The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Balaji Narasimhan - One of the best experts on this subject based on the ideXlab platform.
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single dose of a polyanhydride particle based vaccine generates potent antigen specific antitumor immune responses
Journal of Pharmacology and Experimental Therapeutics, 2019Co-Authors: Emad I Wafa, Balaji Narasimhan, Kathleen A Ross, Sean M Geary, Jonathan T Goodman, Aliasger K SalemAbstract:Many factors affect vaccine efficacy. One of the most salient is the frequency and intervals of vaccine administration. In this study, we assessed the vaccine administration modality for a recently reported polyanhydride-based vaccine formulation, shown to generate antitumor activity. Polyanhydride particles encapsulating ovalbumin (OVA) were prepared using a double-emulsion technique and subcutaneously delivered to mice either as a single-dose or as prime-boost vaccine regimens in which two different time intervals between prime and boost were assessed (7 or 21 days). This was followed by measurement of cellular and humoral immune responses, and subsequent challenge of the mice with a lethal dose of E.G7-OVA cells to evaluate tumor protection. Interestingly, a single dose of the polyanhydride particle-based formulation induced sustained OVA-specific cellular immune responses just as effectively as the prime-boost regimens. In addition, mice receiving single-dose vaccine had similar levels of protection against tumor challenge compared with mice administered prime-boosts. In contrast, measurements of OVA-specific IgG antibody titers indicated that a booster dose was required to stimulate strong humoral immune responses, since it was observed that mice administered a prime-boost vaccine had significantly higher OVA-specific IgG1 serum titers than mice administered a single dose. These findings indicate that the requirement for a booster dose using these particles appears unnecessary for the generation of effective cellular immunity.
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automated high throughput synthesis of protein loaded polyanhydride nanoparticle libraries
ACS Combinatorial Science, 2018Co-Authors: Jonathan T Goodman, Adam S Mullis, Lucas Dunshee, Akash Mitra, Balaji NarasimhanAbstract:The development of high-throughput techniques and combinatorial libraries can facilitate rapid synthesis and screening of biomaterial-based nanocarriers for drug and vaccine delivery. This study describes a high-throughput method using an automated robot for synthesizing polyanhydride nanoparticles encapsulating proteins. Polyanhydrides are a class of safe and biodegradable polymers that have been widely used as drug and vaccine delivery vehicles. The robot contains a multiplexed homogenizer and has the capacity to handle parallel streams of monomer or polymer solutions to synthesize polymers and/or nanoparticles. Copolymer libraries were synthesized using the monomers sebacic acid, 1,6-bis(p-carboxyphenoxy)hexane, and 1,8-bis(p-carboxyphenoxy)-3,6-dioxactane and compared to conventionally synthesized copolymers. Nanoparticle libraries of varying copolymer compositions encapsulating the model antigen ovalbumin were synthesized using flash nanoprecipitation. The amount of the surfactant Span 80 was varied ...
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ph responsive microencapsulation systems for the oral delivery of polyanhydride nanoparticles
Biomacromolecules, 2018Co-Authors: Lindsey A Sharpe, Balaji Narasimhan, Kathleen A Ross, Julia Vela E Ramirez, Olivia M. Haddadin, Nicholas A. PeppasAbstract:Multicompartmental polymer carriers, referred to as Polyanhydride-Releasing Oral MicroParticle Technology (PROMPT), were formed by a pH-triggered antisolvent precipitation technique. Polyanhydride nanoparticles were encapsulated into anionic pH-responsive microparticle gels, allowing for nanoparticle encapsulation in acidic conditions and subsequent release in neutral pH conditions. The effects of varying the nanoparticle composition and feed ratio on the encapsulation efficiency were evaluated. Nanoparticle encapsulation was confirmed by confocal microscopy and infrared spectroscopy. pH-triggered protein delivery from PROMPT was explored using ovalbumin (ova) as a model drug. PROMPT microgels released ova in a pH-controlled manner. Increasing the feed ratio of nanoparticles into the microgels increased the total amount of ova delivered, as well as decreased the observed burst release. The cytocompatibility of the polymer materials were assessed using cells representative of the GI tract. Overall, these r...
