Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

Cell. 2019 May 16;177(5):1153-1171.e28. doi: 10.1016/j.cell.2019.04.012. Epub 2019 May 9.


Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

Keywords: FNA; GC- T(FH); HIV vaccine; affinity maturation; immune complexes; memory B cells; non-human primates; rhesus macaque genome; somatic hypermutation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Female
  • Germinal Center / immunology*
  • Germinal Center / pathology
  • Germinal Center / virology
  • HIV Antibodies / immunology*
  • HIV-1 / immunology*
  • Immunization, Passive*
  • Macaca mulatta
  • Male
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / pathology
  • env Gene Products, Human Immunodeficiency Virus / immunology


  • Antibodies, Neutralizing
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus