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Derek T O'Hagan

Publications and source records attributed to Derek T O'Hagan.

At least 19 recordsLinked to original sources
PubMed2006

Novel approaches to pediatric vaccine delivery.

Although currently available vaccines represent an outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide, it is clear that improvements in vaccine delivery are required. Vaccine delivery improvements may include the addition of novel injectable adjuvants, or the use of novel routes of delivery, including mucosal immunization. Mucosal delivery may be required to provide protection against pathogens that infect at mucosal sites, including sexually transmitted diseases. Alternatively, novel approaches to delivery, including mucosal administration, may be used to improve compliance for existing vaccines. Of particular interest for safer mass immunization are needle-free delivery devices, which would avoid problems due to needle re-use in many parts of the world, or needle-stick injuries.

Adjuvants, Immunologic↗
PubMed2006

Microparticle-based technologies for vaccines.

Microparticles have been effectively used for many years as delivery systems for drugs and therapeutic proteins. Their application to the delivery of vaccines is not as extensive, but is growing. Utility has been demonstrated for the delivery of various types of vaccines (e.g., recombinant proteins, plasmid DNA, and peptides) and other vaccine components (e.g., immune potentiators). With respect to delivery of immune potentiators, synergistic effects are often observed whereby much more potent immune responses are induced with a combination than with either component alone. Hence, the prospects for broad application of microparticle-based delivery systems for vaccines are excellent.

Adjuvants, Immunologic↗
PubMed2006

Antibody responses against HIV in rhesus macaques following combinations of mucosal and systemic immunizations with chimeric alphavirus-based replicon particles.

Mucosal and systemic transmission of HIV is prevalent. Therefore, mucosal followed by parenteral immunizations with chimeric vs. complete alphavirus-based replicon particles, encoding an HIV envelope glycoprotein, were tested. Female rhesus macaques were immunized intranasally and then intramuscularly. Following the immunizations, enhanced mucosal and systemic antibody responses were detected with the chimeric compared to the complete replicon particles. Although similar proportions of the same peripheral blood monocyte lineage target cells were infected with the chimeric vs. the complete replicon particles, the latter resulted in enhanced expression of the gene of interest, suggesting a possible mechanism of the enhanced immunogenicity.

Administration, Intranasal↗
PubMed2006

Hepatitis C virus polyprotein vaccine formulations capable of inducing broad antibody and cellular immune responses.

Although approximately 3 % of the world's population is infected with Hepatitis C virus (HCV), there is no prophylactic vaccine available. This study reports the design, cloning and purification of a single polyprotein comprising the HCV core protein and non-structural proteins NS3, NS4a, NS4b, NS5a and NS5b. The immunogenicity of this polyprotein, which was formulated in alum, oil-in-water emulsion MF59 or poly(dl-lactide co-glycolide) in the presence or absence of CpG adjuvant, was then determined in a murine model for induction of B- and T-cell responses. The addition of adjuvants or a delivery system to the HCV polyprotein enhanced serum antibody and T-cell proliferative responses, as well as IFN-gamma responses, by CD4+ T cells. The antibody responses were mainly against the NS3 and NS5 components of the polyprotein and relatively poor responses were elicited against NS4 and the core components. IFN-gamma responses, however, were induced against all of the individual components of the polyprotein. These data suggest that the HCV polyprotein delivered with adjuvants induces broad B- and T-cell responses and could be a vaccine candidate against HCV.

Adjuvants, Immunologic↗
PubMed2006

Polylactide-co-glycolide microparticles with surface adsorbed antigens as vaccine delivery systems.