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a single dose polyanhydride based vaccine platform promotes and maintains anti gnrh antibody titers
Vaccine, 2018Co-Authors: Robert G Schaut, Sean M. Kelly, Jesse M Hostetter, Matthew T Brewer, Kriscelle Mendoza, Julia E Velaramirez, John K Jackman, Giuseppe Dellanna, Joan M Howard, Balaji NarasimhanAbstract:Abstract Traditionally, vaccination strategies require an initial priming vaccination followed by an antigen boost to generate adequate immunity. Here we describe vaccination against a self-peptide for reproductive sterilization utilizing a three-stage vaccine platform consisting of gonadotropin releasing hormone multiple antigenic peptide (GnRH-MAP) as a soluble injection coupled with subcutaneous administration of polyanhydride-immobilized GnRH-MAP and a cyto-exclusive implant containing GnRH-MAP dendrimer-loaded polyanhydride. This strategy generated and maintained cell-mediated and humoral immunity for up to 41 weeks after a single vaccination in mice with enhanced antibody avidity over time. All intact implants had a grossly visible tissue interface with neovascularization and lymphocytic aggregates. Despite detectable immunity, sterility was not achieved and the immune response did not lead to azoospermia in male mice nor prevent estrus and ovulation in female mice. However, the vaccine delivery device is tunable and the immunogen, adjuvants and release rates can all be modified to enhance immunity. This technology has broad implications for the development of long-term vaccination schemes.
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Room Temperature Stable PspA-Based Nanovaccine Induces Protective Immunity
Frontiers Media S.A., 2018Co-Authors: Danielle A. Wagner-muñiz, Balaji Narasimhan, Michael J Wannemuehler, Shannon L. Haughney, Sean M. KellyAbstract:Streptococcus pneumoniae is a major causative agent of pneumonia, a debilitating disease particularly in young and elderly populations, and is the leading worldwide cause of death in children under the age of five. While there are existing vaccines against S. pneumoniae, none are protective across all serotypes. Pneumococcal surface protein A (PspA), a key virulence factor of S. pneumoniae, is an antigen that may be incorporated into future vaccines to address the immunological challenges presented by the diversity of capsular antigens. PspA has been shown to be immunogenic and capable of initiating a humoral immune response that is reactive across approximately 94% of pneumococcal strains. Biodegradable Polyanhydrides have been studied as a nanoparticle-based vaccine (i.e., nanovaccine) platform to stabilize labile proteins, to provide adjuvanticity, and enhance patient compliance by providing protective immunity in a single dose. In this study, we designed a room temperature stable PspA-based polyanhydride nanovaccine that eliminated the need for a free protein component (i.e., 100% encapsulated within the nanoparticles). Mice were immunized once with the lead nanovaccine and upon challenge, presented significantly higher survival rates than animals immunized with soluble protein alone, even with a 25-fold reduction in protein dose. This lead nanovaccine formulation performed similarly to protein adjuvanted with Alum, however, with much less tissue reactogenicity at the site of immunization. By eliminating the free PspA from the nanovaccine formulation, the lead nanovaccine was efficacious after being stored dry for 60 days at room temperature, breaking the need for maintaining the cold chain. Altogether, this study demonstrated that a single dose PspA-based nanovaccine against S. pneumoniae induced protective immunity and provided thermal stability when stored at room temperature for at least 60 days
Michael J Wannemuehler - One of the best experts on this subject based on the ideXlab platform.
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Room Temperature Stable PspA-Based Nanovaccine Induces Protective Immunity
Frontiers Media S.A., 2018Co-Authors: Danielle A. Wagner-muñiz, Balaji Narasimhan, Michael J Wannemuehler, Shannon L. Haughney, Sean M. KellyAbstract:Streptococcus pneumoniae is a major causative agent of pneumonia, a debilitating disease particularly in young and elderly populations, and is the leading worldwide cause of death in children under the age of five. While there are existing vaccines against S. pneumoniae, none are protective across all serotypes. Pneumococcal surface protein A (PspA), a key virulence factor of S. pneumoniae, is an antigen that may be incorporated into future vaccines to address the immunological challenges presented by the diversity of capsular antigens. PspA has been shown to be immunogenic and capable of initiating a humoral immune response that is reactive across approximately 94% of pneumococcal strains. Biodegradable Polyanhydrides have been studied as a nanoparticle-based vaccine (i.e., nanovaccine) platform to stabilize labile proteins, to provide adjuvanticity, and enhance patient compliance by providing protective immunity in a single dose. In this study, we designed a room temperature stable PspA-based polyanhydride nanovaccine that eliminated the need