Lake Park, NC, United States
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Carroll T.D.,University of California at Davis | Matzinger S.R.,University of California at Davis | Barro M.,Global Vaccines Inc. | Fritts L.,University of California at Davis | And 4 more authors.
Vaccine | Year: 2011

Venezuelan equine encephalitis virus replicon particles (VRP) without a transgene (null VRP) have been used to adjuvant effective humoral [1], cellular [2], and mucosal [3] immune responses in mice. To assess the adjuvant activity of null VRP in the context of a licensed inactivated influenza virus vaccine, rhesus monkeys were immunized with Fluzone® alone or Fluzone® mixed with null VRP and then challenged with a human seasonal influenza isolate, A/Memphis/7/2001 (H1N1). Compared to Fluzone® alone, Fluzone®+null VRP immunized animals had stronger influenza-specific CD4+ T cell responses (4.4 fold) with significantly higher levels of virus-specific IFN-γ (7.6 fold) and IL-2 (5.3 fold) producing CD4+ T cells. Fluzone®+null VRP immunized animals also had significantly higher plasma anti-influenza IgG (p<0.0001, 1.3 log) and IgA (p<0.05, 1.2 log) levels. In fact, the mean plasma anti-influenza IgG titers after one Fluzone®+null VRP immunization was 1.2 log greater (p<0.04) than after two immunizations with Fluzone® alone. After virus challenge, only Fluzone®+null VRP immunized monkeys had a significantly lower level of viral replication (p<0.001) relative to the unimmunized control animals. Although little anti-influenza antibody was detected in the respiratory secretions after immunization, strong anamnestic anti-influenza IgG and IgA responses were present in secretions of the Fluzone®+null VRP immunized monkeys immediately after challenge. There were significant inverse correlations between influenza RNA levels in tracheal lavages and plasma anti-influenza HI and IgG anti-influenza antibody titers prior to challenge. These results demonstrate that null VRP dramatically improve both the immunogenicity and protection elicited by a licensed inactivated influenza vaccine. © 2010 Elsevier Ltd.


Bian T.,National Institute of Environmental Human Science | Gibbs J.D.,Global Vaccines Inc | Orvell C.,Karolinska University Hospital | Imani F.,ViraSource Laboratories
PLoS ONE | Year: 2012

Respiratory syncytial virus (RSV) is the major cause of viral respiratory infections in children. Our previous study showed that the RSV infection induced lung epithelial cell cycle arrest, which enhanced virus replication. To address the mechanism of RSV-induced cell cycle arrest, we examined the contribution of RSV-matrix (RSV-M) protein. In this report, we show that in both the A549 cell line and primary human bronchial epithelial (PHBE) cells, transfection with RSV-M protein caused the cells to proliferate at a slower rate than in control cells. The cell cycle analysis showed that RSV-M protein induced G1 phase arrest in A549 cells, and G1 and G2/M phase arrest in PHBE cells. Interestingly, RSV-M expression induced p53 and p21 accumulation and decreased phosphorylation of retinoblastoma protein (Rb). Further, induction of cell cycle arrest by RSV-M was not observed in a p53-deficient epithelial cell line (H1299). However, cell cycle arrest was restored after transfection of p53 cDNA into H1299 cells. Taken together, these results indicate that RSV-M protein regulates lung epithelial cell cycle through a p53-dependent pathway, which enhances RSV replication. © 2012 Bian et al.


Tilton J.C.,University of Pennsylvania | Amrine-Madsen H.,Glaxosmithkline | Miamidian J.L.,University of Pennsylvania | Kitrinos K.M.,Glaxosmithkline | And 8 more authors.
AIDS Research and Human Retroviruses | Year: 2010

CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals. © 2010, Mary Ann Liebert, Inc.


Steil B.P.,Global Vaccines Inc. | Jorquera P.,Global Vaccines Inc. | Jorquera P.,University of Georgia | Westdijk J.,Institute for Translational Vaccinology Intravacc | And 4 more authors.
Vaccine | Year: 2014

The eradication of poliovirus from the majority of the world has been achieved through the use of two vaccines: the inactivated poliovirus vaccine (IPV) and the live-attenuated oral poliovirus vaccine (OPV). Both vaccines are effective at preventing paralytic poliomyelitis, however, they also have significant differences. Most importantly for this work is the risk of revertant virus from OPV, the greater cost of IPV, and the low mucosal immunity induced by IPV. We and others have previously described the use of an alphavirus-based adjuvant that can induce a mucosal immune response to a co-administered antigen even when delivered at a non-mucosal site. In this report, we describe the use of an alphavirus-based adjuvant (GVI3000) with IPV. The IPV-GVI3000 vaccine significantly increased systemic IgG, mucosal IgG and mucosal IgA antibody responses to all three poliovirus serotypes in mice even when administered intramuscularly. Furthermore, GVI3000 significantly increased the potency of IPV in rat potency tests as measured by poliovirus neutralizing antibodies in serum. Thus, an IPV-GVI3000 vaccine would reduce the dose of IPV needed and provide significantly improved mucosal immunity. This vaccine could be an effective tool to use in the poliovirus eradication campaign without risking the re-introduction of revertant poliovirus derived from OPV. © 2013 Elsevier Ltd.


