2,C.L.R. Lopes', M.A. dos Santos Carneiro2, K.P. Souza2 & C.F.T. Yoshida3
30swaldo CruzInstitute,Rio de Janeiro,RJ, Brazil

GO; of Nursing; PathologyandPublicHealth (IPTSP), FederalUniversity of Tropical of Goids,Goidnia, 1Faculty 2Institute

in revised form27 April2001 Accepted Abstract.Hepatitis B vaccine is the most effective the transmission of hepatitisB strategyfor preventing virus (HBV) in haemodialysiscenters.Nevertheless, lower vaccine responseshave been reportedin haemodialysis patients as compared with healthy subjects. This studyexaminesthe responseto Euvax-Bin Brazilianhaemodialysis patientsand staff. A total of 102 eligible patients (n = 42) and staff members (n = 60) consentedto be studied. Patientswere immunizedintramuscularly with four doses of 40 of Euvax-B vaccine at 0, 1, 2 and 6 months. In tg staff the vaccinewas administered in threedoses members, of 20 gg at 0, 1, and 6 months. Post-vaccinesamples weretakenfrom all subjects1 month aftereach dose. The vaccine responsewas determinedby measuring antibodyto the hepatitisB surfaceantigen(anti-HBs) levels using ELISA. Subjects with anti-HBs titres equal to or higher than 10 UI/L were considered immune protected. Of the haemodialysis patients who receivedfour doses of hepatitisB vaccine,89.5% respondedto Euvax-Bvaccine.The geometricmean of anti-HBs titres was 322.8 IU/L (95% CI: 317.793.3%reachedanti-HBs 328). Among staffmembers, protective titres after the third vaccine dose. The geometric mean of anti-HBs titres was 2209 IU/L (CI: 2198-2219). Age, male gender and body mass index were not associatedwith vaccine responsein either group. This study showed a good immunogenicity responseto Euvax-Bin haemodialysis patients and staff.

Key words:Haemodialysis,HepatitisB, Recombinant hepatitisB vaccine Introduction Hepatitis B remains a significantworldwidehealth problem.Globally,it is estimatedthat thereare >350 million hepatitis B virus (HBV) carriers[1]. As the parenteralroute is the major route for HBV transmission, haemodialysispatients are at high risk of acquiringhepatitis B [2-6]. In some countries,this infection has been controlled in dialysis centers by adherence to stricterinfectioncontrolprocedures and hepatitisB vaccination[5].However,for others,HBV infectionis still a seriousproblemto patientsand staff HBV infectionoutbreaksare still [2-4]. Nevertheless, seen when failures in infection control procedures occur [6]. HepatitisB vaccinationis the most effectivestratof HBV. In the early egy to preventthe transmission HBV vaccinewas licensed 1980s,the plasma-derived and recommended to dialysispatientsand healthcare HBV workers,and some yearslater,the recombinant vaccine was available [1, 7]. Both are immunogenic and effective, although in haemodialysis patients anti-HBstitres have been lower than staff members [8]. As a result of this, in such patientshigherdoses and furthervaccine injectionshave been widely recommendedand favorableresultshave been reported [3, 9-11]. In Brazil, haemodialysispatients still have high HBV prevalencerates [4]. In addition, vaccination has only recentlybeen introducedin dialysiscenters. Until now, therearefew data on the responseto HBV vaccine in Brazilianhaemodialysis patients [12], and to our knowledgethis is the firststudyto evaluatethe response to Euvax-B, a Korean recombinantHBV vaccine,in haemodialysis patientsand staff. Subjectsand methods
Study population

This study was conducted from April 1998 to November 1999 in dialysis centers in Goiafnia City, CentralBrazil.The studiedsubjectsconsistedof centers.Theywere patientsand staffin haemodialysis not previously vaccinated, and all of them were confirmedto be negativefor hepatitisB surfaceantigen (HBsAg), antibodyto hepatitisB core antigen (anti-HBc),and antibody to the hepatitis B surface antigen(anti-HBs).