for a free protein component (i.e., 100% encapsulated within the nanoparticles). Mice were immunized once with the lead nanovaccine and upon challenge, presented significantly higher survival rates than animals immunized with soluble protein alone, even with a 25-fold reduction in protein dose. This lead nanovaccine formulation performed similarly to protein adjuvanted with Alum, however, with much less tissue reactogenicity at the site of immunization. By eliminating the free PspA from the nanovaccine formulation, the lead nanovaccine was efficacious after being stored dry for 60 days at room temperature, breaking the need for maintaining the cold chain. Altogether, this study demonstrated that a single dose PspA-based nanovaccine against S. pneumoniae induced protective immunity and provided thermal stability when stored at room temperature for at least 60 days
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functionalization promotes pathogen mimicking characteristics of polyanhydride nanoparticle adjuvants
Journal of Biomedical Materials Research Part A, 2017Co-Authors: Yashdeep Phanse, Balaji Narasimhan, Brenda R Carrilloconde, Michael J Wannemuehler, Amanda E Ramertait, Scott R. Broderick, Krishna Rajan, Rajarshi Roychoudhury, Nicola L. B. Pohl, Bryan H BellaireAbstract:Rational design of adjuvants and delivery systems will promote development of next-generation vaccines to control emerging and re-emerging diseases. To accomplish this, understanding the immune-enhancing properties of new adjuvants relative to those induced by natural infections can help with the development of pathogen-mimicking materials that will effectively initiate innate immune signaling cascades. In this work, the surfaces of polyanhydride nanoparticles composed of sebacic acid (SA) and 1,6-bis(p-carboxyphenoxy) hexane were decorated with an ethylene diamine spacer partially modified with either a glycolic acid linker or an α-1,2-linked di-mannopyranoside (di-mannose) to confer "pathogen-like" properties and enhance adjuvanticity. Co-incubation of linker-modified nanoparticles with dendritic cells (DCs) elicited significant increases in surface expression of MHC I, MHC II, CD86, and CD40, and enhanced secretion of IL-6, IL-12p40, and TNF-α. An 800% increase in uptake of ethylene-diamine-spaced, linker and di-mannose functionalized polyanhydride nanoparticles was also observed. Together, our data showed that linker-functionalized polyanhydride nanoparticles demonstrate similar patterns of uptake, intracellular trafficking, particle persistence, and innate activation as did DCs exposed to Yersinia pestis or Escherichia coli. These results set the stage for rational selection of adjuvant chemistries to induce pathogen-mimicking immune responses. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2762-2771, 2017.
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polyanhydride nanovaccine against swine influenza virus in pigs
Vaccine, 2017Co-Authors: Santosh Dhakal, Jonathan T Goodman, Kathryn Bondra, Yashavanth Shaan Lakshmanappa, Jagadish Hiremath, Duanliang Shyu, Kang Ouyang, Kyungil Kang, Steven Krakowka, Michael J WannemuehlerAbstract:We have recently demonstrated the effectiveness of an influenza A virus (IAV) subunit vaccine based on biodegradable polyanhydride nanoparticles delivery in mice. In the present study, we evaluated the efficacy of ∼200nm polyanhydride nanoparticles encapsulating inactivated swine influenza A virus (SwIAV) as a vaccine to induce protective immunity against a heterologous IAV challenge in pigs. Nursery pigs were vaccinated intranasally twice with inactivated SwIAV H1N2 (KAg) or polyanhydride nanoparticle-encapsulated KAg (KAg nanovaccine), and efficacy was evaluated against a heterologous zoonotic virulent SwIAV H1N1 challenge. Pigs were monitored for fever daily. Local and systemic antibody responses, antigen-specific proliferation of peripheral blood mononuclear cells, gross and microscopic lung lesions, and virus load in the respiratory tract were compared among the groups of animals. Our pre-challenge results indicated that KAg nanovaccine induced virus-specific lymphocyte proliferation and increased the frequency of CD4+CD8αα+ T helper and CD8+ cytotoxic T cells in peripheral blood mononuclear cells. KAg nanovaccine-immunized pigs were protected from fever following SwIAV challenge. In addition, pigs immunized with the KAg nanovaccine presented with lower viral antigens in lung sections and had 6 to 8-fold reduction in nasal shedding of SwIAV four days post-challenge compared to control animals. Immunologically, increased IFN-γ secreting T lymphocyte populations against both the vaccine and challenge viruses were detected in KAg nanovaccine-immunized pigs compared to the animals immunized with KAg alone. However, in the KAg nanovaccine-immunized pigs, hemagglutination inhibition, IgG and IgA antibody responses, and virus neutralization titers were comparable to that in the animals immunized with KAg alone. Overall, our data indicated that intranasal delivery of polyanhydride-based SwIAV nanovaccine augmented antigen-specific cellular immune response in pigs, with promise to induce cross-protective immunity.
