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Broadly neutralizing antibody-mediated protection of macaques against repeated intravenous exposures to simian-human immunodeficiency virus

Garber, David A.a; Guenthner, Patriciaa; Mitchell, Jamesa; Ellis, Shanona; Gazumyan, Annab; Nason, Marthac; Seaman, Michael S.d; McNicholl, Janet M.a; Nussenzweig, Michel C.b,e; Heneine, Walida

Author Information
doi: 10.1097/QAD.0000000000002934

Abstract

Introduction

Over the last decade, increasing abuse of opioids has caused a dramatic increase in the number of persons who inject drugs (PWID) and has been associated with HIV outbreaks in the United States [1–6]. Sharing needles, syringes or other injection equipment that may contain blood presents a substantial risk for transmission of HIV and other bloodborne pathogens [7,8]. In the United States, approximately 10% of new HIV diagnoses occur among PWID and are attributable to injection drug use (IDU) (6%) or the combined risk of IDU and male-to-male sexual contact (4%) [9]. Globally, it is estimated there are some 15.6 million PWID among whom 18% are living with HIV [10].

Current strategies to reduce the risk of HIV transmission among PWID include needle and syringe service programs, supervised injection facilities, opioid agonist therapy, and administration of antiretrovirals (ARVs), either as a treatment for HIV-infected individuals to reduce their transmission probability (treatment as prevention), or to HIV-uninfected persons as preexposure prophylaxis (PrEP) [11–13]. Although these programmatic and biomedical interventions can be highly efficacious for mitigating HIV infection among PWID when implemented successfully, numerous barriers weigh against their overall effectiveness. Among these are criminalization and stigma concerning injection drug use, and limited access to healthcare – particularly in rural settings where increasing opioid injection practices have resulted in HIV outbreaks within the United States [1,14].

Regarding PrEP among PWID, the Bangkok Tenofovir Study (BTS) demonstrated once-daily oral tenofovir disoproxil fumarate (TDF) reduced HIV incidence by 48.9% overall, with greater reductions (up to 83.5%) observed among PWID who were highly adherent to the daily dosing regimen [15–17]. As a result, daily oral PrEP has been recommended to reduce HIV infection risk among PWID since 2013 [13,18]. However, the BTS, as well as several clinical trials that evaluated the efficacy of daily oral TDF- or TDF/emtricitabine (FTC)-based PrEP regimens to prevent sexually acquired HIV infection, highlight that user adherence to daily dosing regimens remains a significant challenge to maximizing PrEP effectiveness [19–21].

Multiple barriers limit uptake and adherence to daily antiretroviral therapy among HIV-infected PWID and contribute to this group's lower rate of viral suppression (50–55%), as compared to other transmission categories, and may similarly impact adherence of uninfected PWID to daily oral PrEP [22–25]. Development of products and strategies that facilitate PrEP adherence, such as long-acting products as alternatives to those requiring daily dosing, could improve PrEP effectiveness against HIV acquisition via intravenous as well as sexual routes. In this regard, a long-acting injectable formulation of cabotegravir recently has been found to exhibit high efficacy among men who have sex with men (MSM) and transgender women (HPTN083), exceeding that of oral TDF/FTC [26].

Passive immunization using recombinant monoclonal antibodies capable of neutralizing diverse HIV isolates (broadly neutralizing antibodies, bNAbs) is another approach for achieving long-acting PrEP. Numerous preclinical studies in nonhuman primates have characterized bNAb-mediated protection against simian-human immunodeficiency virus (SHIV) infection via rectal, vaginal, or penile acquisition routes [27–29]. The efficacy of bNAb VRC01, when infused once every 8 weeks, to prevent sexual HIV transmission among men or transgender persons who have sex with men (NCT02716675) and women (NCT02568215) was recently evaluated in the Antibody Mediated Prevention (AMP) Study [30,31]. VRC01 had 75% protective efficacy against the most sensitive viruses and overall results suggested higher bNAb concentrations and more potent antibodies with greater breadth would provide more protection [31].

In contrast, the potential for bNAbs to prevent intravenous HIV infection has been characterized less well. In early proof-of-concept studies, polyclonal IgG serum exhibiting HIV neutralization activity (HIVIG) or first-generation bNAbs (2F5, 2G12, F105) were shown capable of preventing intravenous HIV infection of chimpanzees, or SHIV infection of macaques, respectively, when these immunoglobulins were administered within hours to days prior to virus challenge [32–35]. However, translation of such early HIV prevention products was impractical due to their limited potency. Subsequent discovery and development of bNAbs exhibiting much higher potency or neutralization breadth, compared to first generation bNAbs, as well as the identification of mutations that increase IgG half-life in vivo, has reinvigorated evaluation of passive immunization as an HIV prevention modality with the potential for a multimonth dosing window [29,36–38]. Among these, passive administration of bNAb PGT121 has been shown to protect macaques against high-dose intravenous cell-associated SHIV challenge [39,40].

