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Adjuvant Effect of Cationic Liposomes for Subunit Influenza Vaccine: Influence of Antigen Loading Method, Cholesterol and Immune Modulators  [PDF]
Christophe Barnier-Quer,Abdelrahman Elsharkawy,Stefan Romeijn,Alexander Kros,Wim Jiskoot
Pharmaceutics , 2013, DOI: 10.3390/pharmaceutics5030392
Abstract: Cationic liposomes are potential adjuvants for influenza vaccines. In a previous study we reported that among a panel of cationic liposomes loaded with influenza hemagglutinin (HA), DC-Chol:DPPC (1:1 molar ratio) liposomes induced the strongest immune response. However, it is not clear whether the cholesterol (Chol) backbone or the tertiary amine head group of DC-Chol was responsible for this. Therefore, in the present work we studied the influence of Chol in the lipid bilayer of cationic liposomes. Moreover, we investigated the effect of the HA loading method (adsorption versus encapsulation) and the encapsulation of immune modulators in DC-Chol liposomes on the immunogenicity of HA. Liposomes consisting of a neutral lipid (DPPC or Chol) and a cationic compound (DC-Chol, DDA, or eDPPC) were produced by film hydration-extrusion with/without an encapsulated immune modulator (CpG or imiquimod). The liposomes generally showed comparable size distribution, zeta potential and HA loading. In vitro studies with monocyte-derived human dendritic cells and immunization studies in C57Bl/6 mice showed that: (1) liposome-adsorbed HA is more immunogenic than encapsulated HA; (2) the incorporation of Chol in the bilayer of cationic liposomes enhances their adjuvant effect; and (3) CpG loaded liposomes are more efficient at enhancing HA-specific humoral responses than plain liposomes or Alhydrogel.
Production of antibodies with peptide-CpG-DNA-liposome complex without carriers
Dongbum Kim, Sanghoon Kwon, Jae Rhee, Kwang Kim, Young-Eun Kim, Cheung-Seog Park, Myeong Choi, Jun-Gyo Suh, Doo-Sik Kim, Younghee Lee, Hyung-Joo Kwon
BMC Immunology , 2011, DOI: 10.1186/1471-2172-12-29
Abstract: We present that a particular form of natural phosphodiester bond CpG-DNA encapsulated in a specific liposome complex (Lipoplex(O)) induces potent immunomodulatory activity in humans as well as in mice. Additionally, Lipoplex(O) enhances the production of IgG2a specific to antigenic protein in mice. Most importantly, immunization of mice with several peptides co-encapsulated with Lipoplex(O) without carriers significantly induces each peptide-specific IgG2a production in a TLR9-dependent manner. A peptide-specific monoclonal antibody produced against hepatocellular carcinoma-associated antigen has functional effects on the cancer cells.Our overall results show that Lipoplex(O) is a potent adjuvant and that complexes of peptide and Lipoplex(O) are extremely useful for B cell epitope screening and antibody production without carriers. Therefore, our strategy may be promptly used for the development of therapeutic antibodies by rapid screening of potent B cell epitopes.Synthetic oligodeoxynucleotides (ODNs) and bacterial DNA containing unmethylated CpG dinucleotides flanked by specific base sequences (CpG-DNA) have significant immunomodulatory effects on B lymphocytes, macrophages, dendritic cells, and natural killer cells [1-4]. Experimental evidence suggests that CpG-DNA induces the regulation of Th1/Th2 immune responses, antigen-presenting cell activity, and immunoglobulin (Ig) isotype switching [5-7]. Therefore, CpG-DNA has gained attention for its potential use as an immune adjuvant and in therapeutics for allergic and infectious diseases [8,9].Phosphorothioate-modified types of CpG-DNA (PS-ODN), which are resistant to nuclease activity and can be efficiently delivered into cells [10,11], have been utilized in clinical applications [9]. The immunomodulatory activities of PS-ODN are enhanced by liposome-encapsulation [12-14]. However, several studies have suggested that PS-ODN induces backbone-related side effects, such as transient splenomegaly [15], lymphoid folli
Prevention and Therapy of Hepatocellular Carcinoma by Vaccination with TM4SF5 Epitope-CpG-DNA-Liposome Complex without Carriers  [PDF]
Sanghoon Kwon, Dongbum Kim, Byoung Kwon Park, Sunhee Cho, Kwang Dong Kim, Young-Eun Kim, Cheung-Seog Park, Hyun-Jong Ahn, Jae-Nam Seo, Kyung-Chan Choi, Doo-Sik Kim, Younghee Lee, Hyung-Joo Kwon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033121
Abstract: Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a CD4+ cells- and Th1 differentiation-dependent manner. The transmembrane 4 superfamily member 5 protein (TM4SF5) has gained attention as a target for hepatocellular carcinoma (HCC) therapy because it induces uncontrolled growth of human HCC cells via the loss of contact inhibition. Monoclonal antibodies specific to an epitope of human TM4SF5 (hTM4SF5R2-3) can recognize native mouse TM4SF5 and induce functional effects on mouse cancer cells. Pre-immunization with a complex of the hTM4SF5R2-3 epitope and Lipoplex(O) had prophylactic effects against tumor formation by HCC cells implanted in an mouse tumor model. Furthermore, therapeutic effects were revealed regarding the growth of HCC when the vaccine was injected into mice after tumor formation. These results suggest that our improved peptide vaccine technology provides a novel prophylaxis measure as well as therapy for HCC patients with TM4SF5-positive tumors.