Several groups have shown that vaccine antigens can be encapsulated within polymeric microparticles and can serve as potent antigen delivery systems. We have recently shown that an alternative approach involving charged polylactide co-glycolide (PLG) microparticles with surface adsorbed antigen(s) can also be used to deliver antigen into antigen presenting cell (APC). We have described the preparation of cationic and anionic PLG microparticles which have been used to adsorb a variety of agents, which include plasmid DNA, recombinant proteins and adjuvant active oligonucleotides. These PLG microparticles were prepared using a w/o/w solvent evaporation process in the presence of the anionic surfactants, including DSS (dioctyl sodium sulfosuccinate) or cationic surfactants, including CTAB (hexadecyl trimethyl ammonium bromide). Antigen binding to the charged PLG microparticles was influenced by several factors including electrostatic and hydrophobic interactions. These microparticle based formulations resulted in the induction of significantly enhanced immune responses in comparison to alum. The surface adsorbed microparticle formulation offers an alternative and novel way of delivering antigens in a vaccine formulation.

Adjuvants, Immunologic↗
PubMed2005

Encapsulation of the immune potentiators MPL and RC529 in PLG microparticles enhances their potency.

PURPOSE: Monophosphoryl lipid A (MPL) and the synthetic LPS mimetic RC529, encapsulated in poly(lactide-co-glycolide) (PLG) microparticles, were evaluated as immune potentiators in the presence of either HIV-1 gp120 protein or antigen from Neisseria meningitidis serotype B (Men B). The immunogenicity of these formulations was evaluated in mice and compared to CpG containing oligonucleotide. This work was done as part of an ongoing effort to enhance the potency of vaccine candidates against HIV and Men B. METHODS: Microparticles were made by a solvent evaporation method. Blank microparticles as well as microparticles with encapsulated MPL or RC529 were made using the PLG polymer RG503 and the ionic surfactant Dioctylsulfosuccinate by the water-in-oil-in-water emulsion technique. Antigens from HIV-1 and Men B were adsorbed on the surface of these anionic microparticles and the final formulations characterized for protein loading, release, and integrity. The formulations were then tested in mice for their ability to elicit antibodies and bactericidal activity in comparison with CpG containing oligonucleotide. RESULTS: We have found that adding soluble immune potentiators to Men B antigen formulated on PLG microparticles significantly enhanced the immune response to a level comparable to that obtained using CpG. In a separate study, we found that encapsulating MPL or RC529 in PLG microparticles further enhanced the response in comparison to soluble CpG, which is our control group. Similarly, adding soluble immune potentiators to gp120 antigen formulated on PLG microparticles resulted in a significant enhancement of the immune response. Moreover, delivering MPL or RC529 encapsulated in PLG microparticles with gp120 adsorbed on PLG microparticles, resulted in even further enhancement of serum titers over those obtained with soluble immune potentiators. These titers were comparable to or greater than those obtained with soluble CpG, the control group. This effect was observed for both antigens regardless of whether or not the immune potentiator and the antigen were used with the same or with separate particles. In conclusion, the advantages of encapsulating MPL and RC529 lie not only in the enhanced immune response they elicit, but also in the convenience of handling these relatively insoluble compounds, and flexibility in vaccine design. The fact that MPL and RC529 are readily soluble in methylene chloride used for the manufacturing of PLG microparticles makes it easy to avoid solubility issues. Moreover, formulating antigen and immune potentiator with the same particle offers an attractive approach to vaccine delivery.

Adjuvants, Immunologic↗
PubMed2005

A preliminary evaluation of alternative adjuvants to alum using a range of established and new generation vaccine antigens.

Although alum is the most commonly used vaccine adjuvant, it has some limitations for use with the next generation recombinant antigens. We explored the use of alternative adjuvant formulations (poly lactide co-glycolide (PLG) microparticles, MF59 emulsion, CAP and l-tyrosine suspension) in comparison with five different vaccine antigens--namely, diphtheria toxoid (DT), tetanus toxoid (TT), HBsAg, Men C conjugate and MB1. The results indicated that although alum was optimal for bacterial toxoid based vaccines, it was not highly potent for MB1, Men C or HBsAg antigens. MF59 emulsion stood out as a good alternative to alum for TT, HBsAg, MB1 and Men C vaccines. On the other hand l-tyrosine suspension and CAP did not enhance immune responses over alum with most antigens. PLG microparticles were comparable or better than alum with both MB1 and Men C conjugate vaccine. The study indicates that it is possible to replace alum with other adjuvant formulations like MF59 and PLG and maintain and/or improve immune responses with some vaccine antigens.

