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Yasushi Uematsu, Michael Vajdy,
Ying Lian,
Silvia Perri,
Catherine E Greer,
Harold S Legg,
Grazia Galli,
Giulietta Saletti,
Gillis R Otten,
Rino Rappuoli,
Susan W Barnett,
John M Polo
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ABSTRACT: Antivector immunity has been recognized as a potential caveat of using virus-based vaccines. In the present study, an alphavirus-based replicon particle vaccine platform, which has demonstrated robust immunogenicity in animal models, was tested for effects of antivector immunity on immunogenicity against hemagglutinin of influenza virus as a target antigen and efficacy for protection against lethal challenge with the virus. Chimeric alphavirus-based replicon particles, comprising Venezuelan equine encephalitis virus nonstructural and Sindbis virus structural components, induced efficient protective antibody responses, which were not adversely influenced after multiple immunizations with the same vector expressing various antigens.
Clinical and vaccine immunology: CVI 05/2012; 19(7):991-8. · 2.37 Impact Factor
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ABSTRACT: To determine whether long-term immunological B cell memory following mucosal vaccinations is maintained by terminally differentiated Ig-CD45R- plasma cells or Ig+CD45R+ B cells, we immunized mice orally with the non-toxic B subunit of cholera toxin (CTB) as a carrier protein haptenated with FITC (CTB-FITC) plus CT adjuvant. We found that the adoptive transfer of Ig+CD45R+ but not the Ig-CD45R- cells, resulted in higher numbers of FITC-specific IgA-secreting cells in the intestine as well as higher anti-FITC serum IgA titers, suggesting that long term B cell immunological memory following oral vaccinations preferentially resided within the Ig+CD45R+ B cell population.
Immunology letters 03/2011; 138(1):63-70. · 2.91 Impact Factor
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ABSTRACT: Non-replicating protein- or DNA-based antigens generally require immune-enhancing adjuvants and delivery systems. It has been particularly difficult to raise antibodies against gp120 of HIV-1, which constitutes an important approach in HIV vaccine design. While almost all effort in adjuvant research has focused on mimicking the pathogens and the danger signals they engender in the host, relatively little effort has been spent on nutritive approaches. In this study, a new nutritive immune-enhancing delivery system (NIDS) composed of vitamin A, a polyphenol-flavonoid, catechin hydrate, and mustard oil was tested for its adjuvant effect in immune responses against the gp120 protein of HIV-1(CN54). Following a combination of two mucosal and two systemic vaccinations of mice, we found significant enhancement of both local and systemic antibodies as well as cytokine responses. These data have important implications for vaccine and adjuvant design against HIV-1 and other pathogens.
Vaccine 01/2011; 29(13):2429-36. · 3.77 Impact Factor
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ABSTRACT: There are currently over thirty million people infected with HIV and there are no vaccines available to prevent HIV infections or disease. The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes. An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as a major means of protection against mucosal HIV transmission and AIDS.
Structure and cells that comprise the oral, vaginal and rectal mucosa pertaining to HIV transmission and vaccination strategies through each mucosal route to prevent mucosal and systemic infection will be discussed.
Covering publications from 1980s through 2010, mucosal transmission of HIV and current and previous approaches to vaccinations are discussed.
Although oral transmission of HIV is far less common than vaginal and rectal transmissions, infections through this route do occur through oral sex as well as vertically from mother to child. Mucosal vaccination strategies against oral and other mucosal HIV transmissions are under intensive research but the lack of consensus on immune correlates of protection and lack of safe and effective mucosal adjuvants and delivery systems hamper progress towards a licensed vaccine.
