Jeff Fairman

University of Cincinnati, Cincinnati, Ohio, United States

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Publications (17)33.21 Total impact

  • Antiviral Research 04/2010; 86(1). · 3.93 Impact Factor
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    ABSTRACT: Background: CD8 T cells play an important role in clearing virally infected cells after influenza infection. Induction of a strong CD8 T-cell response after vaccination may result in better heterosubtypic protection as it targets less variable internal influenza proteins. Although the hierarchy of CD8 T-cell epitopes after infection is well defined in mice, it is unclear if vaccination induces a similar hierarchy and if so, if this is influenced by vaccine adjuvants. Methods: C57BL/6J mice were either infected intranasally with mouse-adapted H3N2 (HKx31) or vaccinated intramuscularly with whole, inactivated influenza adjuvanted with either aluminum hydroxide (Alum) or a novel adjuvant - cationic lipid-DNA complexes (CLDC). Multiplex MHC-peptide tetramer staining was used to simultaneously assay CD8 T cells with reactivity to several influenza A viral epitopes by flow cytometry in spleen and lung tissue. In this method, biotinylated MHC-peptide tetramers are labeled with a combination of four different streptavidin:fluorophores allowing for sixteen possible color combinations. Results: Multiplex MHC-peptide tetramer staining simultaneously identified seven different CD8 T-cell populations after infection in spleen and lung tissue allowing for direct comparison of CD8 T-cell frequencies. In infected mice, CD8 T cells recognizing PA and NP predominated. Similarly, in vaccinated mice, these two epitopes dominated with NP accounting for most of the CD8 T-cell response after employing a prime:boost strategy. Although CD8 T cell frequencies were similar in Alum and CLDC groups, CLDC-vaccinated mice demonstrated greater numbers of effector CD8 T cells as measured by IFN-gamma production. Conclusion: Multiplex MHC Class I-peptide tetramer staining is a useful method to simultaneously identify multiple CD8 T cell populations after influenza infection or vaccination. Although vaccination with Alum- or CLDC-adjuvanted influenza induced CD8 T cells that followed immunodominant hierarchies similar to intranasal infection, CLDC induced greater numbers of effector CD8 T cells than Alum.
    Infectious Diseases Society of America 2009 Annual Meeting; 10/2009
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    ABSTRACT: Herpes simplex virus (HSV) infections are common but there is no vaccine available. We evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant for an HSV gD2 vaccine and compared it to an MPL/Alum adjuvant in a guinea pig model of genital herpes. The addition of CLDC to the gD2 vaccine significantly decreased acute and recurrent disease and most importantly the number of days with recurrent virus shedding compared to gD2 alone. Reductions in these outcomes were also detected when gD2+CLDC was compared to gD2+MPL/Alum. When the vaccine and adjuvants were evaluated as therapeutic vaccines, they were ineffective. CLDC enhanced protection compared to MPL/Alum and is the first vaccine to reduce recurrent virus shedding, a key to decreasing the spread of HSV-2.
    Vaccine 10/2009; 28(21):3748-53. · 3.77 Impact Factor
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    ABSTRACT: Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further.
    Clinical and vaccine Immunology: CVI 04/2009; 16(5):699-705. · 2.60 Impact Factor
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    ABSTRACT: Many new vaccines under development consist of rationally designed recombinant proteins that are relatively poor immunogens unless combined with potent adjuvants. There is only one adjuvant in common use in the U.S., aluminum phosphate or hydroxide (e.g. alum). This adjuvant, however, has significant limitations, particularly regarding the generation of strong cell-mediated (T-cell) immune responses. A novel adjuvant, JVRS-100, composed of cationic liposome-DNA complexes (CLDC) has been evaluated for immune enhancing activity. The JVRS-100 adjuvant has been shown to elicit robust immune responses compared to CpG oligonucleotides, alum, and MPL adjuvants, and efficiently enhances both humoral and cellular immune responses. Safety has been evaluated in preclinical studies, and the adjuvant is now in early-stage clinical development. One application of this novel adjuvant is to augment the immune responses to recombinant subunit antigens, which are often poorly immunogenic. The JVRS-100 adjuvant, when combined with a recombinant influenza hemagglutinin (H1), elicited increased specific antibody and T-cell responses in mice. Single-dose vaccination and prime/boost vaccinations with JVRS-100-H1 were both shown to be protective (i.e., survival, reduced weight loss) following H1N1 (PR/8/34) virus challenge. Enhanced immunological responses could be critically important for improved efficacy and dose-sparing of a recombinant influenza vaccine.