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146 The first group consisted of 42 chronic renal patients: 18 males and 24 females,with a mean age of 41.3 years (range 14-71 years) and body mass index (BMI) of 21.7 (range 13.7-33.1). All subjectsunderwent bicarbonatehaemodialysiswith polysulphone 3 x 3.5 hr/wk, and the majority(78.6%) membranes, was on treatmentfor less than 3 months. Causes of chronic renal insufficiencywere glomerulonephritis (19%), diabetes mellitus (26.2%), arterialhypertension in (19%), cystic kidney disease (2.4%), hepatic cirrhosis (2.4%), cutaneous erythematous lupus (2.4%), and of unknown origin in 28.6% of the patients. The othergroupwas composedof staff(n = 60): 55 females and five males. The mean age was 26 years (range 19-58 years) and the mean BMI was 22.5 (range 16.5-32.9). Immunization protocol Of 42 haemodialysispatients, 38 completedthe vacvaccineEuvax-B cinationprotocol with recombinant (LG Chemical,Korea).The vaccinewas administered by intramuscular (i.m.) needle injection (deltoid muscle):four consecutivedoses of 40 tg at 0-, 1-, 2and 6-monthintervals.Among staff, the vaccinewas in threedoses of 20 jtg at 0-, 1-, and 6administered month intervals. Adverse effects of immunization such as injection site reactions, fever, and malaise were recordedby passive report. methods Laboratory Priorto vaccination,all serumsamplesweretestedby ELISAfor the presenceof the HBsAg, anti-HBcand anti-HBs (Hepanostika Organon Teknica B.V., Boxtel, Holland). Post-vaccination samples were taken from all subjects I month after each dose. The quantitative anti-HBs antibody was measured by Hepanostika Anti-HBs, and expressedas internationalunits per liter (IU/L) accordingto the World Health Organization standard.The concentrationof anti-HBswas Results patients and 60 staff memForty-two haemodialysis bers were immunizedwith Euvax-Bvaccine.Among the 42 haemodialysis patients, four died before completion of the full vaccination program. Each vaccinedose was well tolerated,and adversereactions were not reportedin any group. Age, sex and BMI were not associatedwith Euvax-Bresponsein either group (p > 0.05). Figure 1 illustratesthe rates of anti-HBs response to Euvax-B vaccine in haemodialysispatients following each dose. After the firstdose, 7.1% (3/42) of the patientsrespondedto the vaccine. Following the second and third doses, the seroresponserates were Of the 23.8%(10/42)and 57.5%(23/40),respectively. 38 haemodialysispatients who received the fourth dose, 89.5% responded to the Euvax-B: seven as low-responders(anti-HBs: 10-100 IU/L) and 27 as > 100 IU/L). Among the high-responders(anti-HBs latter, 48.2% developed anti-HBs titres higher than 1000 IU/L. In addition,two out of four patientswho died duringthe study respondedto the vaccine;they estimatedby testing a dilution seriesof each sample. The standardcurvewas constructedusing the means found with negative,low positiveand of absorbances high positive controls. The criterion for protection of anti-HBsequal to or was definedas concentration higher than 10 IU/L. Thus, the subjectswere classified as non-responders (anti-HBsless than 10 IU/L), low-responders(anti-HBs: 10-100 IU/L) and highresponders(anti-HBsmore than 100 IU/L). Statisticalanalysis in log10scale, and Anti-HBs titers were transformed the geometric means of anti-HBs titres with 95% confidenceintervalwere calculated.The X2test and Fisher'sexact test were used to camparecategorized variables and p value <0.05 taken as statistically significant.