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2016Co-Authors: Michael J Wannemuehler, Yashdeep Phanse, Amanda E. Ramer-tait, L. K. Petersen, Ellen A Ramer-tait, Amphiphilic Polyanhydride, Nanoparticles Stabilize BacillusAbstract:Amphiphilic polyanhydride nanoparticles stabilize bacillus anthracis protective antige
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© 2013 Petersen et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
2016Co-Authors: Latrisha K. Petersen, Balaji Narasimhan, Lucas Huntimer, Michael J Wannemuehler, Amanda E. Ramer-tait, Katharine Walz, Correspondence Balaji NarasimhanAbstract:which permits unrestricted noncommercial use, provided the original work is properly cited. International Journal of Nanomedicine 2013: 8 2213–2225 International Journal of Nanomedicine Combinatorial evaluation of in vivo distribution of polyanhydride particle-based platforms for vaccine deliver
Latrisha K. Petersen - One of the best experts on this subject based on the ideXlab platform.
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© 2013 Petersen et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
2016Co-Authors: Latrisha K. Petersen, Balaji Narasimhan, Lucas Huntimer, Michael J Wannemuehler, Amanda E. Ramer-tait, Katharine Walz, Correspondence Balaji NarasimhanAbstract:which permits unrestricted noncommercial use, provided the original work is properly cited. International Journal of Nanomedicine 2013: 8 2213–2225 International Journal of Nanomedicine Combinatorial evaluation of in vivo distribution of polyanhydride particle-based platforms for vaccine deliver
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combinatorial evaluation of in vivo distribution of polyanhydride particle based platforms for vaccine delivery
International Journal of Nanomedicine, 2013Co-Authors: Latrisha K. Petersen, Lucas Huntimer, Michael J Wannemuehler, Amanda E Ramertait, Katharine Walz, Balaji NarasimhanAbstract:Several challenges are associated with current vaccine strategies, including repeated immunizations, poor patient compliance, and limited approved routes for delivery, which may hinder induction of protective immunity. Thus, there is a need for new vaccine adjuvants capable of multi-route administration and prolonged antigen release at the site of administration by providing a depot within tissue. In this work, we designed a combinatorial platform to investigate the in vivo distribution, depot effect, and localized persistence of polyanhydride nanoparticles as a function of nanoparticle chemistry and administration route. Our observations indicated that the route of administration differentially affected tissue residence times. All nanoparticles rapidly dispersed when delivered intranasally but provided a depot when administered parenterally. When amphiphilic and hydrophobic nanoparticles were administered intranasally, they persisted within lung tissue. These results provide insights into the chemistry- and route-dependent distribution and tissue-specific association of polyanhydride nanoparticle-based vaccine adjuvants.
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evaluation of biocompatibility and administration site reactogenicity of polyanhydride particle based platform for vaccine delivery
Advanced Healthcare Materials, 2013Co-Authors: Lucas Huntimer, Latrisha K. Petersen, Balaji Narasimhan, Kathleen A Ross, Chong Wang, Amanda E Ramertait, Katherine A Walz, Jesse M Hostetter, Michael J WannemuehlerAbstract:Efficacy, purity, safety, and potency are important attributes of vaccines. Polyanhydride particles represent a novel class of vaccine adjuvants and delivery platforms that have demonstrated the ability to enhance the stability of protein antigens as well as elicit protective immunity against bacterial pathogens. This work aims to elucidate the biocompatibility, inflammatory reactions, and particle effects on mice injected with a 5 mg dose of polyanhydride nanoparticles via common parenteral routes (subcutaneous and intramuscular). Independent of polymer chemistry, nanoparticles more effectively disseminated away from the injection site as compared to microparticles, which exhibited a depot effect. Using fluorescent probes, the in vivo distribution of three formulations of nanoparticles, following subcutaneous administration, indicated migration away from the injection site. Less inflammation was observed at the injection sites of mice-administered nanoparticles as compared to Alum and incomplete Freund's adjuvant. Furthermore, histological evaluation revealed minimal adverse injection site reactions and minimal toxicological effects associated with the administration of nanoparticles at 30 days post-administration. Collectively, these results demonstrate that polyanhydride nanoparticles do not induce inflammation as a cumulative effect of particle persistence or degradation and are, therefore, a viable candidate for a vaccine delivery platform.