Westdijk J.,Institute for Translational Vaccinology | Koedam P.,Bilthoven Biologicals | Barro M.,Global Vaccines Inc. | Barro M.,Health-U | And 7 more authors.
Vaccine | Year: 2013

Six different adjuvants, each in combination with inactivated polio vaccine (IPV) produced with attenuated Sabin strains (sIPV), were evaluated for their ability to enhance virus neutralizing antibody titres (VNTs) in the rat potency model. The increase of VNTs was on average 3-, 15-, 24-fold with adjuvants after one immunization (serotypes 1, 2, and 3, respectively). Also after a boost immunization the VNTs of adjuvanted sIPV were on average another 7-20-27 times higher than after two inoculations of sIPV without adjuvant. The results indicate that it is feasible to increase the potency of inactivated polio vaccines by using adjuvants. © 2013 Elsevier Ltd.


Tonkin D.R.,Global Vaccines Inc. | Jorquera P.,Global Vaccines Inc. | Jorquera P.,University of Santiago de Chile | Todd T.,Global Vaccines Inc. | And 4 more authors.
Vaccine | Year: 2010

Venezuelan equine encephalitis virus replicon particles (VRP) function as an effective systemic, cellular and mucosal adjuvant when codelivered with antigen, and show promise for use as a component in new and existing human vaccine formulations. We show here that VRP are effective at low dose and by intramuscular delivery, two useful features for implementation of VRP as a vaccine adjuvant. In mice receiving a prime and boost with antigen, we found that VRP are required in prime only to produce a full adjuvant effect. This outcome indicates that the events triggered during prime with VRP are sufficient to establish the nature and magnitude of the immune response to a second exposure to antigen. Events induced by VRP in the draining lymph node after prime include robust secretion of many inflammatory cytokines, upregulation of CD69 on leukocytes, and increased cellularity, with a disproportionate increase of a cell population expressing CD11c, CD11b, and F4/80. We show that antigen delivered 24 h after administration of VRP does not benefit from an adjuvant effect, indicating that the events which are critical to VRP-mediated adjuvant activity occur within the first 24 h. Further studies of the events induced by VRP will help elucidate the mechanism of VRP adjuvant activity and will advance the safe implementation of this adjuvant in human vaccines. © 2010 Elsevier Ltd. All rights reserved.


Khalil S.M.,Global Vaccines Inc. | Khalil S.M.,University of North Carolina at Chapel Hill | Tonkin D.R.,Global Vaccines Inc. | Mattocks M.D.,Global Vaccines Inc. | And 3 more authors.
Vaccine | Year: 2014

Dengue viruses (DENV1-4) cause 390 million clinical infections every year, several hundred thousand of which progress to severe hemorrhagic and shock syndromes. Preexisting immunity resulting from a previous DENV infection is the major risk factor for severe dengue during secondary heterologous infections. During primary infections in infants, maternal antibodies pose an analogous risk. At the same time, maternal antibodies are likely to prevent induction of endogenous anti-DENV antibodies in response to current live, attenuated virus (LAV) vaccine candidates. Any effective early life dengue vaccine has to overcome maternal antibody interference (leading to ineffective vaccination) and poor induction of antibody responses (increasing the risk of severe dengue disease upon primary infection). In a previous study, we demonstrated that a non-propagating Venezuelan equine encephalitis virus replicon expression vector (VRP), expressing the ectodomain of DENV E protein (E85), overcomes maternal interference in a BALB/c mouse model. We report here that a single immunization with a tetravalent VRP vaccine induced NAb and T-cell responses to each serotype at a level equivalent to the monovalent vaccine components, suggesting that this vaccine modality can overcome serotype interference. Furthermore, neonatal immunization was durable and could be boosted later in life to further increase NAb and T-cell responses. Although the neonatal immune response was lower in magnitude than responses in adult BALB/c mice, we demonstrate that VRP vaccines generated protective immunity from a lethal challenge after a single neonatal immunization. In summary, VRP vaccines expressing DENV antigens were immunogenic and protective in neonates, and hence are promising candidates for safe and effective vaccination in early life. © 2014 Elsevier Ltd.