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147

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to eachdose. in staffaccording vaccine 2. Ratesof anti-HBs (>10 IU/L)to Euvax-B response Figure Euvax-B HBV endemicityhas been reducedin dialysiscenters Table1. Evaluation of GMTof anti-HBs against in haemodialysis andstaff vaccine patients [5]. Currently,HBV vaccines are manufacturedin evalseveralcountries[13], and the immunogenicity GMT(95%CI) uation of those in differentpopulationsis necessary. More recently,a researchcommunicationon the efPatients Staff Timepoint ficacy of the Euvax-B vaccine in Brazilianpatients (month) awaiting liver transplant was published [14]. This 1.3 (0.7-1.9) la 1.4 (0.4-2.5) availablein our country vaccineis not commercially 7.9 (6.5-9.5) 3.7 (0.7-6.8) 2b Brazilian Health Ministry; the was but it by acquired 21.4 (18.6-24.1) 3c recombinant it is a Korean vaccine, containingsub2209 (2198-2219) 7d 322.8 (317.7-328) unit S of HBsAg, subtypeadr. In the presentinvesinterval. CI = Confidence tigation,we evaluatedthe resultsof vaccinationwith aFirstdosefor bothgroups. the Euvax-Bvaccinein chronicrenalpatientsas well b Second dosefor bothgroups. as healthy staff at the haemodialysis centers in cThird doseforpatients. CentralBrazil. d Fourth dosefor patients andthirddosefor occupational Goiainia, Several studies have shown a poor response to riskpersonnel. hepatitis B vaccine in haemodialysispatients, and therefore, other strategies have been proposed to diedafterthe second(15 IU/L) and the thirddoses improve the immune response, among them: new pre-Santigens,higherdose, largernumber adjuvants, (70 IU/L), respectively. of after the first staff members injectionsand alternativeroutes of administration 2), (Figure Among to the Euvax-B vaccine dose,two subjects 15-17]. In this study, using four dose intervals(at [3, responded vaccinedeveloping anti-HBstitresof 77 IU/L and 0, 1, 2 and 6 months) of 40 jg, about 90% of the 110IU/L. After the seconddose, the seroresponse patientsrespondedto Euvax-Bvaccine.This ratewas rate was 48.4%(29/60).Followingthe thirddose, higher than that observed in similar patients using six being vaccine protocols with three doses of 40 jg [3, 18], to Euvax: 93.3%of the subjects responded 50 and Among four doses of 20 tjg [19, 20], and even four doses of high-responders. low-responders them, 66% showed anti-HBstitres higher than 40 jg [11 l, 17]. In addition, other reportshave sug1000 IU/L. gested that better response rates can be obtained Table I shows the evaluation of the geometric vaccinatingchronic renal patients before on at the mean titres (GMT) of anti-HBs against Euvax-B onset of dialysis[9, 10, 21]. In this study,most of the vaccine in haemodialysispatients and staff. An inpatients were on haemodialysistreatment for less crease of GMT levels was observedin both groups than 3 months. Thus, these conditions could have following the vaccine protocols. In haemodialysis contributedto a good vaccine responsein our haepatients,the GMT reachedvaluesof 322.8 IU/L (CI: modialysispatients. HepatitisB vaccinationof healthcare workershas 317.7-328) after the fourth dose. In contrast, GMT was 2209 IU/L (CI: 2198-2219) in staff after the reduced the incidence of occupationally acquired standardschedule. hepatitisB infection[5]. In the presentstudy 93.3% of the healthcareworkersrespondedto the vaccine, and this rate was similarto that reportedelsewhere Discussion [22, 23]. Previousstudieshave showedthat 5-10% of healthy subjectsdo not develop protectiveanti-HBs titresfollowinghepatitisB vaccination.Some factors Sinceit becameavailable,the hepatitisB vaccinehas been recommendedfor haemodialysispatients, and such as male gender, older age, obesity, smoking,