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evaluation of biocompatibility and administration site reactogenicity of polyanhydride particle based platform for vaccine delivery
Advanced Healthcare Materials, 2013Co-Authors: Lucas Huntimer, Latrisha K. Petersen, Balaji Narasimhan, Kathleen A Ross, Chong Wang, Amanda E Ramertait, Katherine A Walz, Jesse M Hostetter, Michael J WannemuehlerAbstract:Efficacy, purity, safety, and potency are important attributes of vaccines. Polyanhydride particles represent a novel class of vaccine adjuvants and delivery platforms that have demonstrated the ability to enhance the stability of protein antigens as well as elicit protective immunity against bacterial pathogens. This work aims to elucidate the biocompatibility, inflammatory reactions, and particle effects on mice injected with a 5 mg dose of polyanhydride nanoparticles via common parenteral routes (subcutaneous and intramuscular). Independent of polymer chemistry, nanoparticles more effectively disseminated away from the injection site as compared to microparticles, which exhibited a depot effect. Using fluorescent probes, the in vivo distribution of three formulations of nanoparticles, following subcutaneous administration, indicated migration away from the injection site. Less inflammation was observed at the injection sites of mice-administered nanoparticles as compared to Alum and incomplete Freund's adjuvant. Furthermore, histological evaluation revealed minimal adverse injection site reactions and minimal toxicological effects associated with the administration of nanoparticles at 30 days post-administration. Collectively, these results demonstrate that polyanhydride nanoparticles do not induce inflammation as a cumulative effect of particle persistence or degradation and are, therefore, a viable candidate for a vaccine delivery platform.
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Rational Design of Pathogen-Mimicking Amphiphilic Materials as Nanoadjuvants
Scientific Reports, 2011Co-Authors: Bret D. Ulery, Latrisha K. Petersen, Yashdeep Phanse, Chang Sun Kong, Scott R. Broderick, Devender Kumar, Amanda E. Ramer-tait, Brenda Carrillo-conde, Krishna Rajan, Michael J WannemuehlerAbstract:An opportunity exists today for cross-cutting research utilizing advances in materials science, immunology, microbial pathogenesis and computational analysis to effectively design the next generation of adjuvants and vaccines. This study integrates these advances into a bottom-up approach for the molecular design of nanoadjuvants capable of mimicking the immune response induced by a natural infection but without the toxic side effects. Biodegradable amphiphilic Polyanhydrides possess the unique ability to mimic pathogens and pathogen associated molecular patterns with respect to persisting within and activating immune cells, respectively. The molecular properties responsible for the pathogen-mimicking abilities of these materials have been identified. The value of using polyanhydride nanovaccines was demonstrated by the induction of long-lived protection against a lethal challenge of Yersinia pestis following a single administration ten months earlier. This approach has the tantalizing potential to catalyze the development of next generation vaccines against diseases caused by emerging and re-emerging pathogens.
Amanda E Ramertait - One of the best experts on this subject based on the ideXlab platform.
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functionalization promotes pathogen mimicking characteristics of polyanhydride nanoparticle adjuvants
Journal of Biomedical Materials Research Part A, 2017Co-Authors: Yashdeep Phanse, Balaji Narasimhan, Brenda R Carrilloconde, Michael J Wannemuehler, Amanda E Ramertait, Scott R. Broderick, Krishna Rajan, Rajarshi Roychoudhury, Nicola L. B. Pohl, Bryan H BellaireAbstract:Rational design of adjuvants and delivery systems will promote development of next-generation vaccines to control emerging and re-emerging diseases. To accomplish this, understanding the immune-enhancing properties of new adjuvants relative to those induced by natural infections can help with the development of pathogen-mimicking materials that will effectively initiate innate immune signaling cascades. In this work, the surfaces of polyanhydride nanoparticles composed of sebacic acid (SA) and 1,6-bis(p-carboxyphenoxy) hexane were decorated with an ethylene diamine spacer partially modified with either a glycolic acid linker or an α-1,2-linked di-mannopyranoside (di-mannose) to confer "pathogen-like" properties and enhance adjuvanticity. Co-incubation of linker-modified nanoparticles with dendritic cells (DCs) elicited significant increases in surface expression of MHC I, MHC II, CD86, and CD40, and enhanced secretion of IL-6, IL-12p40, and TNF-α. An 800% increase in uptake of ethylene-diamine-spaced, linker and di-mannose functionalized polyanhydride nanoparticles was also observed. Together, our data showed that linker-functionalized polyanhydride nanoparticles demonstrate similar patterns of uptake, intracellular trafficking, particle persistence, and innate activation as did DCs exposed to Yersinia pestis or Escherichia coli. These results set the stage for rational selection of adjuvant chemistries to induce pathogen-mimicking immune responses. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2762-2771, 2017.