Tonkin D.R.,Global Vaccines Inc | Whitmore A.,University of North Carolina at Chapel Hill | Johnston R.E.,Global Vaccines Inc | Johnston R.E.,University of North Carolina at Chapel Hill | Barro M.,Global Vaccines Inc
Vaccine | Year: 2012

Replicon particles derived from Venezuelan equine encephalitis virus (VEE) are infectious non-propagating particles which act as a safe and potent systemic, mucosal, and cellular adjuvant when delivered with antigen. VEE and VEE replicon particles (VRP) can target multiple cell types including dendritic cells (DCs). The role of these cell types in VRP adjuvant activity has not been previously evaluated, and for these studies we focused on the contribution of DCs to the response to VRP. By analysis of VRP targeting in the draining lymph node, we found that VRP induced rapid recruitment of TNF-secreting monocyte-derived inflammatory dendritic cells. VRP preferentially infected these inflammatory DCs as well as classical DCs and macrophages, with less efficient infection of other cell types. DC depletion suggested that the interaction of VRP with classical DCs was required for recruitment of inflammatory DCs, induction of high levels of many cytokines, and for stable transport of VRP to the draining lymph node. Additionally, in vitro-infected DCs enhanced antigen-specific responses by CD4 and CD8 T cells. By transfer of VRP-infected DCs into mice we showed that these DCs generated an inflammatory state in the draining lymph node similar to that achieved by VRP injection. Most importantly, VRP-infected DCs were sufficient to establish robust adjuvant activity in mice comparable to that produced by VRP injection. These findings indicate that VRP infect, recruit and activate both classical and inflammatory DCs, and those DCs become mediators of the VRP adjuvant activity. © 2012.


Zellweger R.M.,La Jolla Institute for Allergy and Immunology | Miller R.,La Jolla Institute for Allergy and Immunology | Eddy W.E.,La Jolla Institute for Allergy and Immunology | White L.J.,Global Vaccines Inc. | And 2 more authors.
PLoS Pathogens | Year: 2013

With 2.5 billion people at risk, dengue is a major emerging disease threat and an escalating public health problem worldwide. Dengue virus causes disease ranging from a self-limiting febrile illness (dengue fever) to the potentially fatal dengue hemorrhagic fever/dengue shock syndrome. Severe dengue disease is associated with sub-protective levels of antibody, which exacerbate disease upon re-infection. A dengue vaccine should generate protective immunity without increasing severity of disease. To date, the determinants of vaccine-mediated protection against dengue remain unclear, and additional correlates of protection are urgently needed. Here, mice were immunized with viral replicon particles expressing the dengue envelope protein ectodomain to assess the relative contribution of humoral versus cellular immunity to protection. Vaccination with viral replicon particles provided robust protection against dengue challenge. Vaccine-induced humoral responses had the potential to either protect from or exacerbate dengue disease upon challenge, whereas cellular immune responses were beneficial. This study explores the immunological basis of protection induced by a dengue vaccine and suggests that a safe and efficient vaccine against dengue should trigger both arms of the immune system. © 2013 Zellweger et al.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 532.84K | Year: 2015

DESCRIPTION provided by applicant There are approximately million cases of dengue fever each year with billion people at risk mostly in low income countries There are four serotypes of dengue fever virus DENV and in its uncomplicated form the disease is worthy of its indigenous name andquot break bone feverandquot An individual may suffer sequential infections with multiple DENV serotypes and a second infection is associated with increased risk of dengue hemorrhagic fever dengue shock syndrome DHF DSS a much more serious and potentially fatal disease Altravax Inc AVI has developed a particulate single molecule tetravalent immunogen capable of inducing neutralizing antibodies directed against all four serotypes of DENV Global Vaccines Inc GVI a not for profit vaccine company has developed a novel adjuvant which is not only capable of promoting neutralizing antibody responses induced by other DENV immunogens but also catalyzing the induction of cell mediated immunity As recent evidence suggests that both arms of the immune response contribute to protection against DENV these two companies will collaborate to determine the effect of combining their respective technologies in an improved DENV vaccine The AVI immunogen will be tested in two forms First the protein immunogen will be produced in F cells and purified It then will be administered to Sv mice either alone with the GVI adjuvant or with alum as a positive adjuvant control In a second approach the gene for the AVI immunogen will be cloned into a Venezuelan equine encephalitis virus replicon particle VRP and the VRP will be administered to Sv mice for in vivo expression of the immunogen These formulations will be evaluated for induction of neutralizing antibodies and T cells to each of the four DENV serotypes The polyclonal sera also will be evaluated to determine whether the antibodies induced by the AVI tetravalent immunogen are directed to serotype specific neutralizing epitopes or to a neutralizing epitope s that is are conserved in each of the four serotypes The best of the formulations will be used to immunize Sv mice Serum T cells or a mixture of the two from the fully immunocompetent Sv mice will be transferred to na ve AG mice a congenic DENV sensitive mouse model to assess the ability of the induced immune responses to protect against challenge with each of the four DENV serotypes These experiments are the first to combine these two promising vaccine technologies and represent an important step in the preclinical development of a safe DENV vaccine candidate which induces both protective humoral and cellular responses and is appropriately inexpensive for the majority of persons at risk PUBLIC HEALTH RELEVANCE One third of the worldandapos s population is at risk for dengue fever virus infection Altravax Inc and Global Vaccines Inc a not for profit company will merge ther respective technologies in a new dengue vaccine candidate utilizing a single immunogen and a novel adjuvant to induce protective humoral and cellular immunity to all four dengue virus serotypes The overall goal is to advance this safe effective and inexpensive dengue vaccine approach through pre clinical studies and ultimately to clinical trials

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