Efficacy and safety of the Brazilian vaccine against Hepatitis B in newborns

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1 Rev Saúde Pública 2009;43(6) Expedito José de Albuquerque Lua I José Cássio de Moraes II Lygia Silveira II Hilda Souza Neves Salias III Efficacy ad safety of the Brazilia vaccie agaist Hepatitis B i ewbors ABSTRACT OBJECTIVE: To aalyze the efficacy ad safety of a recombiat Hepatitis B vaccie i ewbors. METHODS: The study was carried out i a geeral hospital i the city of Guarulhos, Southeaster Brazil, betwee 2002 ad The recombiat Hepatitis B vaccie from Istituto Butata (VrHB-IB) was tested i two cliical trials. I both trials, ewbors were radomly allocated to the experimetal or cotrol (referece vaccie) groups. Newbors were give three doses of vaccie, oe up to 24 hours after birth ad the other two 30 ad 180 days later. I the first trial, 538 ewbors completed the immuizatio protocol, ad 486 i the secod. Vaccies were cosidered equivalet whe seroprotectio differece was below 5%. RESULTS: Seroprotectio i the first trial (ati-hbs 10mUI/ml) was 92.5% (247/267) i the experimetal group, compared to 98.5% (267/271) i the cotrol (p = 0.001). With this result, VrHB-IB did ot fulfill the pre-established criterio for equivalece. After icreasig the cocetratio of atige i the vaccie to 25μg, seroprotectio reached 100% i the experimetal group ad 99.2% i the cotrol. No severe adverse effects were recorded. CONCLUSIONS: The reformulated VrHB-IB is cosidered equivalet to the referece vaccie, ad its use is recommeded i ewbors. Descriptors: Hepatitis B Vaccies. Ifat, Newbor. Efficacy. Cliical Trial. Hepatitis B, prevetio & cotrol. I Istituto de Medicia Tropical de São Paulo. Uiversidade de São Paulo. São Paulo, SP, Brasil II Departameto de Medicia Social. Faculdade de Ciêcias Médicas. Sata Casa de Misericórdia de São Paulo. São Paulo, SP, Brasil III Hospital Geral de Guarulhos. Guarulhos, SP, Brasil Correspodece: Expedito José de Albuquerque Lua Istituto de Medicia Tropical de São Paulo Av. Dr. Eéas de Carvalho Aguiar, São Paulo, SP expedito_lua@uol.com.br Received: 5/26/2008 Revised: 2/17/2009 Approved: 8/18/ 2009

2 2 Efficacy of a hepatitis B vaccie Lua EJA et al INTRODUctio Ifectio by the hepatitis B virus is a importat public health problem i Brazil. Certai regios i the coutry are regarded as hyperedemic, icludig the Wester Amazo as well as several microregios i the states of Espírito Sato, Paraá, Sata Cataria, ad Mato Grosso. After the itroductio of uiversal vacciatio, there has bee a importat reductio i prevalece of chroic ifectio i a umber of these areas. 3 Sice the late 1980 s, all available vaccies are produced usig the techiques of molecular biology, i which vaccie atige is produced usig recombiat DNA techology. The recombiat vaccie agaist hepatitis B is highly immuogeic ad protective. A respose is cosidered to be protective whe the vaccie is able to iduce the formatio of atibodies to HBsAg (ati-hbs) at levels 10 mui/ml as measured by immuoezymatic assay. A complete series of three or four doses of hepatitis B vaccie is capable of iducig a protective respose i over 90% of healthy adults ad over 95% of healthy childre ad adolescets. Most vacciatio regimes recommed three or four doses of vaccie (at zero, oe, ad six moths or at zero, oe, two, ad 12 moths, respectively). The first doses iduce detectable atibodies to HBsAg i approximately 70% to 85% of vacciees, but atibody levels are relatively low ( mui/ml). the fial dose iduces a adequate respose i aroud 90% of adults ad i over 95% of childre, atibody levels icreasig by 1,000 3,000 mui i adults ad usually by more tha 5,000 mui/ml i childre. 4 Studies coducted i the Uited States have demostrated the safety of the hepatitis B vaccie based o a evaluatio of 12 millio doses give to ifats. Side-effects are similar betwee all licesed hepatitis B vaccies. Pai ad hyperemia at the ijectio site are the most frequet adverse effects (15%-20%), ad are probably related to the vaccie adjuvat alumium hydroxide. Approximately 15% of vacciees experiece oe or more mild, self-limitig, systemic symptoms, icludig cephalea, fever, ad/or fatigue, usually 24 to 48 hours after ioculatio. 