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sustained release and stabilization of therapeutic antibodies using amphiphilic polyanhydride nanoparticles
Chemical Engineering Science, 2015Co-Authors: Brenda R Carrilloconde, Michael J Wannemuehler, Amanda E Ramertait, Ross J Darling, Steven J Seiler, Balaji NarasimhanAbstract:Abstract Passive administration of antibodies (e.g., anti-serum or monoclonal antibodies) can be successfully used as treatments for infectious agents (e.g., human cytomegalovirus, HIV), chronic inflammation (e.g., anti-TNF), cancer (e.g., anti-HER2, anti-VEGF, anti-CD20), toxins (e.g., anti-ricin), and age-related diseases such as macular degeneration (e.g., anti-VEGF). As with the development of proteinaceous pharmaceuticals, one of the most challenging obstacles facing passive immunotherapies is the physical and the chemical instabilities of the antibodies, which invariably leads to loss of biological activity. In order to avoid these problems, appropriate delivery vehicles need to be designed that minimize the degradation, maximize the in vivo activity, and provide controlled release of the encapsulated biologically active protein. In this study, polyanhydride nanoparticles were used for the delivery of stable and biologically active therapeutic antibodies. Tetanus antitoxin and anti-TNF-α monoclonal antibodies were encapsulated and released from polyanhydride nanoparticles. The nanoparticles provided the ability to control antibody release kinetics and, additionally, preserved antibody functionality and bioactivity upon synthesis and release. In particular, amphiphilic polyanhydride nanoparticles demonstrated the best combination of characteristics compatible for anti-serum or monoclonal antibody preservation and release, making them ideal candidates for use as a delivery system for therapeutic antibodies.
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polyanhydride nanovaccine platform enhances antigen specific cytotoxic t cell responses
TECHNOLOGY, 2014Co-Authors: Lucas Huntimer, Balaji Narasimhan, Kathleen A Ross, Amanda E Ramertait, Ross J Darling, Nicole E Winterwood, Paola M Boggiatto, Michael J WannemuehlerAbstract:Polyanhydride nanoparticle-based vaccines (or nanovaccines) stabilize protein antigens, provide sustained antigen release leading to prolonged antigen presence, enhance activation of antigen presenting cells, and elicit protective immunity against respiratory infections upon challenge. However, induction of cell-mediated immunity when mice are immunized with polyanhydride nanovaccines has not been evaluated. Using a transgenic ovalbumin-specific T cell adoptive transfer model, we report the induction of antigen-specific cytotoxic CD8+ T cells expressing an effector memory phenotype by seven days after immunization with nanovaccine formulations. Furthermore, mice immunized with polyanhydride nanovaccines demonstrated enhanced recall responses after antigen re-exposure 35 days post-immunization indicating the activation and recruitment of antigen-specific memory CD8+ T cells to the site of antigen deposition.
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combinatorial evaluation of in vivo distribution of polyanhydride particle based platforms for vaccine delivery
International Journal of Nanomedicine, 2013Co-Authors: Latrisha K. Petersen, Lucas Huntimer, Michael J Wannemuehler, Amanda E Ramertait, Katharine Walz, Balaji NarasimhanAbstract:Several challenges are associated with current vaccine strategies, including repeated immunizations, poor patient compliance, and limited approved routes for delivery, which may hinder induction of protective immunity. Thus, there is a need for new vaccine adjuvants capable of multi-route administration and prolonged antigen release at the site of administration by providing a depot within tissue. In this work, we designed a combinatorial platform to investigate the in vivo distribution, depot effect, and localized persistence of polyanhydride nanoparticles as a function of nanoparticle chemistry and administration route. Our observations indicated that the route of administration differentially affected tissue residence times. All nanoparticles rapidly dispersed when delivered intranasally but provided a depot when administered parenterally. When amphiphilic and hydrophobic nanoparticles were administered intranasally, they persisted within lung tissue. These results provide insights into the chemistry- and route-dependent distribution and tissue-specific association of polyanhydride nanoparticle-based vaccine adjuvants.