Induction of HCA587-Specific Antitumor Immunity with HCA587 Protein Formulated with CpG and ISCOM in Mice  [PDF]
Juanjuan Chen, Lijie Zhang, Weigang Wen, Jiaqing Hao, Pumei Zeng, Xiaoping Qian, Yu Zhang, Yanhui Yin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047219
Abstract: HCA587 (also known as MAGE-C2) is a “cancer-testis” antigen highly expressed in a number of malignancies with unique immunological properties, making it a promising target for tumor immunotherapy. In this report, we demonstrated that HCA587 protein, when formulated with adjuvants CpG–containing oligodeoxynucleotides (CpG ODN) and ISCOM, was capable of inducing a potent cellular and humoral immune response as indicated by the presence of a large number of HCA587-specific, IFN-γ-producing CD4+ T cells and high levels of HCA587-specific antibodies. More importantly, vaccination with HCA587 conferred protection against challenge with HCA587-expressing B16 melanoma in prophylactic and therapeutic settings. In analysis of the mechanisms underlying the protective effect, we showed that the vaccination was followed by enhanced accumulation of tumor-infiltrating lymphocytes (TILs) with enrichment of conventional CD4+ T cells but reduced representation of Treg cells. Further, the antitumor effect was largely abrogated in mice either depleted of CD4+ T cells or deficient for IFN-γ. These results indicate that HCA587 protein vaccine possesses evident antitumor activity in a mouse model and holds promise for treatment of human cancers.
WSSV ie1 promoter is more efficient than CMV promoter to express H5 hemagglutinin from influenza virus in baculovirus as a chicken vaccine
Fang He, YuenFern Ho, Li Yu, Jimmy Kwang
BMC Microbiology , 2008, DOI: 10.1186/1471-2180-8-238
Abstract: White spot syndrome virus (WSSV) immediate-early promoter one (ie1) was shown to be a stronger promoter for gene expression in insect cells compared with Cytomegalovirus immediate-early (CMV) promoter in luciferase assays. In an attempt to improve expression efficiency, a recombinant baculovirus was constructed expressing hemagglutinin (HA) of H5N1 influenza virus under the control of WSSV ie1 promoter. HA expression in SF9 cells increased significantly with baculovirus under WSSV ie1 promoter, compared with CMV promoter based on HA contents and hemagglutination activity. Further, immunization with baculovirus under WSSV ie1 promoter in chickens elicited higher level anti-HA antibodies compared to CMV promoter, as indicated in hemagglutination inhibition, virus neutralization and enzyme-linked immunosorbent assays. By immunohistochemistry, strong HA antigen expression was observed in different chicken organs with vaccination of WSSV ie1 promoter controlled baculovirus, confirming higher efficiency in HA expression by WSSV ie1 promoter.The production of H5 HA by baculovirus was enhanced with WSSV ie1 promoter, especially compared with CMV promoter. This contributed to effective elicitation of HA-specific antibody in vaccinated chickens. This study provides an alternative choice for baculovirus based vaccine production.The spread of highly pathogenic avian influenza A (H5N1) viruses from Asia to the Middle East, Europe, and Africa poses the threat of an influenza pandemic. Vaccination of poultry is an effective measure to control virus spread [1]. Current production of inactivated influenza vaccine requires high-level biocontainment facilities and large numbers of embryonated chicken eggs, while baculovirus surface displayed recombinant hemagglutinin may be an attractive alternative to the effective influenza vaccine [2-5].White spot syndrome virus (WSSV), a major pathogen in shrimp, can infect a wide range of invertebrate tissues and cells. WSSV genome has 9 repeated
Different Immunity Elicited by Recombinant H5N1 Hemagglutinin Proteins Containing Pauci-Mannose, High-Mannose, or Complex Type N-Glycans  [PDF]
Shih-Chang Lin, Jia-Tsrong Jan, Ben Dionne, Michael Butler, Ming-Hsi Huang, Chung-Yi Wu, Chi-Huey Wong, Suh-Chin Wu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066719
