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

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
Justin Pollara ◽  
Dorothy I. Jones ◽  
Tori Huffman ◽  
R. Whitney Edwards ◽  
Maria Dennis ◽  
...  
Keyword(s):  
Animal Models ◽  
Rhesus Macaque ◽  
Rhesus Macaques ◽  
Rabbit Model ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Target Cells ◽  
Human Natural Killer Cells ◽  
Hiv 1

ABSTRACTStudies 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.

scholarly journals Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Maria Blasi ◽  
Donatella Negri ◽  
Kevin O. Saunders ◽  
Erich J. Baker ◽  
Hannah Stadtler ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Lentiviral Vector ◽  
Rhesus Macaques ◽  
Infected Individual ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Safety And Efficacy ◽  
Env Protein ◽  
Hiv 1

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study, we report the immunogenicity, safety, and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Envs induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/− protein immunizations using the same sequential envelopes. Compared to monkeys immunized with a vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six months after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Although the tested vaccines failed to induce bnAbs and to mediate significant protection following SHIV-challenge, our results show that IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms.

scholarly journals Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

2015 ◽  
Vol 112 (34) ◽  
pp. 10780-10785 ◽  
Author(s):  
Samantha L. Burton ◽  
Katie M. Kilgore ◽  
S. Abigail Smith ◽  
Sharmila Reddy ◽  
Eric Hunter ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Active Immunization ◽  
Antibody Responses ◽  
Challenge Virus ◽  
Gm Csf ◽  
Immunodeficiency Virus

Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

scholarly journals Immunogenicity, safety and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

2020 ◽  
Author(s):  
Blasi Maria ◽  
Negri Donatella ◽  
Saunders O Kevin ◽  
Baker J Erich ◽  
Stadtler Hannah ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Lentiviral Vector ◽  
Rhesus Macaques ◽  
Infected Individual ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Safety And Efficacy ◽  
Broadly Neutralizing Antibody ◽  
Env Protein ◽  
Hiv 1

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study we report the immunogenicity, safety and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Env induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/- protein immunizations using the same sequential envelopes. Compared to monkeys immunized with vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six month after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Our results show that while IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms, the use of non-stabilized sequential envelope trimers did not induce broadly neutralizing antibody responses.

scholarly journals Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

2020 ◽  
Vol 117 (31) ◽  
pp. 18719-18728 ◽  
Author(s):  
Magnus A. G. Hoffmann ◽  
Yotam Bar-On ◽  
Zhi Yang ◽  
Harry B. Gristick ◽  
Priyanthi N. P. Gnanapragasam ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Neutralizing Antibody ◽  
Viral Fitness ◽  
Viral Escape ◽  
Target Cells ◽  
High Avidity ◽  
Viral Control ◽  
Cd4 Binding Site ◽  
Hiv 1

CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy.

scholarly journals Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Philip J. M. Brouwer ◽  
Aleksandar Antanasijevic ◽  
Zachary Berndsen ◽  
Anila Yasmeen ◽  
Brooke Fiala ◽  
...  
Keyword(s):  
Animal Models ◽  
High Efficiency ◽  
Neutralizing Antibody ◽  
Two Component ◽  
Nanoparticle System ◽  
Hiv 1 ◽  
Component Protein

Abstract The development of native-like HIV-1 envelope (Env) trimer antigens has enabled the induction of neutralizing antibody (NAb) responses against neutralization-resistant HIV-1 strains in animal models. However, NAb responses are relatively weak and narrow in specificity. Displaying antigens in a multivalent fashion on nanoparticles (NPs) is an established strategy to increase their immunogenicity. Here we present the design and characterization of two-component protein NPs displaying 20 stabilized SOSIP trimers from various HIV-1 strains. The two-component nature permits the incorporation of exclusively well-folded, native-like Env trimers into NPs that self-assemble in vitro with high efficiency. Immunization studies show that the NPs are particularly efficacious as priming immunogens, improve the quality of the Ab response over a conventional one-component nanoparticle system, and are most effective when SOSIP trimers with an apex-proximate neutralizing epitope are displayed. Their ability to enhance and shape the immunogenicity of SOSIP trimers make these NPs a promising immunogen platform.

scholarly journals Vaccination of Rhesus Macaques with Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Env V3 Elicits Neutralizing Antibody-Mediated Protection against Simian-Human Immunodeficiency Virus with a Homologous but Not a Heterologous V3 Motif