    Biologicals 04/2009; 37(3):141-7. · 1.62 Impact Factor
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    ABSTRACT: Cationic liposome–DNA complexes (CLDC) are cationic/neutral lipid carriers complexed with plasmid DNA that when administered systemically results in a robust TH1 cytokine response. CLDC have been shown to be effective in prophylaxis and therapeutic treatment of animal models of viral disease. To determine the contribution of liposomal delivery and CpG content of the plasmid DNA to the efficacy of CLDC; plasmid, CpG-free plasmid DNA, or CpG-containing oligodeoxynucleotides (ODN) with and without liposomes, as well as poly(I:C12U), were evaluated for their ability to elicit protection against lethal Punta Toro virus (PTV, Bunyaviridae, phlebovirus) challenge in hamsters. CLDC-containing plasmid significantly improved survival, decreased systemic and liver viral loads, and reduced liver damage due to progression of viral infection. Mouse-reactive ODNs complexed with liposomes failed to protect hamsters, whereas ODNs known to cross-react with human and mouse (CpG 2006) or non-liposomal poly(I:C12U) showed survival benefit but did not limit liver injury. Liposomes complexed with a non-CpG motif-containing plasmid reduced liver viral load and tissue damage, but did not protect hamsters from death. To evaluate the mechanisms of the enhanced activity of CLDC, microarray experiments examined differences in the gene expression profile. The results suggest a broad TH1 response elicited by liposomal delivery of a diverse sequence containing CpG and non-CpG elements may be a more effective antiviral treatment than other nucleic acid based immunotherapeutics.
    Antiviral research 01/2009; · 3.61 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that systemically administered immunotherapy can protect mice from systemic challenge with the bacterial pathogen Francisella tularensis. However, for protection from inhalational challenge with this bacterium, we wondered if mucosally administered immunotherapy might be more effective. Therefore, we administered cationic liposome–DNA complexes (CLDC), which are potent activators of innate immunity, intranasally (i.n.) and assessed the effectiveness of protection from lethal inhalational challenge with F. tularensis. We found that pretreatment by i.n. administration of CLDC 24 h prior to bacterial challenge elicited nearly complete protection of BALB/c mice from lethal challenge with F. tularensis LVS strain. We also observed that mucosal CLDC immunotherapy provided a statistically significant increase in survival time in mice challenged with the highly virulent F. tularensis Schu4 strain. Protection was associated with a significant reduction in bacterial burden in the lungs, liver, and spleen. Mucosal administration of CLDC elicited significantly increased expression of IL-12, IFN-γ, TNF-α, IFN-β and IFN-α genes in the lung as detected by real-time quantitative PCR. In vitro treatment of F. tularensis infected macrophages with CLDC-elicited cytokines also significantly suppressed intracellular replication of F. tularensis in infected macrophages. In vivo, depletion of NK cells prior to administration of CLDC completely abolished the protective effects of CLDC immunotherapy. CLDC-elicited protection was also dependent on induction of IFN-γ production in vivo. We conclude therefore that activation of local pulmonary innate immune responses is capable of eliciting significant protection from inhalational exposure to a virulent bacterial pathogen.
    Vaccine 01/2009; · 3.77 Impact Factor
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    ABSTRACT: This pilot study tested the immunogenicity of a novel cationic liposome-DNA complex (CLDC) immunomodulatory vaccine adjuvant. Combined with a specific antigen, CLDC enhanced anti-SIV immune responses induced by various SIV vaccine candidates. Rhesus macaques immunized in the presence of CLDC developed stronger SIV-specific T and B cell responses compared to animals immunized without CLDC. These differences persisted and resulted in better memory responses after an in vivo boost of the animals several months later with whole AT-2 inactivated SIVmac239. Thus, CLDC should be explored further as a potential immunomodulatory adjuvant in HIV vaccine design.