2,10 The Brazilia Miistry of Health s Natioal Immuizatio Program bega to icorporate hepatitis B vacciatio i 1992, i vacciatio campaigs take place i the coutry s hyperedemic areas. I 1998, the recombiat hepatitis B vaccie was icorporated ito the uiversal vacciatio program for ifats i the etire coutry. The Istituto Butata i São Paulo has developed a hepatitis B vaccie (VrHB-IB) produced usig recombiat DNA. The developmet of a molecular biologybased vaccie costitutes a further step toward towards self-sufficiecy i the productio of immuobiologicals i Brazil, which reduces both our reliace o imports ad the price of the vaccie, i additio to esurig vaccie supply for the uiversal program. The VrHB-IB vaccie cotais highly purified particles of HBsAg produced i recombiat yeast (Haseula polymorpha), ad its formulatio icludes the adjuvat alumium hydroxide with iitially 20μg, ad later 25μg, of recombiat atige per ml of diluet. Prelimiary studies usig 10μg per dose i a zero, six, ad ie-moth regime, admiistered to healthy adult volutaries, showed that VrHB-IB did ot iduce sigificat adverse effects, with serocoversio reachig 95.3%. 1 This vaccie was later foud to iduce a weaker immuogeic respose i subjects older tha 45 years, where serocoversio was 70%, compared to 100% i the years age group. Furthermore, differeces i geometric mea titers iduced by 10μg ad 20μg doses led the authors to cosider the eed for icreasig atige cocetratio i the vaccie. 5 VrHB-IB was licesed for use i Brazil i 1998, ad has bee i wide use by Natioal Immuizatio Program sice Subsequet trials have show VrHB-IB to be equivalet i efficacy to the referece vaccie i childre from oe to 11 years of age, less immuogeic, but acceptable for use i ewbors, adolescets, ad youg adults, ad sigificatly less immuogeic i adults aged 31 to 40 years. 6 I light of these results, the maufacturer has icreased the cocetratio of atige i the vaccie from 20 to 25μg/ml. This has geerated the eed for further efficacy trials for the vaccie, ot oly focusig o the group i which the differece i immuogeicity was greatest adults but also o ewbors, the target group of Natioal Immuizatio Program. The objective of the preset study was to aalyze the efficacy ad safety i ewbors of this recombiat hepatitis B vaccie. METHODS The safety ad efficacy i ewbors of the hepatitis B vaccie produced by Istituto Butata (VrHB-IB) were evaluated i two radomized, double-blid cliical trials. Newbors participatig i each of the trials were give three 0.5 ml doses of hepatitis B vaccie by itramuscular ijectio. The first dose was give up to 24 hours after birth, the secod, 30 days later, ad the third, 180 days after the first. Newbors radomized to the experimetal group received VrHB-IB, ad those i the cotrol group received the referece vaccie, a Egerix B, produced by Glaxo Smith Klie. Both vaccies

3 Rev Saúde Pública 2009;43(6) 3 used i the first trial cotaied 20μg/ml of atige. I the secod trial, we used a ew formulatio of VrHB-IB cotaiig 25μg/ml of atige. I both trials, a sigle lot of the experimetal ad cotrol vaccies was used. The first trial was carried out i , ad the secod i All ewbors delivered at a geeral hospital i the city of Guarulhos, Southeaster Brazil, were eligible for participatio. We excluded babies bor to mothers who were HBsAg carriers or with positive serology for HIV or syphilis; bor before term (gestatioal age < 37 weeks); with low birthweight (<2,000 g); carryig cogeital malformatios, geetic diseases or other severe cliical coditios; with 1 miute Apgar < 7 or 5 miute Apgar < 8; ad who received exchage trasfusios or itraveous immuoglobuli. Expectig parets were approached by the study team upo admissio to the hospital for delivery. Durig this iitial iterview, parets were itroduced to the study ad ivited to participate. I case of acceptace, a further iterview was coducted after delivery, whe a Term of Free Iformed Coset was read to ad discussed with parets. Those acceptig to participate i the trial siged the Term, which was also siged by a represetative of the study team. Newbors icluded i the study were vacciated withi the first 24 hours of life, ad a retur appoitmet was scheduled. The study team offered to follow-up erolled ewbors throughout the first year of life. Upo recruitmet, each ewbor was assiged a sequetial umber correspodig to the order of erollmet i the study. Sequetial umbers had bee previously radomized, with a idepedet probability of 50% for each umber. Oly the professioal resposible for the radomizatio ad allocatio of sequetial umbers to each of the groups had access to this iformatio. Noe of the professioals resposible for subject follow-up or for the laboratory testig had access to the radomizatio iformatio. Vaccie vials were modified so as to prevet their idetificatio. Equivalece trials are coceived of as trials of oiferiority of the tested vaccie. 