Role of trimethylated chitosan (TMC) in nasal residence time, local distribution and toxicity of an intranasal influenza vaccine. 2010

Niels Hagenaars, and Marta Mania, and Pascal de Jong, and Ivo Que, and Rob Nieuwland, and Bram Slütter, and Harrie Glansbeek, and Jacco Heldens, and Han van den Bosch, and Clemens Löwik, and Eric Kaijzel, and Enrico Mastrobattista, and Wim Jiskoot
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.

The nose is a promising immunization site and intranasal (i.n.) vaccination studies with whole inactivated influenza virus (WIV) adjuvanted with N,N,N-trimethylchitosan (TMC-WIV) have shown promising results. In this study, the influence of TMC on the i.n. delivery of WIV was studied in mice by comparing the nasal residence time and the specific location in the nasal cavity of WIV and TMC-WIV. Additionally, the local toxicity profile of the WIV formulations was assessed. In vivo fluorescence imaging was used to study the nasal residence time and the fate of the bulk vaccine in mice that received vaccines fluorescently labeled with IRDye800CW. An immunohistochemical (IHC) staining method for nasal cross-sections was developed to visualize the antigen in the nasal cavity. Therefore, mice were sacrificed at different time points after vaccination with various vaccine formulations and nasal cross-sections were made. The local toxicity was assessed using hematoxylin and eosin staining for the nasal cross-sections. No significant differences in the nasal residence time between WIV and TMC-WIV were observed. However, IHC revealed a striking difference in the location and distribution of WIV in the nasal cavity. When formulated as plain WIV, positive staining was mainly found in the nasal cavity, presumably in mucus blobs. TMC-coated WIV, on the other hand, was mostly present as a thin layer on the epithelial surfaces of the naso- and maxilloturbinates. This difference in staining pattern correlates with the observed differences in immunogenicity of these two vaccines and indicates that TMC-WIV results in a much closer interaction of WIV with the epithelial surfaces than WIV alone, potentially leading to enhanced uptake and induction of immune responses. This study further shows that both WIV and TMC-WIV formulations induce minimal local toxicity. Taken altogether, these results provide more insight in the mode of action and safety of TMC and justify further research to develop TMC-adjuvanted nasal vaccines.

UI MeSH Term Description Entries
D007114 Immunization Deliberate stimulation of the host's immune response. ACTIVE IMMUNIZATION involves administration of ANTIGENS or IMMUNOLOGIC ADJUVANTS. PASSIVE IMMUNIZATION involves administration of IMMUNE SERA or LYMPHOCYTES or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). Immunologic Stimulation,Immunostimulation,Sensitization, Immunologic,Variolation,Immunologic Sensitization,Immunological Stimulation,Sensitization, Immunological,Stimulation, Immunologic,Immunizations,Immunological Sensitization,Immunological Sensitizations,Immunological Stimulations,Sensitizations, Immunological,Stimulation, Immunological,Stimulations, Immunological,Variolations
D007252 Influenza Vaccines Vaccines used to prevent infection by viruses in the family ORTHOMYXOVIRIDAE. It includes both killed and attenuated vaccines. The composition of the vaccines is changed each year in response to antigenic shifts and changes in prevalence of influenza virus strains. The flu vaccines may be mono- or multi-valent, which contains one or more ALPHAINFLUENZAVIRUS and BETAINFLUENZAVIRUS strains. Flu Vaccine,Influenzavirus Vaccine,Monovalent Influenza Vaccine,Universal Flu Vaccine,Universal Influenza Vaccine,Flu Vaccines,High-Dose Trivalent Influenza Vaccine,Influenza Vaccine,Influenza Virus Vaccine,Influenza Virus Vaccines,Influenzavirus Vaccines,Intranasal Live-Attenuated Influenza Vaccine,LAIV Vaccine,Monovalent Influenza Vaccines,Quadrivalent Influenza Vaccine,Trivalent Influenza Vaccine,Trivalent Live Attenuated Influenza Vaccine,Universal Flu Vaccines,Universal Influenza Vaccines,Flu Vaccine, Universal,High Dose Trivalent Influenza Vaccine,Influenza Vaccine, Monovalent,Influenza Vaccine, Quadrivalent,Influenza Vaccine, Trivalent,Influenza Vaccine, Universal,Intranasal Live Attenuated Influenza Vaccine,Vaccine, Flu,Vaccine, Influenza,Vaccine, Influenza Virus,Vaccine, Influenzavirus,Vaccine, LAIV,Vaccine, Monovalent Influenza,Vaccine, Quadrivalent Influenza,Vaccine, Trivalent Influenza,Virus Vaccine, Influenza
D008819 Mice, Nude Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses. Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D009666 Nose A part of the upper respiratory tract. It contains the organ of SMELL. The term includes the external nose, the nasal cavity, and the PARANASAL SINUSES. External Nose,External Noses,Nose, External,Noses,Noses, External
D009975 Orthomyxoviridae A family of RNA viruses causing INFLUENZA and other respiratory diseases. Orthomyxoviridae includes INFLUENZAVIRUS A; INFLUENZAVIRUS B; INFLUENZAVIRUS C; INFLUENZAVIRUS D; ISAVIRUS; and THOGOTOVIRUS. Influenza Viruses,Myxoviruses,Orthomyxoviruses,Influenza Virus,Myxovirus,Orthomyxovirus
D002626 Chemistry, Pharmaceutical Chemistry dealing with the composition and preparation of agents having PHARMACOLOGIC ACTIONS or diagnostic use. Medicinal Chemistry,Chemistry, Pharmaceutic,Pharmaceutic Chemistry,Pharmaceutical Chemistry,Chemistry, Medicinal
D005260 Female Females
D000276 Adjuvants, Immunologic Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (Freund's adjuvant, BCG, Corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Immunoactivators,Immunoadjuvant,Immunoadjuvants,Immunologic Adjuvant,Immunopotentiator,Immunopotentiators,Immunostimulant,Immunostimulants,Adjuvant, Immunologic,Adjuvants, Immunological,Immunologic Adjuvants,Immunological Adjuvant,Adjuvant, Immunological,Immunological Adjuvants
D000281 Administration, Intranasal Delivery of medications through the nasal mucosa. Drug Administration, Intranasal,Administration, Intranasal Drug,Administration, Nasal,Intranasal Administration,Intranasal Drug Administration,Administrations, Intranasal,Administrations, Intranasal Drug,Administrations, Nasal,Drug Administrations, Intranasal,Intranasal Administrations,Intranasal Drug Administrations,Nasal Administration,Nasal Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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