Abstract: Highly pathogenic avian influenza H5N1 viruses can result in poultry and occasionally in human mortality. A safe and effective H5N1 vaccine is urgently needed to reduce the pandemic potential. Hemagglutinin (HA), a major envelope protein accounting for approximately 80% of spikes in influenza virus, is often used as a major antigen for subunit vaccine development. In this study, we conducted a systematic study of the immune response against influenza virus infection following immunization with recombinant HA proteins expressed in insect (Sf9) cells, insect cells that contain exogenous genes for elaborating N-linked glycans (Mimic) and mammalian cells (CHO). While the antibody titers are higher with the insect cell derived HA proteins, the neutralization and HA inhibition titers are much higher with the mammalian cell produced HA proteins. Recombinant HA proteins containing tri- or tetra-antennary complex, terminally sialylated and asialyated-galactose type N-glycans induced better protective immunity in mice to lethal challenge. The results are highly relevant to issues that should be considered in the production of fragment vaccines.
H3N2 Influenza Infection Elicits More Cross-Reactive and Less Clonally Expanded Anti-Hemagglutinin Antibodies Than Influenza Vaccination  [PDF]
M. Anthony Moody, Ruijun Zhang, Emmanuel B. Walter, Christopher W. Woods, Geoffrey S. Ginsburg, Micah T. McClain, Thomas N. Denny, Xi Chen, Supriya Munshaw, Dawn J. Marshall, John F. Whitesides, Mark S. Drinker, Joshua D. Amos, Thaddeus C. Gurley, Joshua A. Eudailey, Andrew Foulger, Katherine R. DeRosa, Robert Parks, R. Ryan Meyerhoff, Jae-Sung Yu, Daniel M. Kozink, Brice E. Barefoot, Elizabeth A. Ramsburg, Surender Khurana, Hana Golding, Nathan A. Vandergrift, S. Munir Alam, Georgia D. Tomaras, Thomas B. Kepler, Garnett Kelsoe, Hua-Xin Liao, Barton F. Haynes
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025797
Abstract: Background During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection. Methods and Findings To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject. Conclusion The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.
Expression of hemagglutinin protein from the avian influenza virus H5N1 in a baculovirus/insect cell system significantly enhanced by suspension culture
Nitar Nwe, Qigai He, Sudarat Damrongwatanapokin, Qingyun Du, Ivanus Manopo, Yukol Limlamthong, Beau Fenner, Lynn Spencer, Jimmy Kwang
BMC Microbiology , 2006, DOI: 10.1186/1471-2180-6-16
Abstract: For vaccine production, hemagglutinin (HA1) from avian influenza H5N1 was expressed from a recombinant baculovirus. Recombinant HA1 was expressed in monolayer or suspension culture insect cells by infection with the recombinant baculovirus. The yield of rHA1 from the suspension culture was 68 mg/l, compared to 6 mg/l from the monolayer culture. Immunization of guinea pigs with 50 μg of rHA1 yielded hemagglutinin inhibition and virus neutralization titers of 1:160 after two times vaccination with rHA1 protein.Thus, the production of rHA1 using an insect suspension cell system provides a promising basis for economical production of a H5 antigen.Influenza A viruses have a segmented genome of single-stranded negative-sense RNA and belong to the family Orthomyxoviridae [1]. They have been isolated from a variety of animals, including humans, pigs, horses, sea mammals, and birds [2]. There are 16 subtypes of influenza virus A, among them the highly pathogenic avian H5N1 viruses which caused 18 confirmed infections and six deaths in Hong Kong in 1997. This virus can apparently be transmitted directly from birds to humans with no intermediate mammalian host [3]. Infection of poultry with highly pathogenic avian influenza virus can be devastating in terms of flock morbidity and mortality, economic loss and social disruption [4]. Swayne et al. [5] suggested that vaccination has the potential to reduce environmental contamination with avian influenza virus and prevent subsequent bird-to-bird transmission [5]. In order to prevent spread of influenza viruses, emphasis must be placed on biosecurity and flock management practices, the development of rapid diagnostics [4] and vaccine production [6]. Current influenza vaccines include a subunit vaccine [7-10], attenuated vaccine [11,12], DNA vaccine [13] and inactivated influenza vaccine [14], with the latter being the most widely used on a commercial scale [6].Current inactivated vaccines production requires large numbers of embryo
Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2  [PDF]
Wei Wang,Christine M. Anderson,Christopher J. De Feo,Min Zhuang,Hong Yang,Russell Vassell,Hang Xie,Zhiping Ye,Dorothy Scott,Carol D. Weiss
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002081
Abstract: Pandemic 2009 H1N1 influenza A virus (2009 H1N1) differs from H1N1 strains that circulated in the past 50 years, but resembles the A/New Jersey/1976 H1N1 strain used in the 1976 swine influenza vaccine. We investigated whether sera from persons immunized with the 1976 swine influenza or recent seasonal influenza vaccines, or both, neutralize 2009 H1N1. Using retroviral pseudovirions bearing hemagglutinins on their surface (HA-pseudotypes), we found that 77% of the sera collected in 1976 after immunization with the A/New Jersey/1976 H1N1 swine influenza vaccine neutralized 2009 H1N1. Forty five percent also neutralized A/New Caledonia/20/1999 H1N1, a strain used in seasonal influenza vaccines during the 2000/01–2006/07 seasons. Among adults aged 48–64 who received the swine influenza vaccine in 1976 and recent seasonal influenza vaccines during the 2004/05–2008/09 seasons, 83% had sera that neutralized 2009 H1N1. However, 68% of age-matched subjects who received the same seasonal influenza vaccines, but did not receive the 1976 swine influenza vaccine, also had sera that neutralized 2009 H1N1. Sera from both 1976 and contemporary cohorts frequently had cross-neutralizing antibodies to 2009 H1N1 and A/New Caledonia/20/1999 that mapped to hemagglutinin subunit 2 (HA2). A conservative mutation in HA2 corresponding to a residue in the A/Solomon Islands/3/2006 and A/Brisbane/59/2007 H1N1 strains that circulated in the 2006/07 and 2007/08 influenza seasons, respectively, abrogated this neutralization. These findings highlight a cross-neutralization determinant influenced by a point mutation in HA2 and suggest that HA2 may be evolving under direct or indirect immune pressure.
Liposome-Coupled Peptides Induce Long-Lived Memory CD8+ T Cells Without CD4+ T Cells  [PDF]
Maiko Taneichi,Yuriko Tanaka,Terutaka Kakiuchi,Tetsuya Uchida
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015091
Abstract: CD8+ T cells provide broad immunity to viruses, because they are able to recognize all types of viral proteins. Therefore, the development of vaccines capable of inducing long-lived memory CD8+ T cells is desired to prevent diseases, especially those for which no vaccines currently exist. However, in designing CD8+ T cell vaccines, the role of CD4+ T cells in the induction and maintenance of memory CD8+ T cells remains uncertain. In the present study, the necessity or not of CD4+ T cells in the induction and maintenance of memory CD8+ T cells was investigated in mice immunized with liposome-coupled CTL epitope peptides. When OVA-derived CTL epitope peptides were chemically coupled to the surfaces of liposomes and inoculated into mice, both primary and secondary CTL responses were successfully induced. The results were further confirmed in CD4+ T cell-eliminated mice, suggesting that CD4+ T cells were not required for the generation of memory CD8+ T cells in the case of immunization with liposome-coupled peptides. Thus, surface-linked liposomal antigens, capable of inducing long-lived memory CD8+ T cells without the contribution of CD4+ T cells, might be applicable for the development of vaccines to prevent viral infection, especially for those viruses that evade humoral immunity by varying their surface proteins, such as influenza viruses, HIV, HCV, SARS coronaviruses, and Ebola viruses.
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