    Human vaccines 08/2008; 5(3):141-50. · 3.14 Impact Factor
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    ABSTRACT: An effective vaccine for genital herpes simplex type 2 (HSV-2) infection remains a priority. In our studies we examined the efficacy of JuvImmune, a complex of lipid carrier and non-coding DNA, as a vaccine adjuvant against genital HSV-2 infection in mice. Mice were immunized SC twice at three-week intervals with inactivated HSV-2 or gD2 antigen, and given a lethal intravaginal challenge of HSV-2 (1x104 pfu). In the first two studies, groups included untreated, vaccine (VAC) alone, JuvImmune alone, JuvImmune + VAC, or MPL + VAC. Preliminary results indicate that animals immunized with JuvImmune + VAC developed higher antibody titers compared to VAC alone or MPL + VAC. JuvImmune + VAC reduced HSV-2 disease symptoms and vaginal virus titers compared to MPL + VAC. In the first study, JuvImmune + VAC completely protected mice from death at 21 days compared to 58% in the MPL + VAC group (P < 0.037). In the second study, JuvImmune + VAC protected 75% of mice at 30 days post challenge, compared to only 25% in the MPL + VAC group (P<0.036). In a third study, mice were vaccinated SC with 5μg HSV-2 gD2 antigen alone or combined with either JuvImmune or MPL + Alum, and challenged with HSV-2. Vaccination with JuvImmune + gD2 promoted a greater TH1 antibody response compared to MPL + Alum. Viral titers and disease symptoms were significantly reduced in mice vaccinated with gD2 and either JuvImmune or MPL + Alum. At 21 days post-challenge, vaccination with gD2 alone protected 30% of mice from death, whereas both JuvImmune + gD2 and MPL + Alum + gD2 protected 90-100% of mice from death (P < 0.05). These results suggest that the JuvImmune adjuvant may be superior or equivalent to the MPL adjuvant in protecting mice from genital HSV-2 infection. Further studies will determine the mechanisms of protection provided by the JuvImmune adjuvant.
    Antiviral Research 10/2007; 74(3). · 3.93 Impact Factor
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    ABSTRACT: Background: In cases where neutralizing antibody fail to prevent infection, clearance of influenza is likely dependent on T cells. Thus, it would be ideal for new adjuvants used with existing flu vaccines to induce high levels of antibody and T-cell immunity. Methods: The JuvImmune adjuvant was combined with split vaccine (Fluzone® - Sanofi Pasteur) or heat-inactivated fluA (HKx31) and administered subcutaneously to mice on day 0 and 14. Antibody responses were monitored at day 7, 14, 21, and 28 and IFN-γ responses of splenocytes to restimulation with antigen were monitored at day 14 or 28. In experiments using inactivated virus, matched and mismatched strains [H3N2 (HKx31) vs. H1N1 (PR/8/34)] were used to challenge vaccinated animals and histology, viral load via qRT-PCR, and IFN-γ mRNA expression in the lungs was monitored. Results: Administration of Fluzone® with JuvImmune resulted in a 1-2 log increase in total IgG (1x106 vs. 1x104), IgG1 (1x106 vs. 1x105), and IgG2a (5x106 vs. 7x104). Administration of inactivated virus with JuvImmune also resulted in a 1-2 log increase in total IgG (8x105 vs. 4x104) and IgG2a (1x105 vs. 1x103), with equivalent levels of IgG1. Administration of decreasing amounts of antigenresulted in 10 fold dose sparing based on IgG and IgG2a antibody titer. Stimulation of splenocytes and measurement of IFN-γ at 72hrs demonstrated an increase in cellular response following vaccination with a matched (3700pg/ml vs. 600pg/ml) and mismatched virus (3000pg/ml vs. 100pg/ml). Viral load was diminished by >95% in a matched and ~50% in a mismatched challenge compared with controls. IFN-γ levels in lung suggest this cross-protection is T-cell based, which is consistent with an increase in pulmonary infiltrating lymphocytes shown via histology. Conclusion: The JuvImmune adjuvant has properties that are advantageous for both cross-protection and dose sparing using existing influenza vaccines.