2005 ◽  
Vol 79 (3) ◽  
pp. 1452-1462 ◽  
Author(s):  
Kenji Someya ◽  
Dayaraj Cecilia ◽  
Yasushi Ami ◽  
Tadashi Nakasone ◽  
Kazuhiro Matsuo ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Mycobacterium Bovis ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
High Dose ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Although the correlates of vaccine-induced protection against human immunodeficiency virus type 1 (HIV-1) are not fully known, it is presumed that neutralizing antibodies (NAb) play a role in controlling virus infection. In this study, we examined immune responses elicited in rhesus macaques following vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing an HIV-1 Env V3 antigen (rBCG Env V3). We also determined the effect of vaccination on protection against challenge with either a simian-human immunodeficiency virus (SHIV-MN) or a highly pathogenic SHIV strain (SHIV-89.6PD). Immunization with rBCG Env V3 elicited significant levels of NAb for the 24 weeks tested that were predominantly HIV-1 type specific. Sera from the immunized macaques neutralized primary HIV-1 isolates in vitro, including HIV-1BZ167/X4, HIV-1SF2/X4, HIV-1CI2/X4, and, to a lesser extent, HIV-1MNp/X4, all of which contain a V3 sequence homologous to that of rBCG Env V3. In contrast, neutralization was not observed against HIV-1SF33/X4, which has a heterologous V3 sequence, nor was it found against primary HIV-1 R5 isolates from either clade A or B. Furthermore, the viral load in the vaccinated macaques was significantly reduced following low-dose challenge with SHIV-MN, and early plasma viremia was markedly decreased after high-dose SHIV-MN challenge. In contrast, replication of pathogenic SHIV-89.6PD was not affected by vaccination in any of the macaques. Thus, we have shown that immunization with an rBCG Env V3 vaccine elicits a strong, type-specific V3 NAb response in rhesus macaques. While this response was not sufficient to provide protection against a pathogenic SHIV challenge, it was able to significantly reduce the viral load in macaques following challenge with a nonpathogenic SHIV. These observations suggest that rBCG vectors have the potential to deliver an appropriate virus immunogen for desirable immune elicitations.

scholarly journals Comparison of Neutralizing Antibody Responses Elicited from Highly Diverse Polyvalent Heterotrimeric HIV-1 gp140 Cocktail Immunogens versus a Monovalent Counterpart in Rhesus Macaques

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e114709 ◽  
Author(s):  
Emma J. Bowles ◽  
Torben Schiffner ◽  
Maximillian Rosario ◽  
Gemma A. Needham ◽  
Meghna Ramaswamy ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Hiv 1

scholarly journals Antibody Responses Elicited in Macaques Immunized with Human Immunodeficiency Virus Type 1 (HIV-1) SF162-Derived gp140 Envelope Immunogens: Comparison with Those Elicited during Homologous Simian/Human Immunodeficiency Virus SHIVSF162P4 and Heterologous HIV-1 Infection

2006 ◽  
Vol 80 (17) ◽  
pp. 8745-8762 ◽  
Author(s):  
Nina R. Derby ◽  
Zane Kraft ◽  
Elaine Kan ◽  
Emma T. Crooks ◽  
Susan W. Barnett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Hypervariable Region ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
V3 Loop ◽  
Immunodeficiency Virus ◽  
The Difference ◽  
Hiv 1

ABSTRACT The antibody responses elicited in rhesus macaques immunized with soluble human immunodeficiency virus (HIV) Env gp140 proteins derived from the R5-tropic HIV-1 SF162 virus were analyzed and compared to the broadly reactive neutralizing antibody responses elicited during chronic infection of a macaque with a simian/human immunodeficiency virus (SHIV) expressing the HIV-1 SF162 Env, SHIVSF162P4, and humans infected with heterologous HIV-1 isolates. Four gp140 immunogens were evaluated: SF162gp140, ΔV2gp140 (lacking the crown of the V2 loop), ΔV3gp140 (lacking the crown of the V3 loop), and ΔV2ΔV3gp140 (lacking both the V2 and V3 loop crowns). SF162gp140 and ΔV2gp140 have been previously evaluated by our group in a pilot study, but here, a more comprehensive analysis of their immunogenic properties was performed. All four gp140 immunogens elicited stronger anti-gp120 than anti-gp41 antibodies and potent homologous neutralizing antibodies (NAbs) that primarily targeted the first hypervariable region (V1 loop) of gp120, although SF162gp140 also elicited anti-V3 NAbs. Heterologous NAbs were elicited by SF162gp140 and ΔV2gp140 but were weak in potency and narrow in specificity. No heterologous NAbs were elicited by ΔV3gp140 or ΔV2ΔV3gp140. In contrast, the SHIVSF162P4-infected macaque and HIV-infected humans generated similar titers of anti-gp120 and anti-gp41 antibodies and NAbs of significant breadth against primary HIV-1 isolates, which did not target the V1 loop. The difference in V1 loop immunogenicity between soluble gp140 and virion-associated gp160 Env proteins derived from SF162 may be the basis for the observed difference in the breadth of neutralization in sera from the immunized and infected animals studied here.

scholarly journals ChAdOx1 nCoV-19 protection against SARS-CoV-2 in rhesus macaque and ferret challenge models

2021 ◽  
Author(s):  
Teresa Lambe ◽  
Alexandra Spencer ◽  
Kelly Thomas ◽  
Stephen Thomas ◽  
Andrew White ◽  
...  
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Rhesus Macaque ◽  
Clinical Evaluation ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Lung Pathology ◽  
Virus Shedding ◽  
Antibody Titers ◽  
Immune Profiling

Abstract Vaccines against SARS-CoV-2 are urgently required. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titers were boosted by a second dose. Data from these challenge models and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19.

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