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Combinational delivery of lipid-enveloped polymeric nanoparticles carrying different peptides for anti-tumor immunotherapy

Tan, Songwei; Sasada, Tetsuro; Bershteyn, Anna; Yang, Kunyu; Ioji, Tetsuya; Zhang, Zhiping
AIM/OBJECTIVE:The authors aimed to investigate whether nanotechnology-based delivery of antigenic peptides is feasible for efficiently inducing anti-tumor cytotoxic T lymphocyte responses through vaccination. MATERIALS & METHODS/METHODS:Three different murine melanoma antigens were entrapped in lipid-coated poly(D,L-lactide-co-glycolide) nanoparticles (NPs) by the double emulsion method. RESULTS:The loading efficiency of hydrophilic peptides was greatly improved when lipids were introduced to formulate lipid-coated NPs. The lipid-coated NPs carrying a single peptide and/or combinations of multiple lipid-coated NPs carrying antigenic peptides were characterized in vitro and in vivo in a C57/BL6 (B6) mouse model. Both the single melanoma antigen peptide-loaded NPs and combinational delivery of lipid-coated NPs carrying different peptides could induce antigen-specific T-cell responses. However, single peptide-loaded NPs failed to significantly delay the growth of subcutaneously inoculated B16 melanoma cells in a prophylactic setting. By contrast, the combinational delivery of lipid-coated NPs carrying different peptides significantly suppressed growth of inoculated B16 melanoma cells.
PMID: 23905577
ISSN: 1748-6963
CID: 3796482

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models

Eaton, Jeffrey W; Menzies, Nicolas A; Stover, John; Cambiano, Valentina; Chindelevitch, Leonid; Cori, Anne; Hontelez, Jan A C; Humair, Salal; Kerr, Cliff C; Klein, Daniel J; Mishra, Sharmistha; Mitchell, Kate M; Nichols, Brooke E; Vickerman, Peter; Bakker, Roel; Bärnighausen, Till; Bershteyn, Anna; Bloom, David E; Boily, Marie-Claude; Chang, Stewart T; Cohen, Ted; Dodd, Peter J; Fraser, Christophe; Gopalappa, Chaitra; Lundgren, Jens; Martin, Natasha K; Mikkelsen, Evelinn; Mountain, Elisa; Pham, Quang D; Pickles, Michael; Phillips, Andrew; Platt, Lucy; Pretorius, Carel; Prudden, Holly J; Salomon, Joshua A; van de Vijver, David A M C; de Vlas, Sake J; Wagner, Bradley G; White, Richard G; Wilson, David P; Zhang, Lei; Blandford, John; Meyer-Rath, Gesine; Remme, Michelle; Revill, Paul; Sangrujee, Nalinee; Terris-Prestholt, Fern; Doherty, Meg; Shaffer, Nathan; Easterbrook, Philippa J; Hirnschall, Gottfried; Hallett, Timothy B
BACKGROUND:New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS:We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS/RESULTS:In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. INTERPRETATION/CONCLUSIONS:Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. FUNDING/BACKGROUND:Bill & Melinda Gates Foundation, WHO.
PMID: 25104632
ISSN: 2214-109x
CID: 3796542

Dropout and re-enrollment: implications for epidemiological projections of treatment programs

Klein, Daniel J; Bershteyn, Anna; Eckhoff, Philip A
OBJECTIVE:EMOD-HIV v0.8 has been used to estimate the potential impact of expanding treatment guidelines to allow earlier initiation of antiretroviral therapy (ART) in sub-Saharan Africa with current or improved treatment coverage. In generating these results, a model must additionally make assumptions about the rates of dropout and re-initiation into ART programs before and after the program change, about which little is known. The objective of this work is to rigorously analyze modeling assumptions and the sensitivity of model results with respect to relevant mechanisms and parameters. METHODS:We varied key model assumptions pertaining to ART dropout and re-enrollment to analyze their effect on the cost, impact, and cost-effectiveness of expanding treatment guidelines, and of expanding coverage via improved testing and linkage to care. Additionally, we performed a sensitivity analysis of 17 relevant model parameters. SETTING/METHODS:South Africa. RESULTS:Allowing re-initiation of ART irrespective of prior treatment doubled the cost and impact of expanding treatment guidelines, as compared with a scenario in which re-initiation could only be triggered by a health event (AIDS symptoms, diagnosis of a partner, or an antenatal care visit). Increasing the probability of 'voluntary' re-initiation (not triggered by a health event) was the most cost-effective way to improve the treatment program, especially in the short term because it provided immediate benefits to those who would otherwise have delayed re-initiation until the onset of AIDS symptoms. However, the maximum impact of this change was limited compared with expanding coverage through improvements in testing and linkage to care. Beyond improvements in coverage and re-initiation, further gains could be made by improving retention in care. Only with optimal retention in care was expansion of guidelines cost-saving after 20 years due to reductions in transmission. Re-initiation did not reduce transmission sufficiently to make a guideline change cost-effective due to transmission that occurred while patients were away from care. Sensitivity analysis suggested that enormous health benefits could be attained by improving treatment regimens to have higher efficacy at preventing transmission, increasing the proportion of the population with access to improved healthcare, and reducing 'leaks' in the 'cascade of care.' Increasing the proportion of individuals who receive CD4 cell results was particularly cost-effective at baseline levels of coverage, and increasing retention on ART was particularly cost-effective with expanded coverage. CONCLUSION/CONCLUSIONS:This analysis provides a sense of the magnitude of uncertainty in program cost and impact that policy-makers could anticipate in the face of uncertain future programmatic changes. Our findings suggest that increasing re-initiation is the most cost-effective means of initial program improvement, especially in the short term, but that improvements in retention are necessary in order to reap the full transmission-blocking benefits of a test-and-treat program in the long term.
PMID: 24468946
ISSN: 1473-5571
CID: 3796512

