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

Abstract

35The observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has 36 generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization 37 strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other 38 difficult pathogens, due to the significant immunological hurdles posed, including B cell 39 immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine 40 needle aspirates, we found that two independent methods of slow delivery immunization of rhesus 41 macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells 42 with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 43 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified 44 differential IgV gene usage between slow delivery immunized and conventional bolus immunized 45 animals. The most immunodominant IgV gene used by conventionally immunized animals was 46 associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated 47 targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted 48 in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb 49 development by altering GCs and modulating immunodominance of non-neutralizing epitopes. 50 51

Mapping polyclonal antibody responses in non-human primates vaccinated with HIV Env trimer subunit vaccines

“…C3/V5 was highly immunogenic, and we found a range of approach angles for antibodies binding to this epitope. Some, namely those designated C3/V5-3 antibodies, were only detected in high-titer animals (Figure 3), a finding that is consistent with a prior study (Cirelli et al, 2018). Still, without the additional presence of V1/V3 antibodies, the C3/V5-3 epitope by itself was insufficient for durable protection in the face of repetitive SHIV challenges.…”

“…In an attempt to map NHP antibody responses in the context of both differing neutralization titers and levels of protection from a SHIV challenge (Pauthner et al, 2017, we applied our EMPEM approach to identify and characterize vaccine-induced antibodies that correlated with serum neutralizing titers, and consequently protection . In contrast to rabbits, where the 241/289 glycan hole and trimer base are the predominant targets of the antibody response, several additional epitopes were identified to be immunogenic in NHPs, some of which are likely responsible for the bulk of the neutralization activity (Cirelli et al, 2018;Klasse et al, 2018;Pauthner et al, 2017). These epitopes include the FP, V1/V3, and a newly identified epitope at the gp120/gp120 interface.…”

Targeting Conventional Dendritic Cells to Fine-Tune Antibody Responses

“…Encouraging findings in mice using HIV Env trimers or HIV gp120 as antigen have shown that prolonged antigen release gives better antibody responses when compared to bolus vaccination—an effect that may be further improved by exponentially increasing the immunization dose (75, 76). Studies in non-human primates have shown similar effects (77, 78), demonstrating the translational potential of this immunization strategy. One possible explanation for the improved antibody responses may be that these vaccination strategies more closely mimic antigen availability kinetics of natural infections.…”

Compromised steady‐state germinal center activity with age in nonhuman primates

“…Whether this is the case in aging too is not known and needs further investigation, and (e) an integrated analysis combining novel quantitative multiplexed imaging assays and modeling of imaging data with high dimensional phenotypic and molecular (sequencing) characterization could lead to the construction of “tissue signatures” and the identification of targets for boosting GC dynamics and vaccine responses in old individuals. Given the limited, if any, access to LN biopsies in human clinical trials, alternative strategies (fine needle aspiration—FNA) have been proposed (Cirelli et al, ). However, we should keep in mind that critical information (i.e., tissue structure, cell–cell positioning) cannot be obtained using FNAs, further emphasizing the importance of using the NHP model.…”