Abstract
Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity. We perform longitudinal analyses of HIV Env-specific B-cell receptor responses to SHIVAD8 infection and Env protein vaccination with eight different adjuvants. A subset of the SHIVAD8-infected animals with higher viral loads and greater Env diversity show increased neutralization associated with increasing somatic hypermutation (SHM) levels over time. The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths. Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.
Highlights
Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine
Longitudinal analyses of two cohorts were performed to address the critical questions of how antigen load, diversity, persistence and innate immunity alter antibody responses: (1) nonhuman primates (NHPs) infected with SHIVAD8 provide a model with persistent and diverse Env antigens that has been shown to induce potent cross-clade serum-neutralization responses[10,21,22]; and (2) NHPs vaccinated with gp[140] Env protein and eight different adjuvants (alum or MF59 with or without TLR4 or TLR7 ligands, pIC:LC or immune stimulator complexes (ISCOMs)), which were chosen because they are clinically approved or in advanced development, and because they mediate their effects through distinct innate mechanisms that could influence B-cell immunity
Env probespecific B cells were bulk-sorted from individual animals at various time points after SHIVAD8 infection or Env and adjuvant vaccination (Supplementary Fig. 2), IgG heavy chain (HC) transcripts were amplified by multiplexed primer PCR with unique barcodes, and sequenced by 454 pyrosequencing
Summary
Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Longitudinal analyses of two cohorts were performed to address the critical questions of how antigen load, diversity, persistence and innate immunity alter antibody responses: (1) NHP infected with SHIVAD8 provide a model with persistent and diverse Env antigens that has been shown to induce potent cross-clade serum-neutralization responses[10,21,22]; and (2) NHPs vaccinated with gp[140] Env protein and eight different adjuvants (alum or MF59 with or without TLR4 or TLR7 ligands, pIC:LC or immune stimulator complexes (ISCOMs)), which were chosen because they are clinically approved or in advanced development, and because they mediate their effects through distinct innate mechanisms that could influence B-cell immunity From both of these studies, peripheral antibody transcripts isolated from Env-specific B cells were sequenced to assess SHM, CDR H3 length and variable heavy (VH) gene repertoire.
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