Age-dependent partnering and the HIV transmission chain: a microsimulation analysis

Bershteyn, Anna; Klein, Daniel J; Eckhoff, Philip A
Efficient planning and evaluation of human immunodeficiency virus (HIV) prevention programmes requires an understanding of what sustains the epidemic, including the mechanism by which HIV transmission keeps pace with the ageing of the infected population. Recently, more detailed population models have been developed which represent the epidemic with sufficient detail to characterize the dynamics of ongoing transmission. Here, we describe the structure and parameters of such a model, called EMOD-HIV v. 0.7. We analyse the chains of transmission that allow the HIV epidemic to propagate across age groups in this model. In order to prevent the epidemic from dying out, the virus must find younger victims faster than its extant victims age and die. The individuals who enable such transmission events in EMOD-HIV v. 0.7 are higher concurrency, co-infected males aged 26-29 and females aged 23-24. Prevention programmes that target these populations could efficiently interrupt the mechanisms that allow HIV to transmit at a pace that is faster than the progress of time.
PMCID:3785829
PMID: 23985734
ISSN: 1742-5662
CID: 3796492

Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry

Kim, Mikyung; Song, Likai; Moon, James; Sun, Zhen-Yu J; Bershteyn, Anna; Hanson, Melissa; Cain, Derek; Goka, Selasie; Kelsoe, Garnett; Wagner, Gerhard; Irvine, Darrell; Reinherz, Ellis L
Structural characterization of epitope-paratope pairs has contributed to the understanding of antigenicity. By contrast, few structural studies relate to immunogenicity, the process of antigen-induced immune responses in vivo. Using a lipid-arrayed membrane-proximal external region (MPER) of HIV-1 glycoprotein 41 as a model antigen, we investigated the influence of physicochemical properties on immunogenicity in relation to structural modifications of MPER/liposome vaccines. Anchoring the MPER to the membrane via an alkyl tail or transmembrane domain retained the MPER on liposomes in vivo, while preserving MPER secondary structure. However, structural modifications that affected MPER membrane orientation and antigenic residue accessibility strongly impacted induced antibody responses. The solvent-exposed MPER tryptophan residue (Trp-680) was immunodominant, focusing immune responses, despite sequence variability elsewhere. Nonetheless, immunogenicity could be readily manipulated using site-directed mutagenesis or structural constraints to modulate amino acid surface display. These studies provide fundamental insights for immunogen design aimed at targeting B cell antibody responses.
PMCID:3814781
PMID: 24047898
ISSN: 1083-351x
CID: 3796502

A model of HIV drug resistance driven by heterogeneities in host immunity and adherence patterns

Bershteyn, Anna; Eckhoff, Philip A
BACKGROUND:Population transmission models of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) use simplistic assumptions--typically constant, homogeneous rates--to represent the short-term risk and long-term effects of drug resistance. In contrast, within-host models of drug resistance allow for more detailed dynamics of host immunity, latent reservoirs of virus, and drug PK/PD. Bridging these two levels of modeling detail requires an understanding of the "levers"--model parameters or combinations thereof--that change only one independent observable at a time. Using the example of accidental tenofovir-based pre-exposure prophyaxis (PrEP) use during HIV infection, we will explore methods of implementing host heterogeneities and their long-term effects on drug resistance. RESULTS:We combined and extended existing models of virus dynamics by incorporating pharmacokinetics, pharmacodynamics, and adherence behavior. We identified two "levers" associated with the host immune pressure against the virus, which can be used to independently modify the setpoint viral load and the shape of the acute phase viral load peak. We propose parameter relationships that can explain differences in acute and setpoint viral load among hosts, and demonstrate their influence on the rates of emergence and reversion of drug resistance. The importance of these dynamics is illustrated by modeling long-lived latent reservoirs of virus, through which past intervals of drug resistance can lead to failure of suppressive drug regimens. Finally, we analyze assumptions about temporal patterns of drug adherence and their impact on resistance dynamics, finding that with the same overall level of adherence, the dwell times in drug-adherent versus not-adherent states can alter the levels of drug-resistant virus incorporated into latent reservoirs. CONCLUSIONS:We have shown how a diverse range of observable viral load trajectories can be produced from a basic model of virus dynamics using immunity-related "levers". Immune pressure, in turn, influences the dynamics of drug resistance, with increased immune activity delaying drug resistance and driving more rapid return to dominance of drug-susceptible virus after drug cessation. Both immune pressure and patterns of drug adherence influence the long-term risk of drug resistance. In the case of accidental PrEP use during infection, rapid transitions between adherence states and/or weak immunity fortifies the "memory" of previous PrEP exposure, increasing the risk of future drug resistance. This model framework provides a means for analyzing individual-level risks of drug resistance and implementing heterogeneities among hosts, thereby achieving a crucial prerequisite for improving population-level models of drug resistance.
PMCID:3643872
PMID: 23379669
ISSN: 1752-0509
CID: 3796472