Adjuvants, Immunologic↗
PubMed2005

CpG oligodeoxynucleotides adsorbed onto polylactide-co-glycolide microparticles improve the immunogenicity and protective activity of the licensed anthrax vaccine.

To reduce the biothreat posed by anthrax, efforts are under way to improve the protection afforded by vaccination. This work examines the ability of immunostimulatory CpG oligodeoxynucleotides (ODN) adsorbed onto cationic polylactide-co-glycolide (PLG) microparticles (CpG ODN-PLG) to accelerate and boost the protective immunity elicited by Anthrax Vaccine Adsorbed (AVA, the licensed human anthrax vaccine). The results indicate that coadministering CpG ODN-PLG with AVA induces a stronger and faster immunoglobulin G response against the protective antigen of anthrax than AVA alone. Immunized mice were protected from lethal anthrax challenge within 1 week of vaccination with CpG ODN-PLG plus AVA, with the level of protection correlating with serum immunoglobulin G anti-protective antigen titers.

Animals↗
PubMed2005

Enhanced potency of plasmid DNA microparticle human immunodeficiency virus vaccines in rhesus macaques by using a priming-boosting regimen with recombinant proteins.

DNA vaccines have been used widely in experimental primate models of human immunodeficiency virus (HIV), but their effectiveness has been limited. In this study, we evaluated three technologies for increasing the potency of DNA vaccines in rhesus macaques. These included DNA encoding Sindbis virus RNA replicons (pSINCP), cationic poly(lactide-co-glycolide) (PLG) microparticles for DNA delivery, and recombinant protein boosting. The DNA-based pSINCP replicon vaccines encoding HIV Gag and Env were approximately equal in potency to human cytomegalovirus (CMV) promoter-driven conventional DNA vaccines (pCMV). The PLG microparticle DNA delivery system was particularly effective at enhancing antibody responses induced by both pCMV and pSINCP vaccines and had less effect on T cells. Recombinant Gag and Env protein boosting elicited rapid and strong recall responses, in some cases to levels exceeding those seen after DNA or DNA/PLG priming. Of note, Env protein boosting induced serum-neutralizing antibodies and increased frequencies of gamma interferon-producing CD4 T cells severalfold. Thus, PLG microparticles are an effective means of delivering DNA vaccines in nonhuman primates, as demonstrated for two different types of DNA vaccines encoding two different antigens, and are compatible for use with DNA prime-protein boost regimens.

AIDS Vaccines↗
PubMed2004

Cationic microparticles are a potent delivery system for a HCV DNA vaccine.

We initially evaluated in mice the ability of naked DNA encoding intracellular forms of the E1E2 envelope proteins from HCV to induce antibody responses and compared the responses induced with the same plasmid adsorbed onto cationic poly (lactide co-glycolide) (PLG) microparticles. Although naked DNA was only able to induce detectable responses at the 100 microg dose level, making this approach impractical for evaluation in larger animals, PLG/DNA induced detectable responses at 10 microg. In addition, the PLG/DNA microparticles induced significantly enhanced responses to naked DNA when compared at the same dose level. Remarkably, PLG/DNA induced comparable responses to recombinant E1E2 protein adjuvanted with the emulsion MF59. Furthermore, PLG/DNA effectively primed for a booster response with protein immunization, while naked DNA did not. Therefore, PLG/DNA was selected for further evaluation in a non-human primate model. In a study in rhesus macaques, PLG/DNA induced seroconversion in 3/3 animals following three immunizations. Although the antibody responses appeared lower than those induced with recombinant protein adjuvanted with MF59, following a fourth dose, PLG/DNA and protein induced comparable responses. However, a single booster dose of recombinant protein administered to the animals previously immunized with PLG/DNA induced much higher responses. In addition, one of three animals immunized with PLG/DNA showed a cytotoxic T lymphocyte response in peripheral blood lymphocytes. In conclusion, cationic PLG microparticles with adsorbed HCV DNA generates potent immune responses.