Expert opinion on biological therapy 08/2010; 10(8):1181-95. · 3.22 Impact Factor
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Susan W Barnett,
Brian Burke,
Yide Sun,
Elaine Kan,
Harold Legg,
Ying Lian,
Kristen Bost,
Fengmin Zhou,
Amanda Goodsell,
Jan Zur Megede,
John Polo,
John Donnelly,
Jeffrey Ulmer,
Gillis R Otten,
Christopher J Miller, Michael Vajdy,
Indresh K Srivastava
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ABSTRACT: We have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus SHIV(SF162P4) following sequential immunization with alphavirus replicon particles (VRP) of a chimeric recombinant VEE/SIN alphavirus (derived from Venezuelan equine encephalitis virus [VEE] and the Sindbis virus [SIN]) encoding human immunodeficiency virus type 1 HIV-1(SF162) gp140DeltaV2 envelope (Env) and trimeric Env protein in MF59 adjuvant (R. Xu, I. K. Srivastava, C. E. Greer, I. Zarkikh, Z. Kraft, L. Kuller, J. M. Polo, S. W. Barnett, and L. Stamatatos, AIDS Res. Hum. Retroviruses 22:1022-1030, 2006). The protection did not require T-cell immune responses directed toward simian immunodeficiency virus (SIV) Gag. We extend those findings here to demonstrate antibody-mediated protection against mucosal challenge in macaques using prime-boost regimens incorporating both intramuscular and mucosal routes of delivery. The macaques in the vaccination groups were primed with VRP and then boosted with Env protein in MF59 adjuvant, or they were given VRP intramuscular immunizations alone and then challenged with SHIV(SF162P4) (intrarectal challenge). The results demonstrated that these vaccines were able to effectively protect the macaques to different degrees against subsequent mucosal SHIV challenge, but most noteworthy, all macaques that received the intramuscular VRP prime plus Env protein boost were completely protected. A statistically significant association was observed between the titer of virus neutralizing and binding antibodies as well as the avidity of anti-Env antibodies measured prechallenge and protection from infection. These results highlight the merit of the alphavirus replicon vector prime plus Env protein boost vaccine approach for the induction of protective antibody responses and are of particular relevance to advancing our understanding of the potential correlates of immune protection against HIV infection at a relevant mucosal portal of entry.
Journal of Virology 06/2010; 84(12):5975-85. · 5.40 Impact Factor
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ABSTRACT: Seasonal influenza virus infections cause considerable morbidity and mortality in the world, and there is a serious threat of a pandemic influenza with the potential to cause millions of deaths. Therefore, practical influenza vaccines and vaccination strategies that can confer protection against intranasal infection with influenza viruses are needed. In this study, we demonstrate that using LTK63, a nontoxic mutant of the heat-labile toxin from Escherichia coli, as an adjuvant for both mucosal and systemic immunizations, systemic (intramuscular) immunization or combinations of mucosal (intranasal) and intramuscular immunizations protected mice against intranasal challenge with a lethal dose of live influenza virus at 3.5 months after the second immunization.
Clinical and vaccine immunology: CVI 03/2009; 16(4):471-8. · 2.37 Impact Factor
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Yinling Lin,
Taewoo Kwon,
John Polo,
Yi-Fei Zhu,
Stephen Coates,
Kevin Crawford,
Christine Dong,
Mark Wininger,
John Hall,
Mark Selby,
Doris Coit,
Angelica Medina-Selby,
Colin McCoin,
Philip Ng,
Debbie Drane,
David Chien,
Jang Han, Michael Vajdy,
Michael Houghton
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ABSTRACT: Broad, multispecific CD4(+) and CD8(+) T-cell responses to the hepatitis C virus (HCV), as well as virus-cross-neutralizing antibodies, are associated with recovery from acute infection and may also be associated in chronic HCV patients with a favorable response to antiviral treatment. In order to recapitulate all of these responses in an ideal vaccine regimen, we have explored the use of recombinant HCV polypeptides combined with various Th1-type adjuvants and replication-defective alphaviral particles encoding HCV proteins in various prime/boost modalities in BALB/c mice. Defective chimeric alphaviral particles derived from the Sindbis and Venezuelan equine encephalitis viruses encoding either the HCV envelope glycoprotein gpE1/gpE2 heterodimer (E1E2) or nonstructural proteins 3, 4, and 5 (NS345) elicited strong CD8(+) T-cell responses but low CD4(+) T helper responses to these HCV gene products. In contrast, recombinant E1E2 glycoproteins adjuvanted with MF59 containing a CpG oligonucleotide elicited strong CD4(+) T helper responses but no CD8(+) T-cell responses. A recombinant NS345 polyprotein also stimulated strong CD4(+) T helper responses but no CD8(+) T-cell responses when adjuvanted with Iscomatrix containing CpG. Optimal elicitation of broad CD4(+) and CD8(+) T-cell responses to E1E2 and NS345 was obtained by first priming with Th1-adjuvanted proteins and then boosting with chimeric, defective alphaviruses expressing these HCV genes. In addition, this prime/boost regimen resulted in the induction of anti-E1E2 antibodies capable of cross-neutralizing heterologous HCV isolates in vitro. This vaccine formulation and regimen may therefore be optimal in humans for protection against this highly heterogeneous global pathogen.