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evaluation of biocompatibility and administration site reactogenicity of polyanhydride particle based platform for vaccine delivery
Advanced Healthcare Materials, 2013Co-Authors: Lucas Huntimer, Latrisha K. Petersen, Balaji Narasimhan, Kathleen A Ross, Chong Wang, Amanda E Ramertait, Katherine A Walz, Jesse M Hostetter, Michael J WannemuehlerAbstract:Efficacy, purity, safety, and potency are important attributes of vaccines. Polyanhydride particles represent a novel class of vaccine adjuvants and delivery platforms that have demonstrated the ability to enhance the stability of protein antigens as well as elicit protective immunity against bacterial pathogens. This work aims to elucidate the biocompatibility, inflammatory reactions, and particle effects on mice injected with a 5 mg dose of polyanhydride nanoparticles via common parenteral routes (subcutaneous and intramuscular). Independent of polymer chemistry, nanoparticles more effectively disseminated away from the injection site as compared to microparticles, which exhibited a depot effect. Using fluorescent probes, the in vivo distribution of three formulations of nanoparticles, following subcutaneous administration, indicated migration away from the injection site. Less inflammation was observed at the injection sites of mice-administered nanoparticles as compared to Alum and incomplete Freund's adjuvant. Furthermore, histological evaluation revealed minimal adverse injection site reactions and minimal toxicological effects associated with the administration of nanoparticles at 30 days post-administration. Collectively, these results demonstrate that polyanhydride nanoparticles do not induce inflammation as a cumulative effect of particle persistence or degradation and are, therefore, a viable candidate for a vaccine delivery platform.
Kathleen A Ross - One of the best experts on this subject based on the ideXlab platform.
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single dose of a polyanhydride particle based vaccine generates potent antigen specific antitumor immune responses
Journal of Pharmacology and Experimental Therapeutics, 2019Co-Authors: Emad I Wafa, Balaji Narasimhan, Kathleen A Ross, Sean M Geary, Jonathan T Goodman, Aliasger K SalemAbstract:Many factors affect vaccine efficacy. One of the most salient is the frequency and intervals of vaccine administration. In this study, we assessed the vaccine administration modality for a recently reported polyanhydride-based vaccine formulation, shown to generate antitumor activity. Polyanhydride particles encapsulating ovalbumin (OVA) were prepared using a double-emulsion technique and subcutaneously delivered to mice either as a single-dose or as prime-boost vaccine regimens in which two different time intervals between prime and boost were assessed (7 or 21 days). This was followed by measurement of cellular and humoral immune responses, and subsequent challenge of the mice with a lethal dose of E.G7-OVA cells to evaluate tumor protection. Interestingly, a single dose of the polyanhydride particle-based formulation induced sustained OVA-specific cellular immune responses just as effectively as the prime-boost regimens. In addition, mice receiving single-dose vaccine had similar levels of protection against tumor challenge compared with mice administered prime-boosts. In contrast, measurements of OVA-specific IgG antibody titers indicated that a booster dose was required to stimulate strong humoral immune responses, since it was observed that mice administered a prime-boost vaccine had significantly higher OVA-specific IgG1 serum titers than mice administered a single dose. These findings indicate that the requirement for a booster dose using these particles appears unnecessary for the generation of effective cellular immunity.
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ph responsive microencapsulation systems for the oral delivery of polyanhydride nanoparticles
Biomacromolecules, 2018Co-Authors: Lindsey A Sharpe, Balaji Narasimhan, Kathleen A Ross, Julia Vela E Ramirez, Olivia M. Haddadin, Nicholas A. PeppasAbstract:Multicompartmental polymer carriers, referred to as Polyanhydride-Releasing Oral MicroParticle Technology (PROMPT), were formed by a pH-triggered antisolvent precipitation technique. Polyanhydride nanoparticles were encapsulated into anionic pH-responsive microparticle gels, allowing for nanoparticle encapsulation in acidic conditions and subsequent release in neutral pH conditions. The effects of varying the nanoparticle composition and feed ratio on the encapsulation efficiency were evaluated. Nanoparticle encapsulation was confirmed by confocal microscopy and infrared spectroscopy. pH-triggered protein delivery from PROMPT was explored using ovalbumin (ova) as a model drug. PROMPT microgels released ova in a pH-controlled manner. Increasing the feed ratio of nanoparticles into the microgels increased the total amount of ova delivered, as well as decreased the observed burst release. The cytocompatibility of the polymer materials were assessed using cells representative of the GI tract. Overall, these r...
