C4A deficiency and nonresponse to hepatitis B vaccination.
OBJECTIVE
Hepatitis B vaccination failure has been linked to the presence of certain human leukocyte antigen class II alleles. However, the functional background of these associations has remained unclear. Complement component C 4 is encoded within the major histocompatibility complex and is essential for classical pathway activation.


METHODS
Healthy individuals (n=4269) were vaccinated in a prospective trial with Engerix B. Nonresponse was classified as anti-HBs<10 U/l after the last vaccination. Seventy-three nonresponders (NR) (1.7%) were identified. For comparison 53 responders (R) (anti-HBs>10 IU/l) were drawn randomly from the same cohort. C4 allotyping was carried out by high-voltage agarose gel electrophoresis and C4alpha-chain typing using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. C4 gene deletions (C4Del) were studied by Southern blot.


RESULTS
C4AQ0 alleles were observed in 45/73 (62%) NR compared to 17/53 (32%) R (P=0.001). C4ADel was observed in 24/73 (33%) NR and in 6/52 (12%) R (P=0.006). C4AQO alleles were present in 21/49 (43%) NR without C4Del compared to 10/46 (22%) in R without C4Del (P=0.031). In a logistic regression with DRB1*0301, DRB1*07, DRB1*1301 and C4AQ0 all except for DRB1*0301 showed a significant association.


CONCLUSIONS
C4AQ0 shows a DRB1*0301 independent association with vaccine failure. C4AQ0 alleles probably contribute to inefficient complement activation and failure of B cells to secrete anti-HBs.
Höhler
Thomas
T
I. Department of Internal Medicine, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Mainz, Germany. hoehler@mail.uni-mainz.de
Stradmann-Bellinghausen
Beate
B
Starke
Roland
R
Sänger
Roland
R
Victor
Anja
A
Rittner
Christian
C
Schneider
Peter M
PM
D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology; D015934:Complement C4a / Q000235:genetics* / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006509:Hepatitis B / Q000453:epidemiology / Q000517:prevention & control*; D006510:Hepatitis B Antibodies / Q000097:blood; D017325:Hepatitis B Vaccines / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016036:Seroepidemiologic Studies; D017211:Treatment Failure
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D006510:Hepatitis B Antibodies; D017325:Hepatitis B Vaccines; D015934:Complement C4a