10 I such trials, oe attempts to show that the proportio of subjects with the desired immue respose after receivig the ew vaccie is ot lower tha that of the referece group by more tha a prestated margi of oiferiority. I the two trials, we accepted as idicative of oiferiority differeces smaller tha 5%. Usig as a referece the immuogeicity of the cotrol vaccie i Brazil (98.5%), 8 we calculated the ecessary sample to detect a differece of up to 5%, with a sigificace level of 0.05 ad 80% statistical power. This yielded a sample size of 258 subjects i each group. After addig 20% to compesate for potetial losses, we arrived at a total of 610 subjects, divided equally betwee experimetal ad cotrol groups. The serological marker of vaccie efficacy (outcome variable) was the detectio of ati-hbs atibodies i levels equal to or greater tha 10 mui/ml. Serology was performed o samples collected at T 180 (five moths after the secod dose of vaccie, immediately prior to the third dose), ad T210 (oe moth after the third dose). I additio, we collected blood from the mother at the time of delivery to determie eligibility. Samples were collected, cetrifuged, ad aliquoted by the ivestigatio uit ad processed by the laboratory of the study hospital. Samples from ewbor mothers were aalyzed for serological markers of hepatitis B (HBsAg ad ati-hbc), HIV, ad syphilis. The secod ad third samples of all subjects were aalyzed for serological markers of hepatitis B (HBsAg, ati-hbs, ad ati-hbc). Atibody levels were measured by immuoezymatic assay (ELISA) usig commercially available reagets DiaSori ad Access (Access AbHBsII, Beckma Coulter), the latter for measurig ati-hbs. I the first trial, ati-hbs testig was performed by Istituto Adolfo Lutz (IAL) ad Istituto Evadro Chagas (IEC), ad i the secod trial, by Istituto Oswaldo Cruz. I the first trial, all laboratory tests were carried out simultaeously by the participatig laboratories (IAL ad IEC) usig differet commercially available reagets (DiaSori at IAL ad Access at IEC). I the secod trial, a subsample of 65 voluteers was retested at IEC. To evaluate the vaccie s safety, we recorded ay adverse effects attributable to the vaccie after the day of vacciatio. Adverse effects were actively moitored durig the first 72 hours after vacciatio, by visitig mother ad ewbor i the hospital after the first dose, ad by telephoe after the secod ad third doses. After 72 hours, moitorig was passive, relyig o spotaeous reportig by the mother or care giver ad o iquiry upo the subject s retur to the hospital for eoatal care ad vacciatio. We icluded i the aalysis oly ewbors who completed all stages of the follow-up protocol. Losses were distributed equally betwee experimetal ad cotrol groups i both trials (Table 1). I the first trial, 86.4% of the 630 ewbors completed all stages of the protocol. I the secod trial, 82.2% of the 590 radomized ewbors completed follow-up. Major reasos for loss to follow-up were failure of the subject to show up for a scheduled appoitmet ad iability of the research team to locate the family at the give address; hepatitis B vacciatio somewhere other tha the trial uit; ad dropout from the trial by request of the family. We foud o differeces betwee losses ad ewbors that completed all follow-up stages i terms of ay of the variables ivestigated. We compared the proportio of seroprotectio ad geometric mea ati-hbs titers betwee experimetal ad cotrol groups. We calculated the differece i

4 4 Efficacy of a hepatitis B vaccie Lua EJA et al Table 1. Distributio of ewbors participatig i the trial accordig to selected variables at the time of recruitmet. Guarulhos, Southeaster Brazil, Parameter Experimet group ( = 315) First trial Cotrol group ( = 315) Experimetal group ( = 298) Secod trial Cotrol group ( = 292) % males Mea weight (g) Mea 5 Apgar Mea legth (cm) proportios ad their 95% cofidece itervals. 10,11 We carried out uivariate aalysis of cofactors that could potetially ifluece the outcome. We also compared the frequecy of adverse evets betwee the two groups after each dose of vaccie. For data aalysis, we used Epi Ifo ad SPSS 13.0 software. The study was approved by the Research Ethics Committee of the Irmadade de Sata Casa de Misericórdia de São Paulo (1 st trial: Process o. 061/01; 2 d trial: Process o. 221/03). RESULTS Table 2 presets the distributio of subjects i the experimetal ad cotrol groups accordig to selected variables at the time of erolmet. I both trials, groups were equally distributed i terms of the ivestigated variables with o sigificat differeces betwee groups, which idicates successful radomizatio. I the first trial, the differece i efficacy betwee VrHB-IB ad the referece vaccie was 6% (Table 3), i.e., higher tha the prestated equivalece margi of 5%. However, this value was withi the 95% cofidece iterval of the differece i proportios. I additio to this variable, o other covariable was sigificatly associated with the outcome. I the secod trial, there was o differece i efficacy betwee the two vaccies (Table 4). As i the first trial, there was o associatio betwee the outcome variable ad ay of the covariables ivestigated. Also i the first trial, geometric mea atibody levels