385
Rapid Publication
Genetic basis of nonresponse to hepatitis B vaccine in hemodialyzed patients
Genetic facton are implicated in tbc responu of namaf subjects to hepatitis B vaccine. The aim of our study was to IvestigabifHL4 class fandIfprot&s wuldpartieipateioanpn~~nsetorbisvaffineinimm~ promised, namely hemodial~d, patients. One b.zzwked and ~$2 hemcdiaiyzed patieou (6’3 men and 39 svmne~~,man qe 35 years) were vaccinated with Pasteur Hwac B vaocinc, wilb a mean delay of 2 months following dx onw af cbmnic bemcdialysis. Patients were considered aon~n when their w.nxa antSIBs remained cl0 mUf/ml cm at kast two tnxabms within the 12monthrfollavingthevaadnation. HLA-A,B andDR~tigensweredeterminsdbyoDmplcwnt_dcpendcntmiap Tbc HLA-Al, 88 and DR.3 fr+ lymphotoaicity. Ninety patients (84%) were respwkrs and 17 (16%) nomesponden. quencywas higberin mmrespnnders (35.35 and 44%. respectively) than is responden (18.4 and 14%, respwtively). The ex~cndal haplotypc HLA-Al. BS. Dft3 was more frequent in the former (19%) than in the fatter (2%) (p c 0.03). There was only one female w the nonmspocden (6%) as compared to 37 (41%) in the rerpooders (p < 0.05). We madude that genetic determinants (sex and HLA markers) play a critical role in the induction of an amiHBs immune response in bothimmunoinu~mpetcnt hcmodialyzedpatirnts and normal immunowmperent hosts.
cbmted against hepatitis B vinu dtb Psneur Hevac B vaccine. Tbcy included 68 men and 39 wanen, mepl age 35 years (range 18-60 yeaIs). The vaainatiLm
was per-
formed with a mean d&y of2 months foltig the onset of cbmzdc hemodiafysis (rage from -41 to +69 mombs). The vaccine schedules were pwiously reported (7). In swnmaq. patients in&&d in the study bad no previous known exfxmurc to HJ3V infection. acgative initial blood sampks for fiBsAg. antifals and aaiHTk antibodies. and normal traasa&ne wtivities. They received t&e n four qcclions of 1 ml of w&e slibcualy a* nwnthly foterwk. Each dose of 1 ml mntains 5 pg of HBsAgandab~mbdum ltydmayckisuseda%adjut. HBV markers were tested u&g estzymc linked immuoosorb+x~t “ray te&dqucs Bcmrding to the manufacturer’s imtnctions (Abbott Laboratories. Cldcago, U.S.A.). Sampks wbicb were p&ive for amiHJSs ws,c
s. PC% et
386 titrated and the results were expressed in milli-intemational units per ml (mfU/ml). Patients were considered nonresponders if they had at least two successiveblood samples with antiHBs titers of less than 10 mUUml within the 12 months following tbc brst injection of vaccine. HLA-A, B and DR antigens were determined according to the standard method (complement-depend micmlymphotoxicity). Statistical anal+ was bared on a two-sided Fisher exact test.
Rsulls Among the 107 hemodialyzed patients who were vaccinated, 90 (84.1%) were responders end 17 (15.9%) were nonresponders. There was no difference in the frequency of HLA-A alleles between the hvo groups. HLA-B8 wes more frequent in nonresponders (35%) than in responders (4%) @ = U.WI). There were no differences in the frequency of HLA-DR7 antigen or of the extended haplotype HLA-R44, DR7 between the two groups. HLA-DR3 frequency in nonresponders (43.8%) was higher than in responders (13.6%) (p = 0.01) or the white general pop ulation (23%). A single DR3 (which may reflect either a homozygous DR allele or a DR3 antigen with a blank) was present in 12.5% of the nonresponders as compared to 6.8% of the responders (N.S.). The extended haplotype HLA-B8, DR3 or ALA-Al, 88, DR3 was @ifi. caotly more ftequent in nonresponders (‘25 and 198, re. spcctively) titan in responders (2.2%) (p C 0.03) (Table 1). None of the responden and one among the 16 nonres-
ponders (6.3%) assumed a HLA-B8, DR3 homozygoty, as compared to 0.9% in the general population. There was only one female within the nonresponders (6.3%), but 37 in the responders (41.1%) @ C 0.005).