    Infectious Diseases Society of America 2007 Annual Meeting; 10/2007
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    ABSTRACT: Background: CLDC represent a promising new adjuvant for vaccines. Antibody and T cell responses to WHsAg adjuvanted with either CLDC or conventional alum were compared in the woodchuck model of hepatitis B virus (HBV) infection. Methods: Four groups of 5 woodchucks each received vaccine at wks 0, 4, and 8, and were followed for 12 wks. Results: IM vaccination with WHsAg + CLDC elicited anti-WHs antibody earlier and in more animals than did WHsAg + alum. Antibody responses were greater with WHsAg + CLDC than with WHsAg + alum. Responses at wk 8 were 2 to 5-fold higher in the groups given vaccines IM than in groups given vaccine SC. Woodchucks given SC vaccine at wks 0 and 4 received the wk 8 vaccine IM, and antibody responses increased to levels comparable to woodchucks given WHsAg + CLDC by the IM route 3 times. At wk 5, differences between groups in T cell responses to WHsAg and selected WHsAg peptides were detected: 3 of 5 woodchucks given WHsAg + CLDC by IM had strong T cell responses and most WHsAg peptides were recognized. In contrast, only 1 of 5 woodchucks in the other 3 vaccine groups had T cell responses to WHsAg that were weaker and recognized fewer peptides. After the third immunization, T cell responses were similar in all vaccinated groups. Conclusion: CLDC-adjuvanted WHsAg administered by the IM route results in a more rapid enhancement of humoral and cellular immune responses compared to a conventional alum-adjuvanted vaccine. While less rapid, the response following SC administration can prime the IM response. The enhanced adjuvant activity of CLCD over alum could be beneficial for therapeutic vaccination in chronic HBV infection which can be studied in woodchucks with chronic WHV infection.
    Infectious Diseases Society of America 2007 Annual Meeting; 10/2007
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    ABSTRACT: The Goal of the current studies is to test the efficacy of cationic lipid-DNA complexes (CLDC) to enhance anti-SIV immune responses induced by various SIV vaccine candidates. Methods: In a pilot study, rhesus macaques were immunized with whole inactivated SIVmac239-AT2 in the presence or absence of CLDC. Each animal received 3 subcutaneous immunizations spaced 4 weeks apart. Animals were then followed for 3 months. Throughout the immunization period, SIV-specific T cell and antibody responses were monitored. Results: Rhesus macaques immunized with SIVmacAT-2 and CLDC, but not without CLDC, developed SIV-specific T cell responses as determined by multicolor FACS analysis. While these responses were not sustained in peripheral blood, animals that were immunized in the presence of CLDC had at least 10-fold higher SIV-specific antibody titers throughout the whole study period. This difference between SIV-specific antibody titers reached statistical significance. Conclusions: Immunization in combination with CLDC can induce more robust immune responses in non-human primates than antigen alone. Although the SIV-specific cellular response induced in CLDC/ SIVmacAT-2 immunized animals was only transiently detectable in peripheral blood, it was sufficient to elicit and maintain strong antibody responses. Future Directions: Ongoing studies will examine the immunogenicity of SIVmacAT-2 and SIV protein antigens administered together in the presence of CLDC. Cellular and humoral immune responses will be measured. In addition, we will examine the activation of dendritic cells to determine if CLDC can enhance antigen presentation to T cells.
    Infectious Diseases Society of America 2007 Annual Meeting; 10/2007
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    ABSTRACT: Background: There are interspecies differences in response to various CpG configurations. This variability presents difficulty in development when responses cannot be translated between the species used in modeling disease and toxicity. JuvImmuneTM has been shown to elicit TH1 cytokines and type I interferons following in administration. This cytokine response has been shown to be efficacious in a number of viral and intracellular bacterial challenge models. To facilitate development, demonstration of functionality among species would be necessary. Methods: Mice were administered JuvImmuneTM via subcutaneous, intraperitoneal, and intravenous administration in various doses and cytokines determined at 1-24 hrs post administration. Non-human primates were administered JuvImmuneTM via intravenous injection and IFN-γ and TNF-α monitored at 1-24 hrs post administration. In subsequent experiments, non-human primate peripheral blood mononuclear cells (PBMC) were exposed to JuvImmuneTM or CpG and IFN-α and IFN-γ was measured at 6-24 hrs post exposure. Human PBMC were exposed to JuvImmuneTM in culture and IL-6 and IFN-γ were measured. Results: Murine experiments demonstrated that the administration of JuvImmuneTM results in a TH1 cytokine response that is both route and dose-dependent. There was strong similarity between the in vivo mouse and non-human primate response to administration of JuvImmuneTM. In vitro non-human primate data demonstrated that the magnitude of the response to JuvImmuneTM was significantly greater than CpG ODN at considerably decreased dose levels. Exposure of human PBMC to JuvImmuneTM elicited a robust TH1 response as measured by IFN-α and IFN-γ production in vitro. Conclusion: JuvImmuneTM elicits a robust TH1 response which is not constrained by species. Based on rodent data, the magnitude of this response is route and dose dependent.