Robust IgG responses to nanograms of antigen using a biomimetic lipid-coated particle vaccine

Bershteyn, Anna; Hanson, Melissa C; Crespo, Monica P; Moon, James J; Li, Adrienne V; Suh, Heikyung; Irvine, Darrell J
New subunit vaccine formulations with increased potency are of interest to improve immune responses against poorly immunogenic antigens, to avoid vaccine shortages in pandemic situations, and to promote dose-sparing of potent adjuvant molecules that can cause unacceptable side effects in prophylactic vaccination. Here we report strong class-switched, high avidity humoral immune responses elicited by a vaccine system based on poly(lactide-co-glycolide) micro- or nano-particles enveloped by PEGylated phospholipid bilayers, with protein antigens covalently anchored to the lipid surface and lipophilic adjuvants inserted in the bilayer coating. Strikingly, these particles elicited high endpoint antigen-specific IgG titers (>10(6)) sustained for over 100 days after two immunizations with as little as 2.5 ng of antigen. At such low doses, the conventional adjuvant alum or the molecular adjuvants monophosphoryl lipid A (MPLA) or α-galactosylceramide (αGC) failed to elicit responses. Co-delivery of antigen with MPLA or αGC incorporated into the particle bilayers in a pathogen-mimetic fashion further enhanced antibody titers by ~12-fold. MPLA provided the highest sustained IgG titers at these ultra-low antigen doses, while αGC promoted a rapid rise in serum IgG after one immunization, which may be valuable in emergencies such as disease pandemics. The dose of αGC required to boost the antibody response was also spared by particulate delivery. Lipid-enveloped biodegradable micro- and nano-particles thus provide a potent dose-sparing platform for vaccine delivery.
PMCID:3811132
PMID: 21820024
ISSN: 1873-4995
CID: 3796452

HIV treatment as prevention: systematic comparison of mathematical models of the potential impact of antiretroviral therapy on HIV incidence in South Africa

Eaton, Jeffrey W; Johnson, Leigh F; Salomon, Joshua A; Bärnighausen, Till; Bendavid, Eran; Bershteyn, Anna; Bloom, David E; Cambiano, Valentina; Fraser, Christophe; Hontelez, Jan A C; Humair, Salal; Klein, Daniel J; Long, Elisa F; Phillips, Andrew N; Pretorius, Carel; Stover, John; Wenger, Edward A; Williams, Brian G; Hallett, Timothy B
BACKGROUND:Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. METHODS AND FINDINGS/RESULTS:Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. CONCLUSIONS:Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.
PMCID:3393664
PMID: 22802730
ISSN: 1549-1676
CID: 3796462

Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses

Moon, James J; Suh, Heikyung; Bershteyn, Anna; Stephan, Matthias T; Liu, Haipeng; Huang, Bonnie; Sohail, Mashaal; Luo, Samantha; Um, Soong Ho; Khant, Htet; Goodwin, Jessica T; Ramos, Jenelyn; Chiu, Wah; Irvine, Darrell J
Vaccines based on recombinant proteins avoid the toxicity and antivector immunity associated with live vaccine (for example, viral) vectors, but their immunogenicity is poor, particularly for CD8(+) T-cell responses. Synthetic particles carrying antigens and adjuvant molecules have been developed to enhance subunit vaccines, but in general these materials have failed to elicit CD8(+) T-cell responses comparable to those for live vectors in preclinical animal models. Here, we describe interbilayer-crosslinked multilamellar vesicles formed by crosslinking headgroups of adjacent lipid bilayers within multilamellar vesicles. Interbilayer-crosslinked vesicles stably entrapped protein antigens in the vesicle core and lipid-based immunostimulatory molecules in the vesicle walls under extracellular conditions, but exhibited rapid release in the presence of endolysosomal lipases. We found that these antigen/adjuvant-carrying vesicles form an extremely potent whole-protein vaccine, eliciting endogenous T-cell and antibody responses comparable to those for the strongest vaccine vectors. These materials should enable a range of subunit vaccines and provide new possibilities for therapeutic protein delivery.
PMID: 21336265
ISSN: 1476-1122
CID: 3796442

Therapeutic cell engineering with surface-conjugated synthetic nanoparticles

Stephan, Matthias T; Moon, James J; Um, Soong Ho; Bershteyn, Anna; Irvine, Darrell J
A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.
PMCID:2935928
PMID: 20711198
ISSN: 1546-170x
CID: 3796432