Journal of Virology 09/2008; 82(15):7492-503. · 5.40 Impact Factor
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ABSTRACT: In this study, immunizations at 2 weeks vs. 6 weeks intervals, with an HIV-1 envelope protein in adjuvants, through intra-nasal (IN), intra-muscular (IM), IN followed by IM (IN/IM) and IM/IN, were compared for induction of mucosal and systemic immune responses. IN/IM immunizations at 2, but not at 6, week intervals induced the highest mucosal and systemic immune responses compared to other immunization routes. Following a resting memory phase, IN boosting of IN/IM-immunized mice, compared to IM-boosting of IM-immunized mice, induced increased IgA responses. Thus, depending on the immunization intervals, IN/IM may be more effective than IM immunizations for short- and long-term immunity.
Vaccine 06/2008; 26(22):2796-806. · 3.77 Impact Factor
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Amanda Goodsell,
Fengmin Zhou,
Soumi Gupta,
Manmohan Singh,
Padma Malyala,
Jina Kazzaz,
Catherine Greer,
Harold Legg,
Tony Tang,
January Zur Megede,
Ranjana Srivastava,
Susan W Barnett,
John J Donnelly,
Paul A Luciw,
John Polo,
Derek T O'Hagan, Michael Vajdy
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ABSTRACT: Vaccination strategies that can block or limit heterosexual human immunodeficiency virus (HIV) transmissions to local and systemic tissues are the goal of much research effort. Herein, in a mouse model, we aimed to determine whether the enhancement of antibody responses through mucosal and systemic immunizations, previously observed with protein-based vaccines, applies to immunizations with DNA- or RNA-based vectors. Intranasal (i.n.) followed by intramuscular (i.m.) immunizations (i.n./i.m.) with polylactide-coglycolide (PLG)-DNA microparticles encoding HIV-gag (PLG-DNA-gag) significantly enhanced serum antibody responses, compared with i.m., i.n. or i.m. followed by i.n. (i.m./i.n.) immunizations. Moreover, while i.n./i.m., i.n. or i.m./i.n. immunizations with PLG-DNA-gag resulted in genital tract antibody responses, i.m. immunizations alone failed to do so. Importantly, beta7-deficient mice developed local and systemic antibody responses following i.n./i.m. immunization, or immunization via any other route, similar to those of wild-type mice. To compare the DNA with an RNA delivery system, immunizations were performed with VEE/SIN-gag replicon particles, composed of Venezuelan equine encephalitis virus (VEE) replicon RNA and Sindbis surface structure (SIN). i.n./i.m., compared with any other immunizations, i.n./i.m. immunization with VEE/SIN-gag resulted in enhanced genital tract but not serum antibody responses. These data show for the first time that mucosal followed by systemic immunizations with gene delivery systems enhance B-cell responses independent of the mucosal homing receptors alpha4beta7 and alphaEbeta7.
Immunology 04/2008; 123(3):378-89. · 3.32 Impact Factor
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ABSTRACT: The objective of this work was to evaluate the potency of the CpG containing oligonucleotide encapsulated within poly(lactide-co-glycolide), and coadministered with antigen adsorbed to poly(lactide-co-glycolide) microparticles (PLG particles). The formulations evaluated include, CpG added in soluble form, CpG adsorbed, and CpG encapsulated. The antigen from Neisseria meningitidis serotype B (Men B) was used in these studies. The immunogenicity of these formulations was evaluated in mice. Poly(lactide-co-glycolide) microparticles were synthesized by a w/o/w emulsification method in the presence of a charged surfactant for the formulations. Neisseria meningitidis B protein was adsorbed to the PLG microparticles, with binding efficiency and initial release measured. CpG was either added in the soluble or adsorbed or encapsulated form based on the type of formulation. The binding efficiency, loading, integrity and initial release of CpG and the antigen were measured from all the formulations. The formulations were then tested in mice for their ability to elicit antibodies, bactericidal activity and T cell responses. Encapsulating CpG within PLG microparticles induced statistically significant higher antibody, bactericidal activity and T cell responses when compared to the traditional method of delivering CpG in the soluble form. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1155–1164, 2008
Journal of Pharmaceutical Sciences 02/2008; 97(3):1155 - 1164. · 3.06 Impact Factor
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ABSTRACT: The roles that T helper type 1 (Th1) and T helper type 2 (Th2) Helicobacter pylori-specific immune responses play in protection from H. pylori challenge are poorly understood. It is expected that Th2 immune responses are required for protection against extracellular bacteria, such as H. pylori. However, recent studies have suggested that Th1 immunity is required for protection. The mechanisms by which this might occur are unknown. Our goal in this study was to more clearly define the effects of a Th1- versus a Th2-promoting H. pylori vaccine on immunity and protection. Therefore, we tested a Th1 vaccine consisting of an H. pylori sonicate and CpG oligonucleotides (CpG) and a Th2 vaccine consisting of a lipopolysaccharide (LPS)-depleted H. pylori sonicate combined with cholera toxin (CT). We demonstrate that although the Th2-promoting vaccine induced stronger systemic and local immune responses, only the Th1-promoting vaccine was protective.