i the experimetal ad cotrol groups were ad 1,769.9 mui/ml, respectively. I the secod trial, mea levels were 2,616 ad 10,051 mui/ml, respectively. These differeces were sigificat i both trials. I the first trial, the itraclass correlatio coefficiet betwee the results of serological tests (atibody levels) from the two laboratories usig distict commercial kits was (95% CI: 0.856; 0.897). I the secod trial, the itraclass correlatio coefficiet betwee the two labs, usig the same commercial kit, was (95% CI: 0.959; 0.997). Regardig reactogeicity, families reported a icrease i adverse effects betwee the first ad third doses i both trials. Localized reactios were the most frequetly reported evets after the first dose. After the secod ad third doses, most reports were of icreased cryig/irritability ad low fever. Almost all adverse Table 2. Distributio of losses to follow-up accordig to study group. Guarulhos, Southeaster Brazil, Group First trial Secod trial Losses Losses Experimetal Cotrol Total Table 3. Results of ati-hbs serology after the third dose of vaccie i the first trial. Guarulhos, Southeaster Brazil, Vaccie No-reactive Ati-HBs serology Reactive Total % seroprotectio Experimetal Cotrol Total χ 2 (Yates correctio) = p = D = - 6 (95% CI: 9.5; 2.5). D: Differece i proportios.

5 Rev Saúde Pública 2009;43(6) 5 Table 4. Results of ati-hbs serology after the third dose of vaccie i the secod trial. Guarulhos, Southeaster Brazil, Vaccie No-reactive Ati-HBs serology Reactive Total % seroprotectio Experimetal Cotrol Total χ 2 (Yates correctio) = 0.50 p = 0.48 D = 0.8 (95% CI: 1.9; 0.3). D: Differece i proportios. Table 5. Distributio of the frequecy of adverse effects after vacciatio agaist hepatitis B, accordig to dose ad vaccie used. Guarulhos, Southeaster Brazil, Dose Experimetal First trial Cotrol Experimetal Secod trial First Secod Third 47 22* * p < 0,01 Cotrol evets were observed i the first 72 hours after vaccie admiistratio. The third dose was admiistered simultaeously with the DTP vaccie. No severe adverse reactios were observed i ay of the trials. Oly after the third dose i the first trial was the frequecy of adverse evets sigificatly higher i oe of the groups (VrHB-IB). No differeces i frequecy of adverse effects betwee the two vaccies were detected after the first two doses i the first trial, ad after all doses i the secod trial (Table 5). DISCUSSION After icreasig atige cocetratio to 25μg/ml, the immuogeicity of VrHB-IB was practically idetical to that of the referece vaccie, havig iduced high atibody titers i the majority of voluteers (97.5% with titers higher tha 100 mui/ml). I the two trials, the ull hypothesis of oiferiority could ot be rejected. VrHB-IB showed a similar reactogeicity ad safety profile to that of the referece vaccie. The majority of adverse effects recorded cosisted of localized reactios ad low fever. Oly at oe of the aalyzed time poits after the third dose of the first trial we observed a sigificat differece i the frequecy of adverse effects betwee the two vaccies. Cosiderig that these were mild evets, ad that this excess of adverse evets did ot repeat itself i the secod trial, it is possible that such differece was due to chace. The admiistratio of DTP vaccie cocomitatly with the third dose of hepatitis B vaccie may have led to the greater frequecy of adverse effects reported after this dose, but ot for the differece observed betwee the two vaccies. As i other trials assessig the safety of other recombiat hepatitis B vaccies, o severe adverse effects were reported. 7 Several factors ca ifluece the results of recombiat hepatitis B vaccie trials, icludig differeces i vaccie formulatio ad productio, differet vacciatio regimes, age at vacciatio, site of vaccie admiistratio, cocomitat immuizatio with other vaccies, differeces i the laboratory assays used for outcome measuremet, ad differeces betwee the study populatios, amog others. Therefore, comparisos betwee differet studies should be udertake with cautio. Our preset results describe part of the course of developmet of VrHB-IB. The first trial, combied with the results reported by Martis et al, 6 led to a icrease i cocetratio of atige i the vaccie, ad the results of the followig trial cofirmed the expected icrease i immuogeicity of the reformulated product. Our preset results i ewbors, alog with those of aother trial coducted simultaeously, by the same team, i a sample of adults, allow us to coclude that the performace of VrHB-IB is idetical to that of the referece vaccie, warratig its large-scale use i the cotrol of a importat edemic disease of i Brazil. 9 ACKNOWLEDGEMENTS To the laboratory teams of Aldolfo Lutz, Evadro Chagas ad Oswaldo Cruz Istitutes for coductig the immuoezymatic assays.

