Last data update: Sep 23, 2024. (Total: 47723 publications since 2009)
Records 1-10 (of 10 Records) |
Query Trace: Garber DA [original query] |
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Broadly neutralizing antibody-mediated protection against SHIV infection among macaques with vaginal sexually transmitted infections
Garber DA , Guenthner P , Zhao C , Mitchell J , Ellis S , Jia H , Manganare M , Gazumyan A , Seaman MS , Vishwanathan SA , Heneine W , McNicholl JM . AIDS 2023 37 (5) 723-731 OBJECTIVE: Sexually transmitted infections (STIs) increase mucosal HIV infection risk and have the potential to reduce preexposure prophylaxis efficacy. Clinical trials of a broadly neutralizing antibody (bNAb) provided proof-of-concept that passive immunization against HIV can be efficacious in people. We sought to evaluate preclinically the protective efficacy of passive bNAb immunization against simian-human immunodeficiency virus (SHIV) infection in the context of concurrent vaginal STIs. DESIGN: Using a macaque model of combined ulcerative and nonulcerative vaginal STIs caused by Treponema pallidum, Chlamydia trachomatis, and Trichomonas vaginalis, we determined the protection that passively administered bNAb 10-1074 conferred against repeated vaginal SHIV challenges and compared correlates of protection to contemporaneous and historical controls without STIs. METHODS: Plasma viremia was monitored via RT-qPCR assay. Concentrations of 10-1074 were determined longitudinally in plasma samples via TZM-bl pseudovirus neutralization assay. RESULTS: Among macaques with vaginal STIs, a single subcutaneous injection of 10-1074 durably protected against vaginal SHIV acquisition, as compared with untreated controls. Interestingly, the median plasma concentration of 10-1074 at the time of SHIV breakthrough among macaques with STIs was significantly higher (10-fold) than that previously observed among 10-1074-treated macaques in the absence of STIs. CONCLUSION: Passive immunization with 10-1074 conferred significant protection against repeated vaginal SHIV challenges among macaques harboring vaginal STIs. However, our findings suggest that higher bNAb concentrations may be required for prophylaxis when STIs are present. Our findings potentially impact dose selection for the clinical development of bNAbs and highlight the importance of additional preclinical efficacy testing in STI models. |
Broadly neutralizing antibody-mediated protection of macaques against repeated intravenous exposures to simian-human immunodeficiency virus
Garber DA , Guenthner P , Mitchell J , Ellis S , Gazumyan A , Nason M , Seaman MS , McNicholl JM , Nussenzweig MC , Heneine W . AIDS 2021 35 (10) 1567-1574 OBJECTIVE: The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous SHIV infection in macaques. DESIGN: Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10 mg each kg-1) and were repeatedly challenged intravenously once weekly with SHIVAD8-EO (130 TCID50), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically. METHODS: Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins. RESULTS: Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo. The median plasma level of 10-1074 at SHIV breakthrough was 1.1 μg ml-1 (range: 0.6-1.6 μg ml-1), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6 μg ml-1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls. CONCLUSIONS: Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting pre-exposure prophylaxis for persons who inject drugs. |
Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies
Garber DA , Adams DR , Guenthner P , Mitchell J , Kelley K , Schoofs T , Gazumyan A , Nason M , Seaman MS , McNicholl J , Nussenzweig MC , Heneine W . Nat Commun 2020 11 (1) 3195 Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 mug ml(-1) correlated with >/=99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women. |
Implementation of a three-tiered approach to identify and characterize anti-drug antibodies raised against HIV-specific broadly neutralizing antibodies
Bharadwaj P , Riekofski C , Lin S , Seaman MS , Garber DA , Montefiori D , Sarzotti-Kelsoe M , Ackerman ME , Weiner JA . J Immunol Methods 2020 479 112764 The ability to detect, quantify, and interrogate the properties of immune responses raised against biological therapeutics is not only important to our understanding of these molecules, but also to their success in the clinic. A tiered assay approach to identify the presence, specificity, and titer of anti-drug antibody (ADA) responses has been adopted as a gold standard by industry leaders, the FDA, and the EMA. In order to support pre-clinical and clinical trials, these assays must be standardized, and their performance sufficiently characterized to ensure the accuracy and reproducibility of results under relevant testing conditions. Here we present implementation of electrochemiluminiscence assays that fit into the tiered paradigm of ADA testing for five HIV broadly neutralizing antibodies (3NC117, 3BNC117-LS, 10-1074, PGT121, and PGDM1400) in compliance with Good Clinical Laboratory practices. Assay sensitivities and matrix effects were evaluated and used to inform the development of positivity cut points. Once cut points were established, assay precision, specificity, free-drug tolerance, and robustness were defined. In all cases, assay characteristics met or surpassed recommendations set forth by the FDA. To further evaluate the performance of these assays and the tiered approach, samples from non-human primates that had received a subset of the five therapeutics were evaluated. In sum, this study reports qualification of a set of ADA assays available to the scientific community as pre-clinical and clinical trials of broadly HIV-neutralizing antibodies proceed, and a framework that is easily adapted as new drug products are advanced in the clinic. |