Microbial Pathogenesis 02/2008; 44(1):20-7. · 1.94 Impact Factor
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Susan W Barnett,
Indresh K Srivastava,
Elaine Kan,
Fengmin Zhou,
Amanda Goodsell,
Anthony D Cristillo,
Maria Grazia Ferrai,
Deborah E Weiss,
Norman L Letvin,
David Montefiori,
Ranajit Pal, Michael Vajdy
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ABSTRACT: Worldwide, the majority of human immunodeficiency virus (HIV) infections occur by heterosexual transmission. Thus, the development of a vaccine that can prevent intravaginal HIV infection is an important goal of AIDS vaccine research.
To determine which single or combination of systemic and mucosal routes of immunizations of female rhesus macaques with an HIV-1 SF162 envelope protein vaccine induced protection against intravaginal challenge with SHIV.
Female rhesus macaques were immunized with an HIV-1 SF162 envelope protein vaccine administered systemically (intramuscularly), or mucosally (intranasally), or as a sequential combination of both routes. The macaques were then challenged intravaginally with SHIV SF162P4, expressing an envelope that is closely matched (homologous) to the vaccine.
Macaques receiving intramuscular immunizations, alone or in combination with intranasal immunizations, were protected from infection, with no detectable plasma viral RNA, provirus, or seroconversion to nonvaccine viral proteins, and better preservation of intestinal CD4+ T cells. Serum neutralizing antibodies against the challenge virus appeared to correlate with protection.
The results of this study demonstrate that, in the nonhuman primate model, it is possible for vaccine-elicited immune responses to prevent infection after intravaginal administration of virus.
AIDS (London, England) 02/2008; 22(3):339-48. · 4.91 Impact Factor
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ABSTRACT: The ability to induce long-term immunity to Helicobacter pylori is necessary for an effective vaccine. This study was designed to establish the most efficient route(s) (systemic, mucosal, or a combination) of immunization for induction of long-term immunity and to define correlates of protection. Mice were immunized orally alone (oral group), intramuscularly (i.m.) alone (i.m. group), orally followed by i.m. (oral/i.m. group), or i.m. followed by orally (i.m./oral group). Long-term protective immunity to oral H. pylori challenge was observed 3 months after immunization through the i.m. or oral/i.m. route. Protection correlated with an increase in H. pylori-specific interleukin-12 and both immunoglobulin G1 (IgG1) and IgG2a serum titers following challenge. Mice that were not protected (oral or i.m./oral) had increased levels of IgA in both sera and Peyer's patches. This study demonstrates the ability to induce long-term immunity against H. pylori, provides correlates of protection, and illustrates the crucial role of the immunization route(s).
Infection and Immunity 08/2007; 75(7):3462-9. · 4.16 Impact Factor
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ABSTRACT: Influenza infections are a major cause of mortality and morbidity worldwide. Therefore, there is a need to establish vaccines and immunization protocols that can prevent influenza infections. Herein, we show that one intranasal (IN) followed by one intramuscular (IM) immunizations with a combination of cell culture produced hemagglutinin (HA) antigens derived from 3 different influenza strains induced significantly higher serum hemagglutination inhibition (HI) and serum IgG antibody titers as well as T cell responses, compared to 2 IM, 2 IN or 1 M followed by 1 IN immunizations. Moreover, while 2 IM immunizations did not induce any antibody responses in nasal secretions or cervical lymph nodes, which drain the nasal mucosa, IN immunizations alone or in combination with IM immunization induced mucosal and local responses. These data show that the IN followed by IM immunization strategy holds promise to significantly raise serum and local antibody and T cell responses against seasonal influenza strains, and possibly pandemic influenza strains, for which no pre-existing immunity exists.
Clinical Immunology 06/2007; 123(2):166-75. · 4.05 Impact Factor
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ABSTRACT: Parainfluenza virus type 3 (PIV3) infections continue to be a significant health risk for infants, young children, and immunocompromised adults. We describe a gene-based vaccine strategy against PIV3 using replication-defective alphavirus vectors. These RNA replicon vectors, delivered as virus-like particles and expressing the PIV3 hemagglutinin-neuraminidase glycoprotein, were shown to be highly immunogenic in mice and hamsters, inducing PIV3-specific neutralizing antibody responses. Importantly, the replicon particle-based vaccine administered intramuscularly or intranasally protected against mucosal PIV3 challenge in hamsters, preventing virus replication in both nasal turbinates and lungs. These data suggest that the alphavirus replicon platform can be useful for a PIV3 vaccine and possibly other respiratory viruses.