Among current generation bNAbs, 10-1074 and 3BNC117, which target nonoverlapping epitopes on the V3 loop or CD4 binding site of HIV gp120, respectively, are in advanced clinical development for HIV prevention and treatment [41,42]. They have been shown to be well tolerated when administered to HIV-infected or uninfected persons and capable of suppressing HIV viremia among infected persons [37,43–46].

The utility of 10-1074 or 3BNC117 for preventing sexual transmission of HIV has been modeled preclinically in nonhuman primates, by others and us, where durable protection has been observed against repeated SHIV challenges via rectal, vaginal or penile exposure routes [27,47,48]. Here, we evaluated the protective efficacy that a single subcutaneous dose of both 10-1074 and 3BNC117 conferred against repeated intravenous SHIV challenges in cynomolgus macaques and used probit regression analysis to estimate plasma bNAb concentrations that correlated with protection against infection and discuss implications for dose selection.

Methods

Macaques

Seven adult cynomolgus macaques (Macaca fascicularis) were used to perform the intravenous SHIV challenge study. All animals were housed at the Centers for Disease Control and Prevention (CDC; Atlanta, Georgia, USA) in accordance with the Guide for the Care and Use of Laboratory Animals (8th edition) in an AAALAC-accredited facility, according to institutional standard operating procedures. For housing, macaques were maintained in cages that met or exceeded the minimum size requirements as stipulated in the Guide. Animals were provided enrichments that included objects to manipulate, assortments of fresh fruits and vegetables, suitable feeding methods (foraging and task-oriented), and humane interactions with caregivers and research staff. Prior to the initiation of virus challenges, compatible macaques were pair-housed to the extent possible. Animal studies were approved by the CDC Institutional Animal Care and Use Committee (IACUC, protocol 2804GARMONC). To minimize animal discomfort or suffering, all biomedical procedures were performed on animals under ketamine (10 mg kg−1) or Telazol (2–6 mg kg−1) anesthesia.

Antibodies and passive immunization

Monoclonal antibodies 10-1074 and 3BNC117 were produced in the laboratory of M. Nussenzweig as previously described [43,44]. Antibodies were formulated individually for injection at 52 mg ml−1 in 5 mM sodium acetate, 5 mM l-histidine, 280 mM trehalose, 0.05% Tween20 (pH 5.5) or 10 mM l-histidine, 280 mM trehalose, 0.05% Tween20 (pH 5.2), for 10-1074 and 3BNC117, respectively. Antibodies were administered via subcutaneous injection in macaques at 10 mg kg−1 in the upper back (3BNC117 on the left side, 10-1074 on the right side) via 22G1 needle. Weights of treated animals ranged from 4.5 to 6.9 kg. Thus, each animal received a total of two injections (one injection of 3BNC117 and one injection of 10-1074), each comprised of an injection volume ≤1.3 ml.

Virus challenges

Preparation of the cell-free stock of SHIVAD8-EO used in this study has been described [27]. Briefly, infectious virus was obtained from supernatants of 293T cell cultures following transfection with plasmid pSHIV AD8-EO (provided by Malcolm Martin, NIAID) and amplification in CD8-depleted/concanavalin-A-stimulated rhesus macaque PBMCs. Supernatants were clarified via centrifugation and aliquots of the cell-free challenge virus stock were stored in the vapor phase of liquid nitrogen. Sensitivity of the challenge virus stock to neutralization by 10-1074 was assessed via single-cycle TZM-bl assay in the presence of 100 uM indinavir (Supplemental Figure 2, http://links.lww.com/QAD/C141).

For intravenous challenges, macaques were administered 130 TCID50 SHIVAD8-EO, in a 1 ml volume, via a catheter inserted into the saphenous vein; tubing was flushed with isotonic saline to ensure full delivery of virus. Intravenous SHIV challenges were performed once weekly until the systemic infection was confirmed by detection of vRNA in plasma.

Viral load assay

SHIV RNA in plasma was quantified via real-time reverse transcription PCR assay with a 60 vRNA copies/ml limit of detection, as previously described [27,49].