Our results establish that genetic dnerminaets (sex and HLA type) play a critical role in the induction of an antiHBs immune response in immunodeficient, hemodialyzed patients as well ash normal immunocompetent subjects. The frequency of HLA-B8, HLA-DR3 01 of the haplo. type HLA-Al, B8, DR3 is higher in hemodiaiyzed nooresponders than in responders, which suggests evident fore genetic modulation of the immune response hepatitis B vaccine in immunodefident patients. Genetic (HLA) factors of nanresponsiveneu have been reported in both health care workers and homowxual men (2.89) implying an impaired immune response which could be linked to a genetic predisposition, the renal disease or hemedialysis. Alper et al. (8) have clearly demomtrated a
to
genetic prediction of nonresponse to hepatitis B vacebte in normal subjects by esteblisbing that a low respmue was due to both the absence of e dominant immune response gene in the major histoampatibility complex (MHC) and to the preseace of MHC extended haplotypcs such 8s HLA-B8, SCOl, DR3 on both cbmmmomes. ‘Ihey assumed that the production of tmtiHBs antibodies was a dominant trait and that the inability to pmdw high titers of antiHBs after adequate immunization wes P recusive trait. Based on contlicting data, Watanek et al. (10) have found that nonresponders were lagely heterozygous for MHC markets. They therefore portelated that the immune suppression
Hemodialyred Hemdial,zed “o”rerpo”den responders ,N=lli ,Y=W,
‘p
Rapid Publication
Genetic basis of nonresponse to hepatitis B vaccine in hemodialyzed patients
Genetic facton are implicated in tbc responu of namaf subjects to hepatitis B vaccine. The aim of our study was to IvestigabifHL4 class fandIfprot&s wuldpartieipateioanpn~~nsetorbisvaffineinimm~ promised, namely hemodial~d, patients. One b.zzwked and ~$2 hemcdiaiyzed patieou (6’3 men and 39 svmne~~,man qe 35 years) were vaccinated with Pasteur Hwac B vaocinc, wilb a mean delay of 2 months following dx onw af cbmnic bemcdialysis. Patients were considered aon~n when their w.nxa antSIBs remained cl0 mUf/ml cm at kast two tnxabms within the 12monthrfollavingthevaadnation. HLA-A,B andDR~tigensweredeterminsdbyoDmplcwnt_dcpendcntmiap Tbc HLA-Al, 88 and DR.3 fr+ lymphotoaicity. Ninety patients (84%) were respwkrs and 17 (16%) nomesponden. quencywas higberin mmrespnnders (35.35 and 44%. respectively) than is responden (18.4 and 14%, respwtively). The ex~cndal haplotypc HLA-Al. BS. Dft3 was more frequent in the former (19%) than in the fatter (2%) (p c 0.03). There was only one female w the nonmspocden (6%) as compared to 37 (41%) in the rerpooders (p < 0.05). We madude that genetic determinants (sex and HLA markers) play a critical role in the induction of an amiHBs immune response in bothimmunoinu~mpetcnt hcmodialyzedpatirnts and normal immunowmperent hosts.