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148

2. CovicA, IancuL, Apetrei virusinimmune deficiencyhave been associatedwith an inC, et al. Hepatitis in fection from Moldavia. haemodialysis patients creased risk for non-responseto vaccination[1, 22, Nephrol Dial Transplant1999;14:40-45. 24, 25]. However, in the present investigation,the 3. FabriziF, Di FilippoS, MarcelliD, et al. Recombinant majority of the subjects showed characteristics hepatitis B vaccine use in chronic haemodialysis pa(young healthy subjects, females, no smokers and tients: Long-term evaluation and cost-effectiveness non-obese),which have been associatedwith a good analysis.Nephron 1996;72: 536-543. vaccineresponse. 4. Teles SA, MartinsRMB, Silva SA, et al. HepatitisB High anti-HBsantibody GMT(s) levels have been virus infectionprofilein CentralBrazilianhaemodialfound in healthy subjects following full standard ysis population.Rev Inst Med trop S Paulo 1998;40: vaccine schedule [22]. However, in haemodialysis 281-286. 5. TokarsJI, MillerER, AlterMJ, ArduinoMJ. National patients, reinforcedvaccine schedulesappear to be of dialysisassociated diseasesin the United surveillance of high anti-HBstitres necessaryfor the development States, 1995.ASAIO J 1998;44: 98-107. [10, 11, 17], due to the immunedeficiencyassociated of hepatitisB virus infectionamong 6. CDC. Outbreaks with chronic renal failure [26]. In fact, our data haemodialysispatients - California, Nebraska, and showed that staff achievedanti-HBsantibody GMT Texas. MMWR 1996;45: 285-289. level of 2209 IU/L using 60 tg of Euvax-B,whereas 7. DesmyterJ, De Groote G, ColaertJ, et al. Efficacy of the haemodialysis patientsneededa total of 160 tgto heat-inactivated hepatitis B vaccine in haemodialysis achievea GMT level of 322.8 IU/L. patientsand staff. Lancet 1983;2: 1323-1327. Many authors have suggestedthat the length of 8. SteketeeRW, ZiarnikME, Davis JP. Seroresponse to to the peak of of anti-HBsis proportional persistence hepatitisB vaccinein patientsand staffof renaldialysis post-vaccinationanti-HBslevels and that this could centers,Wisconsin.Am J Epidemiol 1988; 127: 772duration of of 781. an indication protection[1, 10, provide CDC. 9. vaccine elicited that Euvax-B data showed Our HepatitisB virus:A comprehensive strategyfor 17]. in transmission the United States eliminating through in other titres both elevated peak groups. However, childhood vaccination: Universal Recommendations of studieswill be necessaryto evaluatethe persistence of the ImmunizationPractices Advisory Committee with this reantibodylevels following immunization (ACIP). MMWR 1991;40(RR-13):1-19. combinanthepatitisB vaccine. In addition, the pre10. ChengC-H, HuangC-C, Leu M-L, ChiangC-YF, Wu sent vaccine contains subunit S of HBsAg, subtype M-S, Lai P-C. Hepatitis B vaccine in haemodialysis adr. This is generallyfound in Asiaticpopulation[27] patientswith hepatitisC viral infection.Vaccine 1997; and uncommon in our population [28, 29]. Thus, 15: 1353-1357. furtherstudies will be also desirableto evaluatethe 11. Peces R, De La Torre M, Alcazar R, Urra JM. Prothe antibody efficacy of Euvax-B vaccine against the HBV subspectiveanalysisof the factorsinfluencing paresponse to hepatitis B vaccine in haemodialysis types circulatingin CentralBrazil. tients.Am J KidneyDis 1997;29: 239-245. In conclusion, our findings show a satisfactory 12. Yoshida CFT, TakahashiC, Mercadante LAC, Camanti-HBs response after Euvax-B vaccination,espeHG. Antibody Response to argo IF, Schatzmayr cially in haemodialysispatients. In addition, our reB heat-inactivated hepatitis vaccine (CLB-3pg) in sults reinforcethe importanceof earliervaccination and occupationalrisk personhaemodialysis patients protocols combined with higher doses and larger nel: a one year follow-up.Rev Inst Med trop S Paulo numberof vaccine doses to obtain more efficacious 1988;30: 11-16. immune responses in chronic renal failure patients 13. Kane MA. Status of hepatitis B immunizationproprograms. undergoinghaemodialysis in Vaccine 1998. 1998;16: S104-S108. grammes
Acknowledgements We dedicate this article to all patients and staff of the haemodialysis centers in Goiinia, Goids, Brazil. This work was supported by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Conselho Cientifico e Tecnol6gico do Estado de Goiis (CONCITEG). The authors thank Dr Renato Rosental for English revision of the manuscript. 14. Branda-o A, Alvarez R, Famer S, et al. Efficacyof a recombinanthepatitis B vaccine (Euvax-B)in adult
patients awaiting liver transplantation: preliminary results. Transplant Proc 1999; 31: 3055-3056. 15. Anandh U, Bastani B, Ballal S. Granulocyte-macrophage colony-stimulating factor as an adjuvant to hepatitis B vaccination in maintenance haemodialysis patients. Am J Nephrol 2000; 20: 53-56. 16. Jungers P, Chauveu P, Courouce AM, et al. Immunogenicity of the recombinant GenHevac B Pasteur vaccine against hepatitis B in chronic uremic patients. J

InfectDis 1994; 169:399-402.

