Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens

Immunity. 2018 Jan 16;48(1):133-146.e6. doi: 10.1016/j.immuni.2017.11.023. Epub 2017 Dec 26.


How precursor frequencies and antigen affinities impact interclonal B cell competition is a particularly relevant issue for candidate germline-targeting HIV vaccine designs because of the in vivo rarity of naive B cells that recognize broadly neutralizing epitopes. Knowing the frequencies and affinities of HIV-specific VRC01-class naive human B cells, we transferred B cells with germline VRC01 B cell receptors into congenic recipients to elucidate the roles of precursor frequency, antigen affinity, and avidity on B cell responses following immunization. All three factors were interdependently limiting for competitive success of VRC01-class B cells. In physiological high-affinity conditions using a multivalent immunogen, rare VRC01-class B cells successfully competed in germinal centers (GC), underwent extensive somatic hypermutation, and differentiated into memory B cells. The data reveal dominant influences of precursor frequency, affinity, and avidity for interclonal GC competition and indicate that germline-targeting immunogens can overcome these challenges with high-affinity multimeric designs.

Keywords: HIV; T follicular helper (Tfh); VRC01; affinity maturation; antibody; avidity; humoral immunity; immunoglobulins; interclonal competition; vaccine.

Publication types

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

MeSH terms

  • AIDS Vaccines / immunology*
  • Animals
  • Antibodies, Monoclonal / immunology*
  • B-Lymphocytes / immunology*
  • Broadly Neutralizing Antibodies
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Germinal Center / immunology*
  • HIV Antibodies
  • HIV-1 / immunology*
  • Male
  • Mice
  • Mice, Transgenic


  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Broadly Neutralizing Antibodies
  • HIV Antibodies
  • VRC01 monoclonal antibody