Optimization and qualification of a functional anti-drug antibody assay for HIV-1 bnAbs
Seaman MS , Bilska M , Ghantous F , Eaton A , LaBranche CC , Greene K , Gao H , Weiner JA , Ackerman ME , Garber DA , Rosenberg YJ , Sarzotti-Kelsoe M , Montefiori DC . J Immunol Methods 2020 479 112736 The recent identification of human monoclonal antibodies with broad and potent neutralizing activity against HIV-1 (bnAbs) has resulted in substantial efforts to develop these molecules for clinical use in the prevention and treatment of HIV-1 infection. As with any protein therapeutic drug product, it is imperative to have qualified assays that can accurately detect and quantify anti-drug antibodies (ADA) that may develop in patients receiving passive administration of HIV-1 bnAbs. Here, we have optimized and qualified a functional assay to assess the potential of ADA to inhibit the neutralizing function of HIV-1 bnAbs. Using a modified version of the validated TZM-bl HIV-1 neutralization assay, murine anti-idiotype antibodies were utilized to optimize and evaluate parameters of linearity, range, limit of detection, specificity, and precision for measuring inhibitory ADA activity against multiple HIV-1 bnAbs that are in clinical development. We further demonstrate the utility of this assay for detecting naturally occurring ADA responses in non-human primates receiving passive administration of human bnAbs. This functional assay format complements binding-antibody ADA strategies being developed for HIV-1 bnAbs, and when utilized together, will support a multi-tiered approach for ADA testing that is compliant with Good Clinical Laboratory Practice (GCLP) procedures and FDA guidance. |
Impact of Q-Griffithsin anti-HIV microbicide gel in non-human primates: In situ analyses of epithelial and immune cell markers in rectal mucosa
Gunaydin G , Edfeldt G , Garber DA , Asghar M , Noel-Romas L , Burgener A , Wahlby C , Wang L , Rohan LC , Guenthner P , Mitchell J , Matoba N , McNicholl JM , Palmer KE , Tjernlund A , Broliden K . Sci Rep 2019 9 (1) 18120 Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin(+) cells, CD4(+) cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin(+) cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4(+) cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4(+) cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4(+) lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4(+) rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa. |
Development of a repeat-exposure penile SHIV infection model in macaques to evaluate biomedical preventions against HIV
Garber DA , Mitchell J , Adams D , Guenthner P , Deyounks F , Ellis S , Kelley K , Johnson R , Dobard C , Heneine W , McNicholl J . PLoS One 2018 13 (3) e0194837 Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIVsf162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4-600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50) and urethra (16 TCID50) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1-12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men. |
Rectal application of a highly osmolar personal lubricant in a macaque model induces acute cytotoxicity but does not increase risk of SHIV infection
Vishwanathan SA , Morris MR , Wolitski RJ , Luo W , Rose CE , Blau DM , Tsegaye T , Zaki SR , Garber DA , Jenkins LT , Henning TC , Patton DL , Hendry RM , McNicholl JM , Kersh EN . PLoS One 2015 10 (4) e0120021 BACKGROUND: Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15. METHODS: Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure. RESULTS: Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models). CONCLUSIONS: Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission. |
Pharmacokinetic and safety analyses of tenofovir and tenofovir-emtricitabine vaginal tablets in pigtailed macaques
Pereira LE , Clark MR , Friend DR , Garber DA , McNicholl JM , Hendry RM , Doncel GF , Smith JM . Antimicrob Agents Chemother 2014 58 (5) 2665-74 Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups (n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group (n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of <30 min following vaginal application of the RDTs was noted, with negligible effects on local inflammatory cytokines, vaginal pH, and microflora. TFV pharmacokinetics were generally similar for both RDTs and gel, with peak median concentrations in vaginal tissues and vaginal secretions being on the order of 10(4) to 10(5) ng/g (147 to 571 muM) and 10(6) ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 10(4) ng/g (374 muM) and 10(6) ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period. |
Deletion of specific immune-modulatory genes from modified vaccinia virus Ankara-based HIV vaccines engenders improved immunogenicity in rhesus macaques.
Garber DA , O'Mara LA , Gangadhara S , McQuoid M , Zhang X , Zheng R , Gill K , Verma M , Yu T , Johnson B , Li B , Derdeyn CA , Ibegbu C , Altman JD , Hunter E , Feinberg MB . J Virol 2012 86 (23) 12605-15 Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1beta receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVADelta4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVADelta5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 x 10(8) PFU) or low-dose (1 x 10(7) PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates. |
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