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The variation in immune responses to standard inoculation of the hepatitis-B virus vaccine suggest that host factors influence response in ways that are not presently understood. We studied 25 low/nonresponding health care workers (anti-HBs titer <50 IU/l) after the third inoculation of an experimental hepatitis-B vaccine to determine their immune status (through lymphocyte phenotypes) and HLA type. After application of a fourth inoculation, the seroconverting subjects showed only low anti-HBs levels; three male subjects remained anti-HBs negative. Twelve months after the fourth inoculation only 9 of 25 subjects (36%) maintained anti-HBs titer >10 IU/l. Almost all subjects had normal B-cell and CD-4 and CD-8 counts and ratios. Relative to other European populations HLA-A-10 (P<0.05), B-12 (P<0.025), CW-5 (P<0.05), DR-3 (P<0.025), and DR-5 (P<0.025) were increased, whereas DR-2 (P<0.05) was decreased. However, after correction of theP-values for the number of HLA antigens determined, these differences were no longer significant. Furthermore, these HLA types were not the same as those reported in other studies (except for DR-3). We suggest that larger sample sizes or even not yet available immunogenetic markers will be required to prove an "immunogenetic background" in low/nonresponders, if it exists.