Intranasal immunization with live attenuated influenza vaccine plus chitosan as an adjuvant protects mice against homologous and heterologous virus challenge
Shanghai Institute of Biological Products, Shanghai 200052, China. Archives of Virology
(Impact Factor: 2.39).
05/2012; 157(8):1451-61. DOI: 10.1007/s00705-012-1318-7
Our previous studies have proven the adjuvanticity of chitosan in mice when administered with inactivated and subunit influenza vaccine. In this study, we investigated the adjuvant effect of chitosan on the immunogenicity and protective efficacy of a live attenuated influenza vaccine. Mice were inoculated intranasally with live attenuated influenza vaccine plus chitosan and then challenged with a high, lethal dose of homologous or heterologous virus. Antibody responses, secretion of IFN-γ by spleen cells, body weight loss, survival rates, and residual lung virus titers were tested. The results demonstrated that live attenuated influenza vaccine with chitosan adjuvant not only protected mice completely against challenge with the homologous virus but also provided good cross-protection against a heterologous virus. In addition, chitosan as adjuvant could significantly increase the levels of antigen-specific antibodies and the population of IFN-γ-secreting T cells. These results reveal the potential of chitosan as a candidate adjuvant for use in a live attenuated influenza vaccine.
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ABSTRACT: Several global outbreaks of highly pathogenic avian influenza (HPAI) H5N1 virus have increased the urgency of developing effective and safe vaccines against H5N1. Compared with H5N1 inactivated vaccines used widely, H5N1 live-attenuated influenza vaccines (LAIVs) have advantages in vaccine efficacy, dose-saving formula, long-lasting effect, ease of administration and some cross-protective immunity. Furthermore, H5N1 LAIVs induce both humoral and cellular immune responses, especially including improved IgA production at the mucosa. The current trend of H5N1 LAIVs development is toward cold-adapted, temperature-sensitive or replication-defective vaccines, and moreover, H5N1 LAIVs plus mucosal adjuvants are promising candidates. This review provides an update on the advantages and development of H5N1 live-attenuated influenza vaccines.
Available from: Zhiguo Su
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ABSTRACT: PEGylation, including non-specific and site-directed ways, is a well-established and validated strategy to increase the stability, in vivo plasma retention time, and efficacy of protein pharmaceutics come together with the reduction of immunogenicity and hydrophobicity. Site-directed conjugation by PEG-aldehyde is the most widely used method for N-terminal modification, however, the generation of multi-modified products is inevitable due to lysine chemistry which always leads to difficulties in purification and quantification procedure. In this study, we developed a specific PEGylation strategy through the periodation of N-terminus of interferon beta-1b (IFN-β-1b) followed by the coupling of PEG-hydrazide. The prolonged elimination half-life and significantly diminished immunogenicity of PEG hydrazide-modified protein indicated an effective process in improving the properties of pharmacology and immunogenicity of IFN-β-1b. We further conducted comparisons on selectivity, velocity, yield and pharmacokinetics of the two methods. Results demonstrated that the hydrazide-based conjugation was a highly specific coupling reaction that only produced homogeneous N-terminal mono-PEGylated conjugate, while heterogeneous multi-modified products were generated in aldehyde-based process. In addition, fairly higher PEGylation yield was presented in the hydrazide conjugation compared with that of aldehyde strategy. These investigations supplied a practical approach for site specific modification of proteins with N-terminal serine or threonine to achieve improved homogeneity of conjugates as well as enhanced pharmacological properties.
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ABSTRACT: Subunit/split influenza vaccines are less reactogenic compared with the whole virus vaccines. However, their immunogenicity is relatively low and thus required proper adjuvant and/or delivery vehicle for immunogenicity enhancement. Influenza vaccines administered intramuscularly induce minimum, if any, mucosal immunity at the respiratory mucosa which is the prime site of the infection. In this study, chitosan (CS) nanoparticles were prepared by ionic cross-linking of the CS with sodium tripolyphosphate (TPP) at the CS/TPP ratio of 1:0.6 using 2 h mixing time. The CS/TPP nanoparticles were used as delivery vehicle of an intranasal influenza vaccine made of hemagglutinin (HA)-split influenza virus product. Innocuousness, immunogenicity, and protective efficacy of the CS/TPP-HA vaccine were tested in influenza mouse model in comparison with the antigen alone vaccine. The CS/TPP-HA nanoparticles had required characteristics including nano-sizes, positive charges, and high antigen encapsulation efficiency. Mice that received two doses of the CS/TPP-HA vaccine intranasally showed no adverse symptoms indicating the vaccine innocuousness. The animals developed higher systemic and mucosal antibody responses than vaccine made of the HA-split influenza virus alone. The CS/TPP-HA vaccine could induce also a cell-mediated immune response shown as high numbers of IFN-γ-secreting cells in spleens while the HA vaccine alone could not. Besides, the CS nanoparticle encapsulated HA-split vaccine reduced markedly the influenza morbidity and also conferred 100% protective rate to the vaccinated mice against lethal influenza virus challenge. Overall results indicated that the CS nanoparticles invented in this study is an effective and safe delivery vehicle/adjuvant for the influenza vaccine.
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