Vaccine 02/2007; 25(3):481-9. · 3.77 Impact Factor
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Soumi Gupta,
Fengmin Zhou,
Catherine E Greer,
Harold Legg,
Tony Tang,
Paul Luciw,
Jan zur Megede,
Susan W Barnett,
John J Donnelly,
Derek T O'Hagan,
John M Polo, Michael Vajdy
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ABSTRACT: 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.
AIDS Research and Human Retroviruses 11/2006; 22(10):993-7. · 2.25 Impact Factor
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Michael Vajdy,
Mark Selby,
Angelica Medina-Selby,
Doris Coit,
John Hall,
Laura Tandeske,
David Chien,
Celine Hu,
Domenico Rosa,
Manmohan Singh,
Jina Kazzaz,
Steve Nguyen,
Steve Coates,
Philip Ng,
Sergio Abrignani,
Yin-Ling Lin,
Michael Houghton,
Derek T O'Hagan
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ABSTRACT: 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.
Journal of General Virology 09/2006; 87(Pt 8):2253-62. · 3.36 Impact Factor
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ABSTRACT: Helicobacter pylori (H. pylori) infection is prevalent worldwide and results in chronic gastritis, which may lead to peptic ulcer disease or gastric cancer. The goal of this study was to determine the role that H. pylori lipopolysaccharide (LPS) plays in stimulating host immune responses in the context of a vaccine. We compared H. pylori SS1 sonicate (LPS+) to a sonicate depleted of LPS (LPS-) in immunized BALB/c mice. Naïve splenocytes produced high levels of TNF-alpha and IL-10 after incubation with LPS+ sonicate, while cells incubated with LPS- sonicate did not. Mice immunized with LPS+ sonicate developed a prominent innate response characterized by increased TNF-alpha and IL-10, as well as a strong antigen specific Th1 response including, IFN-gamma, IL-2 and high IgG2a serum titers. Mice that received LPS- sonicate were strongly Th2 biased in their immune response, with significantly more IL-4 than IFN-gamma and serum IgG1 titers higher than IgG2a. Together these studies suggest that H. pylori LPS in a whole cell sonicate vaccine promotes a Th1 immune response that may aid in protection or clearance of H. pylori infection.
Vaccine 07/2006; 24(23):4987-94. · 3.77 Impact Factor
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ABSTRACT: HIV poses a serious health threat in the world. Mucosal transmission of HIV through the genitourinary tract may be the most important route of transmission. Intranasal immunisations induce vaginal and systemic immune responses. Various protein-, DNA- and RNA-based immunopotentiating adjuvants/delivery systems and live bacterial and viral vectors are available for intranasal immunisations, and these systems may differ in their ability to induce a specific type of immune response (e.g., a cytotoxic T cell versus an antibody response). As the protection against HIV may require both cytotoxic T cell and antibodies, a combination of adjuvants/delivery systems for combinations of mucosal and parenteral immunisations may be required in order to develop a protective anti-HIV vaccine.
Expert Opinion on Drug Delivery 04/2006; 3(2):247-59. · 4.90 Impact Factor
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Michael Vajdy
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ABSTRACT: Currently, over 40 million HIV-infected individuals are found around the globe, with an additional 15,000 daily infections. There is a general consensus that the most effective way to prevent new infections is to introduce a prophylactic vaccine. It is also generally agreed that both cytotoxic T lymphocytes (CTLs) and neutralising antibodies are important to mediate protection. The neutralising antibodies must be broadly reactive to neutralise multiple primary isolates. There is also increasing agreement that CTLs and neutralising antibodies should be present at mucosal sites of HIV entry, the draining lymph nodes and systemically. The route of immunisation is important when determining the site where protection is desired, i.e. the female genitourinary tract versus the male or female rectum versus systemic tissues, as are the type of HIV-related antigens, immunopotentiating adjuvants and delivery systems. Finally, multiple vaccine delivery systems may be required to be administered through both mucosal and parenteral routes to induce optimal immune responses and protection against HIV infection through rectal, vaginal or systemic routes of transmission. This review discusses current efforts on the generation of optimal immune responses against HIV in the genitourinary and intestinal tracts using mucosal immunisations alone or combinations of mucosal and parenteral immunisations.
Drugs in R & D 02/2006; 7(5):267-88. · 1.35 Impact Factor