    Infectious Diseases Society of America 2007 Annual Meeting; 10/2007
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    ABSTRACT: Background: CLDC/inactivated influenza A virus vaccinations elicit high level of influenza-specific antibodies as well as high cell-mediated immunity. The DNA component of the vaccine (containing both CpG and non-CpG motifs but no cDNA segment) is thought to induce secretion of high level of cytokines that promote Th1 immunity (e.g., IL-12) and type I interferons (IFN-alphas and IFN-beta) through triggering of Toll-like receptor (TLR)-9 present in cells of the innate system. Plasmacytoid dendritic cells (pDCs), which express TLR-9, and conventional dendritic cells (cDCs) have been shown to interact to provide optimal innate immune response. Here we investigate the impact of pDC depletion on influenza vaccine-induced adaptive immune responses. Methods: To deplete pDCs, C57BL/6 mice were injected with 200 ug rat anti-mPDCA-1 antibody or control rat IgG. Mice were vaccinated 24h later by intraperitoneal injection of CLDC-heat-inactivated HKx31 (H3N2) virus. Induction of influenza-specific antibodies was tested at 2 and 4 weeks following vaccination, and IFN-gamma production (evaluation for Th1 immunity) was measured in splenocyte cultures after in vitro re-stimulation. The pDC depletion was monitored by FACS staining and by the decrease of IFN-alpha production following intravenous injection of CpG oligo. Results: We obtained about 80% pDC depletion in the spleen as seen by FACS staining. The levels of influenza-specific IgG1 and IgG2c at 2 and 4 weeks were very similar in both groups of mice. These groups show also comparable levels of protective antibodies. Re-stimulated splenocytes from the pDC-depleted mice did not show a decrease in IFN-gamma production as compared to the controls. Conclusions: pDCs appear to be dispensable for influenza vaccine-induced adaptive immune responses. Experiments are in progress to determine whether the relatively small number of residual pDCs following could account for our results.
    Infectious Diseases Society of America 2007 Annual Meeting; 10/2007
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    ABSTRACT: Intravenous gene delivery using liposome-DNA complexes (LDC) has previously been shown to elicit antitumor activity, but only in rodent tumor models. Therefore, we conducted a study to determine in a large animal spontaneous tumor model whether intravenous infusions of LDC could target gene expression to cutaneous tumor tissues and whether repeated treatments had an effect on tumor growth or angiogenesis. A total of 13 dogs with cutaneous soft tissue sarcomas were enrolled in the study and were randomized to receive a series of 6 weekly infusions of LDC containing either canine endostatin DNA or DNA encoding an irrelevant gene (luciferase). Serial tumor biopsies were obtained to assess transgene expression, tumor microvessel density (MVD), and intratumoral leukocyte inflammatory responses. We found that intravenous infusion of LDC did not result in detectable gene expression in cutaneous tumor tissues. However, two of 13 treated dogs had objective tumor responses and eight dogs had stable disease during the treatment period. In addition, a significant decrease in tumor MVD was noted in six of 12 treated dogs at the completion of six treatments. These results suggest that intravenous infusions of LDC may elicit nonspecific antitumor activity and inhibit tumor angiogenesis.
    Cancer Gene Therapy 04/2006; 13(3):306-17. · 2.95 Impact Factor
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    ABSTRACT: Cationic liposome-DNA complexes (CLDC) have been demonstrated to induce potent antitumor activities. The ability of these complexes to elicit protective immunity against viral infections has not been fully explored. Here we report findings on the use of CLDC as an antiviral agent in a mouse model of acute phleboviral (Punta Toro virus) disease. CLDC treatment of mice challenged with Punta Toro virus (PTV) resulted in dramatic increases in survival and reduced viral burden and other parameters indicative of protection against disease. CLDC were effective when administered by intraperitoneal and intravenous routes and elicited protective immunity when given within 1 day of virus challenge. Treatments administered 36 h or longer after challenge, however, were not effective in preventing mortality or disease. CLDC treatment induced release of a number of potential antiviral cytokines including IFN-gamma, IL-12, and IFN-alpha. Taken together, our findings indicate that non-specific immunotherapy with CLDC appears to be an effective treatment for blocking PTV-induced disease and suggests that further exploration in other viral disease models may be warranted.
    Antiviral Research 04/2006; 69(3):165-72. · 3.93 Impact Factor
  • ADVS Faculty Publications. 01/2006;