Determination of 10-1074 and 3BNC117 concentrations

Concentrations of 10-1074 and 3BNC117 in macaque plasma were determined using selectively sensitive pseudoviruses X2088.c9 or Q769.d22, respectively, in TZM-bl neutralization assays as previously described [27].

Detection of antidrug antibody responses

Plasma ADA responses were assayed via ELISA using plates coated with the target bNAb, as previously described [27].

Statistical analysis

Statistical comparisons between groups using t-, Mann–Whitney-, or log-rank tests were conducted using Prism 7.0 (GraphPad Software, Inc., San Diego, California, USA). Probit modeling and bootstrap analyses were conducted in R version 3.4.4 as previously described [27].

Results

We sought to determine the protective efficacy that passive immunization with a combination of 10-1074 and 3BNC117 conferred against intravenous SHIV acquisition in cynomolgus macaques. Five macaques in the treatment group (Group 1) received a one-time subcutaneous injection of both 10-1074 and 3BNC117 (human IgG1 isotypes that did not contain the LS or any other half-life modifying mutations) at 10 mg each/kg body weight at one week prior to the start of intravenous SHIVAD8-EO challenges (Fig. 1a). Macaques in the control group were not administered any antibodies and were challenged identically with SHIVAD8-EO (Fig. 1a). Intravenous SHIVAD8-EO challenges (130 TCID50) were repeated once weekly until systemic infections were confirmed via positive RT-qPCR viral load assay for macaques in the treatment group (Fig. 1b), or untreated control group (Fig. 1c). Macaques that received 10-1074 and 3BNC117 were protected against a median of 5 weekly challenges (range = 4–9), which was significantly greater than untreated controls, which were infected following a single challenge (P = 0.014, log-rank test) (Fig. 1d). A trend toward lower levels of peak viremia and early SHIV replication, measured as vRNA area under the curve (AUC) through 11 weeks postinfection, was observed among treated animals versus controls (Supplemental Figure 1, http://links.lww.com/QAD/C140).

Fig. 1
Fig. 1:
Passive immunization of macaques with bNAbs 10-1074 and 3BNC117 delays SHIV infection following repeated intravenous SHIV challenges.

Plasma levels of 10-1074 and 3BNC117 were determined longitudinally among treated macaques (Fig. 1e, Supplemental Table 1, http://links.lww.com/QAD/C142 -2, http://links.lww.com/QAD/C143). The mean maximum plasma levels of 10-1074 (28.2 ± 8.7 μg ml−1) and 3BNC117 (2.0 ± 0.5 μg ml−1) were observed at 1 week following injection of bNAbs, which was the earliest timepoint sampled, and was 14-fold greater for 10-1074 than 3BNC117 (P = 0.002, two-tailed paired t test) (Fig. 1e). Plasma levels of 10-1074 exhibited a mean half-life of 8.8 ± 3.2 days and remained above the level of detection (0.10 μg ml−1) in all macaques throughout their respective SHIV challenge phases. In contrast, plasma levels of 3BNC117 became undetectable in 3 of 5 animals within 3 weeks following injection, due partly to the development of ADA responses against 3BNC117 (Fig. 1g) [50,51].

At the time of SHIV breakthrough, the median plasma concentration of 10-1074 was 1.0 μg ml−1 (range = 0.6–1.6 μg ml−1) (Fig. 1f). In contrast, 3BNC117 was undetectable among all treated macaques at SHIV breakthrough and had been below the level of detection (0.20 μg ml−1) for a median of 3 weeks (range = 2–5 weeks) prior to SHIV breakthrough. As such, the protection observed against SHIV infection among treated animals was likely attributable to 10-1074.

We fit curves to each treated animal's observed plasma levels of 10-1074 over time, and then used probit regression to estimate the per-challenge probability of SHIV infection as a function of the imputed levels of 10-1074 in plasma at the time of challenge (Fig. 2). Among untreated control macaques, a single IV SHIV challenge resulted in systemic infection (probability = 1.0, 95% CI: 0.16, 1.0) (Fig. 2). Based on the probit regression model, we estimated that the per-challenge risk of SHIV infection was reduced to 0.01 among treated animals (i.e. 99% reduction as compared to untreated controls) at a plasma 10-1074 concentration of 6.64 μg ml−1 (Bootstrapped 95% CI: 1.86, 9.55 μg ml−1) (Fig. 2).

Fig. 2
Fig. 2:
Plasma 10-1074 antibody concentration predicts the probability of infection following intravenous SHIV challenge.

