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Genome Med. 2016 Jun 16;8(1):68. doi: 10.1186/s13073-016-0322-z.

B-cell repertoire dynamics after sequential hepatitis B vaccination and evidence for cross-reactive B-cell activation.

Author information

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Center, Oxford, OX3 7LE, UK.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Center, Oxford, OX3 7LE, UK.
Paediatric Immunology, University Children's Hospital Zürich, Zürich, 8032, Switzerland.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford, OX3 9DS, UK.



A diverse B-cell repertoire is essential for recognition and response to infectious and vaccine antigens. High-throughput sequencing of B-cell receptor (BCR) genes can now be used to study the B-cell repertoire at great depth and may shed more light on B-cell responses than conventional immunological methods. Here, we use high-throughput BCR sequencing to provide novel insight into B-cell dynamics following a primary course of hepatitis B vaccination.


Nine vaccine-naïve participants were administered three doses of hepatitis B vaccine (months 0, 1, and 2 or 7). High-throughput Illumina sequencing of the total BCR repertoire was combined with targeted sequencing of sorted vaccine antigen-enriched B cells to analyze the longitudinal response of both the total and vaccine-specific repertoire after each vaccine. ELISpot was used to determine vaccine-specific cell numbers following each vaccine.


Deconvoluting the vaccine-specific from total BCR repertoire showed that vaccine-specific sequence clusters comprised <0.1 % of total sequence clusters, and had certain stereotypic features. The vaccine-specific BCR sequence clusters were expanded after each of the three vaccine doses, despite no vaccine-specific B cells being detected by ELISpot after the first vaccine dose. These vaccine-specific BCR clusters detected after the first vaccine dose had distinct properties compared to those detected after subsequent doses; they were more mutated, present at low frequency even prior to vaccination, and appeared to be derived from more mature B cells.


These results demonstrate the high-sensitivity of our vaccine-specific BCR analysis approach and suggest an alternative view of the B-cell response to novel antigens. In the response to the first vaccine dose, many vaccine-specific BCR clusters appeared to largely derive from previously activated cross-reactive B cells that have low affinity for the vaccine antigen, and subsequent doses were required to yield higher affinity B cells.


Antibody; B-cell repertoire; Hepatitis B; Polyreactive; VDJ; Vaccination

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