17. Waite NM, Thomson LG, Goldstein MB. Successful vaccination with intradermal hepatitis B vaccine in haemodialysis patients previously nonresponsive to intramuscular hepatitis B vaccine. J Am Soc Neprol 1995; 5: 1930-1934. 18. Fernandez E, Betriu MA, G6mez R, Montoliu J. Reponse to the hepatitis B virus vaccine in haemodialysis

References
with a 1. Assad S, FrancisA. Overa decadeof experience yeast recombinanthepatitisB vaccine. Vaccine 2000; 18: 57-67.

This content downloaded from 181.15.183.213 on Thu, 14 Nov 2013 22:59:46 PM All use subject to JSTOR Terms and Conditions

149 and its importance patients:Influenceof malnutrition as a risk factor for morbidityand mortality.Nephrol Dial Transplant1996;11: 1559-1563. 19. AllegraV, VasileA, MaschioM, MengozziG. Immune hepatitis responseafter vaccinationwith recombinant surfaceantigenin maintenance haemodialysis patients and healthycontrols.Nephron 1992;61: 339-340. 20. Docci D, Cipolloni PA, Baldrati L, Capponcini C, TurciF, FelettiC. Immuneresponseto a recombinant patients.Int J Artif hepatitisB vaccinein haemodialysis Organs1990; 13:451-453. 21. SeaworthB, DruckerJ, Starling J, DruckerR, Stevens in patients with B vaccines J. Hamilton C, Hepatitis chronicrenalfailurebeforedialysis.J InfectDis 1988; 157:332-337. 22. AverhoffF, MahoneyF, ColemanP, Schatz G, Hurof hepatitis B witz E, Margolis H. Immunogenicity for personsat occupationalrisk vaccines:Implications of hepatitisB virusinfection.Am J PrevMed 1998;15: 1-8. 23. MarinhoRT, PedroM, RamalhoF, De MouraJVMC. Vacinagaocontra hepatiteB - Oito anos de experinncia. Acta Med Port 1998;11: 971-977. 24. HavlichekD, RosenmanK, SimmsM, Guss P. Agerates in health care relatedhepatitisB seroconversion workers.Am J Infec Control 1997;25: 418-420. 25. LoutherJ, FeldmanJ, RiveraP, Villa N, DeHovitz J, SepkowitzKA. HepatitisB vaccinationprogramat a seroconverNew York City hospital:Seroprevalence, sion, and declination.Am J Infec Control 1998; 26: 423-427. 26. GoldblumSE, Reed WP. Host defensesand immunowith chronichaemodialysis. associated logic alterations Ann InternMed 1980;93: 597-613. 27. Magnius LO, Norder H. Subtypes, genotypes and of the hepatitisB virus as remolecularepidemiology flected by sequencevariabilityof the S-gene. Intervirology 1995;38: 24-34. distribution 28. GasparAMC, YoshidaCFT. Geographic of HBsAg subtypesin Brazil.Mem Inst OswaldoCruz 1987;82: 253-258. 29. Teles SA, MartinsRMB, Vanderborght B, StuyverL, Gaspar AMC, Yoshida CTF. HepatitisB virus: Genotypes and subtypesin Brazilianhaemodialysispatients.Art Organs1999;23: 1074-1078.
Address for correspondence: R.M.B. Martins, Institute of

Tropical Pathology and Public Health (IPTSP), Federal Goiania, Universityof GoiAs,CaixaPostal 131,74605-050, GO, Brazil Fax: + 55-62-202-3066 E-mail:rbringel@terra.com.br

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