Adjuvants, Immunologic↗
PubMed2004

Enhanced protective efficacy of a tuberculosis DNA vaccine by adsorption onto cationic PLG microparticles.

Immunization with plasmid DNA vectors represents a promising new approach to vaccination. It has been shown to elicit humoral and cellular immunity and protection in various infection models. Here, we assessed the immunogenicity and protective efficacy of a DNA vaccine vector encoding the antigen 85A (Ag85A) of Mycobacterium tuberculosis. Since intramuscular (i.m.) immunization with naked DNA requires considerable amounts of DNA in order to be effective, we evaluated a strategy to reduce the amount of DNA needed. To this end, we used Ag85A DNA adsorbed onto cationic poly(DL-lactide-co-glycolide) (PLG) microparticles and observed similar levels of protection against aerosol challenge in mice using doses of PLG-DNA two orders of magnitude lower than with naked DNA itself.

Adsorption↗
PubMed2004

Anionic microparticles are a potent delivery system for recombinant antigens from Neisseria meningitidis serotype B.

The adsorption behavior of model proteins onto anionic poly(lactide-co-glycolide) (PLG) microparticles was evaluated. PLG microparticles were prepared by a w/o/w solvent evaporation process in the presence of the anionic surfactant dioctyl sodium sulfosuccinate (DSS). The effect of surfactant concentration and adsorption conditions on the adsorption efficiency and release rates in vitro was also studied. Subsequently, the microparticle formulation was tested to evaluate the efficacy of anionic microparticles as delivery systems for recombinant antigens from Neisseria meningitides type B (Men B), with and without CpG adjuvant. Protein (antigen) binding to anionic PLG microparticles was influenced by both electrostatic interaction and by other mechanisms, including hydrophobic attraction. The Men B antigens adsorbed efficiently onto anionic PLG microparticles and, following immunization in mice, induced potent enzyme-linked immunosorbent assay (ELISA) and serum bactericidal activity in comparison to alum-adsorbed formulations. These Men B antigens represent an attractive approach for vaccine development.

Adjuvants, Immunologic↗
PubMed2004

Adsorption of a novel recombinant glycoprotein from HIV (Env gp120dV2 SF162) to anionic PLG microparticles retains the structural integrity of the protein, whereas encapsulation in PLG microparticles does not.

PURPOSE: To evaluate the delivery of a novel HIV-1 antigen (gp120dV2 SF162) by surface adsorption or encapsulation within polylactide-co-glycolide microparticles and to compare both the formulations for their ability to preserve functional activity as measured by binding to soluble CD4. METHODS: Poly(lactide-co-glycolide) microparticles were synthesized by a water-in-oil-in-water (w/o/w) emulsification method in the presence of the anionic surfactant dioctylsulfosuccinate (DSS) or polyvinyl alcohol. The HIV envelope glyocoprotein was adsorbed and encapsulated in the PLG particles. Binding efficiency and burst release measured to determine adsorption characteristics. The ability to bind CD4 was assayed to measure the functional integrity of gp120dV2 following different formulation processes. RESULTS: Protein (antigen) binding to PLG microparticles was influenced by both electrostatic interaction and other mechanisms such as hydrophobic attraction and structural accommodation of the polymer and biomolecule. The functional activity as measured by the ability of gp120dV2 to bind CD4 was maintained by adsorption onto anionic microparticles but drastically reduced by encapsulation. CONCLUSIONS: The antigen on the adsorbed PLG formulation maintained its binding ability to soluble CD4 in comparison to encapsulation, demonstrating the feasibility of using these novel anionic microparticles as a potential vaccine delivery system.

Adsorption↗
PubMed2004

Novel approaches to vaccine delivery.