6 6 Efficacy of a hepatitis B vaccie Lua EJA et al REFEReces 1. Costa AA, Ieami M, Juarez E, Llace PD, Raw I. Prelimiary Report of the Use of a Recombiat Yeastderived Hepatitis B Vaccie Maufactured by Istituto Butata. Rev Ist Med Trop Sao Paulo. 1997;39(1): DOI: /S Desombere I, Haser P, Rossau R, Paradijs J, Leroux- Roels G. Norespoders to hepatitis B vaccie ca preset evelope particles to T lymphocytes. J Immuol. 1995;154(2): Figueiredo GM. Breve histórico da emergêcia da hepatite B como problema de saúde pública. J Bras AIDS. 2007;8(1): Hadler SC, Margolis HS. Hepatitis B immuizatio: vaccie types, efficacy ad idicatios for immuizatio. Curr Cli Top Ifect Dis. 1992;12: Ioshimoto LM, Rissato ML, Boilha VSJ, Miyaki C, Raw I, Graovsky N. Safety ad immuuogeicity of hepatitis B vaccie Butag i adults. Rev Ist Med Trop Sao Paulo. 1999;41(3):191-3 DOI: /S Martis RM, Besabath G, Arraes LC, Oliveira ML, Miguel JC, Barbosa GG, et al. Multiceter Study o the Immuogeicity ad Safety of Two Recombiat Vaccies Agaist Hepatitis B. Mem Ist Oswaldo Cruz. 2004;99(8): DOI: /S Mast EE, Margolis HS, Fiore AE, Brik EW, Goldstei ST, Wag SA, et al. A comprehesive immuizatio strategy to elimiate trasmissio of hepatitis B virus ifectio i the Uited States: recommedatios of the Advisory Committee o Immuizatio Practices (ACIP) part 1: immuizatio of ifats, childre, ad adolescets. MMWR Recomm Rep. 2005;54(RR- 16): Motta MSF, Mussi-Pihata MM, Jorge SM, Yoshida CFT, Souza CBS. Immuogeicity of hepatitis B vaccie i preterm ad full term ifats vacciated withi the first week of life. Vaccie. 2002;20(11-12): DOI: /S X(01) Moraes JC, Lua EJA, Grimaldi RA. Imuogeicidade da vacia brasileira cotra hepatite B em adultos. Rev Saude Publica.2010;44(2). I press. 10. Piaggio G, Elboure DR, Altma DG, Pocock SJ, Evas SJW, CONSORT Group. Reportig of Noiferiority ad Equivalece Radomized Trials, a Extesio of the CONSORT statemet. JAMA. 2006;295(10): DOI: /jama World Health Orgaizatio. Guidelies o cliical evaluatio of vaccies: regulatory expectatios. Geeva; (WHO Techical Report series, 924). Research supported by Fudação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, research grat, process o. 01/ ), Brazilia Miistry of Health/FUNASA (cotract o. 24/2001), Agêcia Nacioal de Vigilâcia Saitária (ANVISA, cotract UNESCO ED-10541/2002), São Paulo State Secretariat of Health (TA 003/2003), ad Brazilia Miistry of Health (cotract o. 136/2004).

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