[PDF][PDF] Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

KM Cirelli, DG Carnathan, B Nogal, JT Martin… - Cell, 2019 - cell.com
KM Cirelli, DG Carnathan, B Nogal, JT Martin, OL Rodriguez, AA Upadhyay, CA Enemuo…
Cell, 2019cell.com
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 (T FH) cell
responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle …
Summary
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.
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