Bridging Vaccine-Induced HIV-1 Neutralizing and Effector Antibody Responses in Rabbit and Rhesus Macaque Animal Models

Abstract

Studies in animal models are essential prerequisites for clinical trials of candidate HIV vaccines. Small animals, such as rabbits, are used to evaluate promising strategies prior to further immunogenicity and efficacy testing in nonhuman primates. Our goal was to determine how HIV-specific vaccine-elicited antibody responses, epitope specificity, and Fc-mediated functions in the rabbit model can predict those in the rhesus macaque (RM) model. Detailed comparisons of the HIV-1-specific IgG response were performed on serum from rabbits and RM given identical modified vaccinia virus Ankara-prime/gp120-boost immunization regimens. We found that vaccine-induced neutralizing antibody, gp120-binding antibody levels and immunodominant specificities, antibody-dependent cellular phagocytosis of HIV-1 virions, and antibody-dependent cellular cytotoxicity (ADCC) responses against gp120-coated target cells were similar in rabbits and RM. However, we also identified characteristics of humoral immunity that differed across species. ADCC against HIV-infected target cells was elicited in rabbits but not in RM, and we observed differences among subdominantly targeted epitopes. Human Fc receptor binding assays and analysis of antibody-cell interactions indicated that rabbit vaccine-induced antibodies effectively recruited and activated human natural killer cells, while vaccine-elicited RM antibodies were unable to activate either human or RM NK cells. Thus, our data demonstrate that both Fc-independent and Fc-dependent functions of rabbit antibodies can be measured with commonly usedin vitroassays; however, the ability of immunogenicity studies performed in rabbits to predict responses in RM will vary depending on the particular immune parameter of interest.IMPORTANCENonneutralizing antibody functions have been associated with reduced infection risk, or control of virus replication, for HIV-1 and related viruses. It is therefore critical to evaluate development of these responses throughout all stages of preclinical testing. Rabbits are conventionally used to evaluate the ability of vaccine candidates to safely elicit antibodies that bind and neutralize HIV-1. However, it remained unexplored how effectively rabbits model the development of nonneutralizing antibody responses in primates. We administered identical HIV-1 vaccine regimens to rabbits and rhesus macaques and performed detailed comparisons of vaccine-induced antibody responses. We demonstrated that nonneutralizing HIV-specific antibody responses can be studied in the rabbit model and have identified aspects of these responses that are common, and those that are unique, to rabbits and rhesus macaques. Our findings will help determine how to best utilize preclinical rabbit and rhesus macaque models to accelerate HIV vaccine candidate testing in human trials.

Optimized Mucosal Modified Vaccinia Virus Ankara Prime/Soluble gp120 Boost HIV Vaccination Regimen Induces Antibody Responses Similar to Those of an Intramuscular Regimen

“…7 and 8). As reported by Pollara et al (49), there were no significant differences in ADCC activity against gp120-coated target cells or antibody-dependent cellular phagocytosis (ADCP) of HIV-1 virions between the two vaccination regimens.…”

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

“…We identified similar peak phagocytosis activity (10 weeks), but intriguingly we noted enhanced phagocytosis in gB FL vaccinees at 20 weeks indicating more robust phagocytosis durability in this group (median %phagocytosing cells: FL = 10.1% vs. mRNA = 7.1%, p<0.01, Kruskal-Wallis + post hoc Mann-Whitney U test). Next, we assessed NK cell degranulation activity (CD107a upregulation) when vaccine-elicited antibodies are incubated with HCMV-infected cells ( Figure 5F ), which we previously identified to approximate antibody-dependent cellular cytotoxicity (ADCC) for rabbits [17]. However, we were unable to measure NK degranulation activity for the majority of animals, suggesting that antibodies mediating this non-neutralizing effector function are not a dominant response elicited by gB FL, gB ecto, or gB mRNA vaccines.…”

“…HCMV preclinical vaccine development is hindered by the fact that small animal models poorly represent host-pathogen biology and mechanisms of disease pathogenesis [26, 27]. We chose to test immunogenicity in rabbits because we previously demonstrated that vaccination can elicit antibodies with both neutralizing and non-neutralizing in vitro functionality [17]. In this study we were able to epitope-map and define the function of antibodies elicited by these three experimental vaccines, then compare to previously-reported immune correlates of protection (Nelson, Journal of Infectious Diseases , 2019, in press).…”

“…Cell-surface expression of CD107a was used as a marker for NK cell degranulation, which we have previously shown to have good agreement with antibody-dependent cellular cytotoxicity activity for rabbit sera [17]. MRC-5 cells were infected with BadrUL131-Y4 with a MOI of 1.0 for 48 hours at 37°C, at 4×10 4 cells/well in 96-well flat-bottom tissue culture plates.…”

“…Here we present an investigation into the immunogenicity of two novel gB vaccines aiming to reduce exposure to AD-3: a truncated gB protein subunit vaccine (lacking the AD-3 epitope) administered with MF59-like squalene adjuvant AddaVax (gB ectodomain vaccine) and a gB nucleoside-modified mRNA vaccine packaged in lipid nanoparticles (gB mRNA-LNP vaccine). New Zealand White rabbits were selected for this study because we previously identified that neutralizing and non-neutralizing antibodies are elicited in rabbits by vaccination, and that F c receptor-independent and dependent effector functions can be measured in vitro [17]. Three groups of rabbits were vaccinated with either: 1) full-length gB + AddaVax (immunogen from gB/MF59 vaccine trial; ‘gB FL’), 2) gB ectodomain + AddaVax (‘gB ecto’), or 3) gB mRNA-LNP (‘gB mRNA).…”