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

Abstract

Highlights d Slow delivery immunization enhances HIV neutralizing antibody development in monkeys d Slow delivery immunization alters immunodominance of the responding B cells d Weekly longitudinal germinal center (GC) B and T FH analyses provides new GC insights d High-resolution rhesus immunoglobulin locus genomic reference sequence

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

“…Another notable phenotype for the high-titer animals was a different angle of approach by which Fabs bound to the C3/V5-3 epitope: three of six animals exhibited this phenotype, with the low-titer macaques favoring the GH-1 in lieu of this putative high-titer correlate (compare Figure 2 with Figure 3A, 3B, and 3F). This observation was consistent in additional unchallenged low and high-titer animals from the immunization study ( Figure S3D) (Cirelli et al, 2019;Pauthner et al, 2017). Overall, high-titer group displayed an increased diversity in the targeted epitopes, especially with the appearance of V1/V3 binding antibodies, and an associated increase in trimer occupancy ( Figure 3), with apparently unique angles of approach as well, factors that may have contributed to these animals' resistance to infection.…”

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

“…The development of GC immune responses is a highly regulated, multifactorial process requiring the spatial organization and (Cirelli et al, 2019). 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.…”

Targeting HIV Env immunogens to B cell follicles in non-human primates through immune complex or protein nanoparticle formulations

“…Concentration of antigen in follicles was observed by multiple methods, including by whole organ clarification and by tissue sectioning and immunofluorescent staining. This was the first time that such a process has been shown in NHPs for Env-presenting NPs, although the pattern of antigen deposition is reminiscent of the localization recently shown for animals receiving sustained antigen delivery via osmotic pumps or repeated injections 46,47 . The similarity lends support to the hypothesis that ICs from early antigen-specific IgM and IgG were the driving factors for FDC deposition in those "slow delivery" vaccine administration studies.…”

“…However, it has been shown that glycans of soluble Env trimers are recognized by SIGN-R1-expressing macrophages in lymph nodes, leading to capture of Env immunogens in interfollicular regions of lymph nodes following immunization 20,36 . Env immunogen accumulation on FDCs has been demonstrated by using novel immunization strategies that deliver antigen delivery over time periods of several weeks through implanted osmotic pumps or repeated injections 46,47 , but such strategies may not be clinically practical.…”

“…In the setting of HIV vaccines, complexation with mAbs has been used to alter the accessibility of neutralizing vs. non-neutralizing epitopes or alter conformations of the immunogen, promoting B cell responses against neutralizing epitopes 28 . Motivated by the recent findings that the base of Env trimers is a highly immunodominant non-neutralizing target on SOSIP immunogens 46,49,50 , we utilized a mAb isolated from macaques recognizing a base epitope for IC formation, with the goal of masking humoral responses against the base. To allow for the in vivo formation of ICs, we preinjected animals intravenously (i.e.…”