Although the currently available vaccines represent an outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide, it is clear that improvements are required in the current vaccine delivery technologies. Improvements are required to enable the successful development of vaccines against infectious diseases that have so far proven difficult to control with conventional approaches. Improvements may include the addition of novel injectable adjuvants or the use of novel routes of delivery, including mucosal immunization. Mucosal delivery may be required to provide protection against pathogens that infect at mucosal sites, including sexually transmitted diseases. Alternatively, novel approaches to delivery, including mucosal administration, may be used to improve compliance for existing vaccines. Of particular interest for safer mass immunization campaigns are needle-free delivery devices, which would avoid problems due to needle re-use in many parts of the world and would avoid needle-stick injuries.

Adjuvants, Immunologic↗
PubMed2004

Mucosal and systemic anti-HIV responses in rhesus macaques following combinations of intranasal and parenteral immunizations.

There is an urgent need to develop vaccines that can elicit immunological memory responses against HIV. Using the rhesus macaque model and a combination of intranasal (IN) and parenteral immunizations with DNA or protein adsorbed to microparticles or mixed with mucosal adjuvants we sought to induce anti-HIV memory-type immune responses in both the mucosal and systemic compartments. Prime/boost immunizations were performed through five IN immunizations alone with HIV-env oligomeric gp140 (Ogp140) or HIV-gag-p24 mixed with Escherichia coli heat labile-derived mutant adjuvants or two parenteral immunizations with DNA encoding HIV-env or -gag adsorbed to microparticles followed by three IN immunizations with p24 gag protein and the mutant adjuvants. Both modes of immunizations induced anti-gp140 plasma and vaginal IgG and IgA as well as interferon (IFN)-gamma secreting peripheral blood mononuclear cells (PBMC) after HIV-env and -gag peptide restimulation. After a resting period of 4 months, when the levels of humoral and cellular responses had decreased, intramuscular (IM) booster immunizations with p55-gag protein adsorbed to microparticles and Ogp140 in MF59 oil in water emulsion significantly enhanced anti-HIV plasma and vaginal antibody, as well as peripheral blood IFN-gamma responses in all groups of vaccinated macaques. Importantly, plasma neutralization activity against both homologous and heterologous HIV strains was observed in all groups following the IM booster immunizations with protein. These findings show that IN priming alone or combinations of parenteral and IN immunizations followed by IM booster immunizations hold promise to significantly enhance mucosal and systemic memory-type immune responses against HIV-1 antigens.

AIDS Vaccines↗
PubMed2004

Microparticles for the delivery of DNA vaccines.

DNA vaccines have demonstrated a lack of adequate potency in humans, which has necessitated the exploration of various adjunct technologies. Inefficient delivery of DNA vaccines, particularly to antigen-presenting cells, may be contributing to this lack of potency. One effective means of facilitating delivery of DNA vaccines to APCs is through the use of microparticles. In this article, we review the background and rationale for microparticles as a vaccine delivery system, data demonstrating their utility and mode of action for DNA delivery, and the prospects for their development.

Adjuvants, Immunologic↗
PubMed2004

Charged polylactide co-glycolide microparticles as antigen delivery systems.

Polymeric microparticles with encapsulated antigens have become well-established in the last decade as potent antigen delivery systems and adjuvants, with experience being reported from many groups. However, the authors have recently shown that an alternative approach involving charged polylactide co-glycolide (PLG) microparticles with surface adsorbed antigen(s) can also be used to deliver antigen into antigen-presenting cell populations. The authors have described the preparation of cationic and anionic PLG microparticles that have been used to adsorb a variety of agents, to include plasmid DNA, recombinant proteins and adjuvant active oligonucleotides. These novel PLG microparticles were prepared using a w/o/w solvent evaporation process in the presence of the anionic surfactants, such as dioctyl sodium sulfosuccinate, or cationic surfactants, such as hexadecyl trimethyl ammonium bromide. Antigen binding to the charged PLG microparticles was influenced by both electrostatic interaction and other mechanisms, including hydrophobic interactions. Adsorption of antigens to microparticles resulted in the induction of significantly enhanced immune responses in comparison with alternative approaches. The surface adsorbed microparticle formulation offers an alternative way of delivering antigens as a vaccine formulation.

Animals↗