cbmted against hepatitis B vinu dtb Psneur Hevac B vaccine. Tbcy included 68 men and 39 wanen, mepl age 35 years (range 18-60 yeaIs). The vaainatiLm
was per-
formed with a mean d&y of2 months foltig the onset of cbmzdc hemodiafysis (rage from -41 to +69 mombs). The vaccine schedules were pwiously reported (7). In swnmaq. patients in&&d in the study bad no previous known exfxmurc to HJ3V infection. acgative initial blood sampks for fiBsAg. antifals and aaiHTk antibodies. and normal traasa&ne wtivities. They received t&e n four qcclions of 1 ml of w&e slibcualy a* nwnthly foterwk. Each dose of 1 ml mntains 5 pg of HBsAgandab~mbdum ltydmayckisuseda%adjut. HBV markers were tested u&g estzymc linked immuoosorb+x~t “ray te&dqucs Bcmrding to the manufacturer’s imtnctions (Abbott Laboratories. Cldcago, U.S.A.). Sampks wbicb were p&ive for amiHJSs ws,c
s. PC% et
386 titrated and the results were expressed in milli-intemational units per ml (mfU/ml). Patients were considered nonresponders if they had at least two successiveblood samples with antiHBs titers of less than 10 mUUml within the 12 months following tbc brst injection of vaccine. HLA-A, B and DR antigens were determined according to the standard method (complement-depend micmlymphotoxicity). Statistical anal+ was bared on a two-sided Fisher exact test.
Rsulls Among the 107 hemodialyzed patients who were vaccinated, 90 (84.1%) were responders end 17 (15.9%) were nonresponders. There was no difference in the frequency of HLA-A alleles between the hvo groups. HLA-B8 wes more frequent in nonresponders (35%) than in responders (4%) @ = U.WI). There were no differences in the frequency of HLA-DR7 antigen or of the extended haplotype HLA-R44, DR7 between the two groups. HLA-DR3 frequency in nonresponders (43.8%) was higher than in responders (13.6%) (p = 0.01) or the white general pop ulation (23%). A single DR3 (which may reflect either a homozygous DR allele or a DR3 antigen with a blank) was present in 12.5% of the nonresponders as compared to 6.8% of the responders (N.S.). The extended haplotype HLA-B8, DR3 or ALA-Al, 88, DR3 was @ifi. caotly more ftequent in nonresponders (‘25 and 198, re. spcctively) titan in responders (2.2%) (p C 0.03) (Table 1). None of the responden and one among the 16 nonres-
ponders (6.3%) assumed a HLA-B8, DR3 homozygoty, as compared to 0.9% in the general population. There was only one female within the nonresponders (6.3%), but 37 in the responders (41.1%) @ C 0.005).
Our results establish that genetic dnerminaets (sex and HLA type) play a critical role in the induction of an antiHBs immune response in immunodeficient, hemodialyzed patients as well ash normal immunocompetent subjects. The frequency of HLA-B8, HLA-DR3 01 of the haplo. type HLA-Al, B8, DR3 is higher in hemodiaiyzed nooresponders than in responders, which suggests evident fore genetic modulation of the immune response hepatitis B vaccine in immunodefident patients. Genetic (HLA) factors of nanresponsiveneu have been reported in both health care workers and homowxual men (2.89) implying an impaired immune response which could be linked to a genetic predisposition, the renal disease or hemedialysis. Alper et al. (8) have clearly demomtrated a
to
genetic prediction of nonresponse to hepatitis B vacebte in normal subjects by esteblisbing that a low respmue was due to both the absence of e dominant immune response gene in the major histoampatibility complex (MHC) and to the preseace of MHC extended haplotypcs such 8s HLA-B8, SCOl, DR3 on both cbmmmomes. ‘Ihey assumed that the production of tmtiHBs antibodies was a dominant trait and that the inability to pmdw high titers of antiHBs after adequate immunization wes P recusive trait. Based on contlicting data, Watanek et al. (10) have found that nonresponders were lagely heterozygous for MHC markets. They therefore portelated that the immune suppression
Hemodialyred Hemdial,zed “o”rerpo”den responders ,N=lli ,Y=W,
‘p