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pH-Responsive Microencapsulation Systems for the Oral Delivery of Polyanhydride Nanoparticles
2018Co-Authors: Lindsey A. Sharpe, Balaji Narasimhan, Kathleen A Ross, Julia Vela E Ramirez, Olivia M. Haddadin, Nicholas A. PeppasAbstract:Multicompartmental polymer carriers, referred to as Polyanhydride-Releasing Oral MicroParticle Technology (PROMPT), were formed by a pH-triggered antisolvent precipitation technique. Polyanhydride nanoparticles were encapsulated into anionic pH-responsive microparticle gels, allowing for nanoparticle encapsulation in acidic conditions and subsequent release in neutral pH conditions. The effects of varying the nanoparticle composition and feed ratio on the encapsulation efficiency were evaluated. Nanoparticle encapsulation was confirmed by confocal microscopy and infrared spectroscopy. pH-triggered protein delivery from PROMPT was explored using ovalbumin (ova) as a model drug. PROMPT microgels released ova in a pH-controlled manner. Increasing the feed ratio of nanoparticles into the microgels increased the total amount of ova delivered, as well as decreased the observed burst release. The cytocompatibility of the polymer materials were assessed using cells representative of the GI tract. Overall, these results suggest that pH-dependent microencapsulation is a viable platform to achieve targeted intestinal delivery of polyanhydride nanoparticles and their payload(s)
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hemagglutinin based polyanhydride nanovaccines against h5n1 influenza elicit protective virus neutralizing titers and cell mediated immunity
International Journal of Nanomedicine, 2014Co-Authors: Kathleen A Ross, Lucas Huntimer, Scott R. Broderick, Krishna Rajan, Hyelee Loyd, Shaheen Ahmed, Anthony R Sambol, Zachary Flickinger, Tatiana K Bronich, Surya K. MallapragadaAbstract:H5N1 avian influenza is a significant global concern with the potential to become the next pandemic threat. Recombinant subunit vaccines are an attractive alternative for pandemic vaccines compared to traditional vaccine technologies. In particular, polyanhydride nanoparticles encapsulating subunit proteins have been shown to enhance humoral and cell-mediated immunity and provide protection upon lethal challenge. In this work, a recombinant H5 hemagglutinin trimer (H53) was produced and encapsulated into polyanhydride nanoparticles. The studies performed indicated that the recombinant H53 antigen was a robust immunogen. Immunizing mice with H53 encapsulated into polyanhydride nanoparticles induced high neutralizing antibody titers and enhanced CD4+ T cell recall responses in mice. Finally, the H53-based polyanhydride nanovaccine induced protective immunity against a low-pathogenic H5N1 viral challenge. Informatics analyses indicated that mice receiving the nanovaccine formulations and subsequently challenged with virus were similar to naive mice that were not challenged. The current studies provide a basis to further exploit the advantages of polyanhydride nanovaccines in pandemic scenarios.
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structural and antigenic stability of h5n1 hemagglutinin trimer upon release from polyanhydride nanoparticles
Journal of Biomedical Materials Research Part A, 2014Co-Authors: Kathleen A Ross, Lucas Huntimer, Michael J Wannemuehler, Hyelee Loyd, Susan Carpenter, Balaji NarasimhanAbstract:Although H5N1 avian influenza has not yet acquired the capacity to readily infect humans, should it do so, this viral pathogen would present an increasing threat to the immunologically naive human population. Subunit vaccines based on the viral glycoprotein hemagglutinin (HA) can provide protective immunity against influenza. Polyanhydride nanoparticles have been shown to enhance efficacy of subunit vaccines, providing the dual advantages of adjuvanticity and sustained delivery resulting in enhanced protein stability and immunogenicity. In this work, a recombinant trimer of H5 (H53 ) was encapsulated and released from polyanhydride nanoparticles. Release kinetics of the encapsulated H53 were found to be dependent on polymer chemistry (i.e., hydrophobicity and molecular weight). Polyanhydride nanoparticles composed of sebacic anhydride and 1,6-bis(p-carboxyphenoxy)hexane (CPH; that degrade into more acidic monomers) released structurally stable HA H53 , while H53 released from formulations composed of CPH and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) (that are amphiphilic and whose degradation products are less acidic) displayed unfolding of tertiary structure. However, the antigenicity of the H53 based on binding of a H5-specific monoclonal antibody was preserved upon release from all the formulations studied, demonstrating the value of polyanhydride nanoparticles as a viable platform for HA-based influenza vaccines.