Discussion

Although nearly 73 000 adult PWID in the US had indications for PrEP use in 2015, PrEP uptake within this population remains low [52–56]. Although tailored interventions could improve upon barriers such as low PrEP awareness or limited engagement with healthcare providers, suboptimal user adherence to daily oral PrEP regimens is likely to remain a significant factor that constrains PrEP effectiveness [19]. This suggests that development of long-acting PrEP modalities, such as bNAbs, could improve HIV prevention among PWID. Here, we conducted a preclinical study in nonhuman primates to evaluate protection conferred by bNAbs 10-1074 and 3BNC117 against intravenous SHIV infection.

Our results demonstrated protection up to 9 weeks against repeated intravenous SHIV challenges of macaques following a single subcutaneous injection of 10-1074 and 3BNC117. This protection was attributable to 10-1074, due to the observed difference in antibody pharmacokinetics following subcutaneous dosing, which resulted in a period of effective 10-1074 monotherapy among all treated macaques preceding SHIV infection. Similar observations of relatively higher peak systemic levels of 10-1074 vs. 3BNC117, or by 10-1074-LS vs. 3BNC117-LS, following equivalent subcutaneous dosing in macaques have been made and suggest an intrinsic pharmacokinetic difference between these bNAb lineages with regard to subcutaneous dosing [27,57]. Using probit regression, we estimated that per-challenge intravenous infection risk was reduced by 99% among macaques with a minimum plasma 10-1074 concentration of 6.64 μg ml−1. This value is approximately six-fold higher than that determined previously to reduce per-challenge infection risk by 99% among DMPA-treated rhesus macaques following repeated vaginal challenges with a 2.3-fold higher dose of the same challenge virus stock [27]. Given the epidemiological estimate of per-act probability of acquiring HIV from an infected source is ∼8-fold higher due to needle-sharing/injection drug use (63/10 000 exposures) than receptive vaginal intercourse (8/10 000 exposures) it was not unexpected that relatively higher bNAb concentrations would be required to prevent intravenous infection, as compared to mucosal acquisition [58]. Nevertheless, the plasma 10-1074 concentration of 6.64 μg ml−1 that we determined to reduce intravenous SHIV infection risk by 99% in our macaque model is clinically relevant, as plasma 10-1074 concentrations ≥10 μg ml−1 persisted for ≥12 weeks following a single infusion of 10-1074 (10 mg kg−1) singly, or in combination with 3BNC117, among HIV-uninfected individuals [43,46]. The AMP study of VRC01's ability to prevent HIV infection indicated that higher in vivo concentrations of bNAbs than indicated by in-vitro sensitivity studies may be needed [31]. More potent antibodies and use of bNAbs in combination, rather than individually, for preexposure prophylaxis could also provide higher coverage against diverse incident HIV isolates. Delivery of larger volumes of bNAbs can be achieved by increasing the number of injection sites, but this is impractical. Towards reducing the number of injection sites for subcutaneous bNAb delivery, a high-concentration co-formulation of 10-1074-LS and 3BNC117-LS has been described recently [59] and phase-I evaluation of co-administration of recombinant human hyaluronidase, to enable bNAb delivery in larger subcutaneous dosing volumes (e.g. >10 ml) per site, is ongoing (VRC069; NCT:03538626).

In summary, we evaluated the protective efficacy that a combination of 10-1074 and 3BNC117 conferred against intravenous SHIV infection in cynomolgus macaques and determined a plasma 10-1074 concentration as a correlate of protection. Our findings inform dose selection for clinical development and show a large reduction in intravenous infection probability at plasma 10-1074 concentrations that are clinically achievable in a manner consistent with long-acting PrEP. Subcutaneously administered bNAbs, given intermittently to provide durable protection, could be particularly suitable for PWID who may have difficulties accessing or adhering to daily oral PrEP. As such, our findings extend prior preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the continued development of bNAbs as a long-acting HIV prevention for men, women and persons who inject drugs.

Acknowledgements

Funding for this study was from CDC intramural funds. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or National Institutes of Health.

Author contributions: D.A.G., J.McN., M.C.N., and W.H. developed the concept and designed the experiments; P.G., J.M., and S.E. performed experiments or animal procedures; A.G. generated bNAbs used in this study; M.S. determined bNAb concentrations; M.N. performed probit modeling and bootstrap analyses; D.A.G wrote the manuscript; All authors edited or reviewed the manuscript.

Conflicts of interest

There are patents on 10-1074 (US Provisional Application No. 61/486,960) on which MCN is an inventor. The authors declare no further conflicts of interest.

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Keywords:

broadly neutralizing antibody; HIV; intravenous; macaque; preexposure prophylaxis; simian human immunodeficiency virus

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