The development of stable influenza vaccine powder formulations for new needle-free dosage forms Amorij, Jean-Pierre
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1 University of Groningen The development of stable influenza vaccine powder formulations for new needle-free dosage forms Amorij, Jean-Pierre IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2008 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Amorij, J-P. (2008). The development of stable influenza vaccine powder formulations for new needle-free dosage forms. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:
2 Introduction Chapter I
3 Few infectious diseases cause such a huge annual toll of morbidity, mortality, and economic loss as influenza. Each year influenza affects millions of people [1]. Although antiviral drugs can be used for prophylaxis and therapy of influenza infections, vaccination is recognized as the most cost-effective method for controlling the disease. Current influenza vaccines are mostly formulations composed of whole inactivated virus, virosomes, split virus or subunit antigen, i.e. purified haemagglutinin (HA) and neuraminidase (NA), which are administered parenterally [2]. However, currently also a cold-adapted live influenza vaccine is marketed for nasal administration [3]. Stabilization of influenza vaccines Today's influenza vaccines are all formulated as liquids. In the aqueous environment, however, they are subjected to physical and chemical degradation processes that may lead to loss of activity. Elevated temperatures increase the rate of degradation of the vaccine compounds [4, 5], while temperatures below the freezing point of the dispersion cause formation of ice and solute concentration, processes that also may damage the antigen [5, 6]. Therefore (inactivated) influenza vaccines have to be stored within the narrow temperature range of 2 to 8 C. This relatively narrow temperature range requires a well-controlled cold chain, which makes the process of distribution and storage complicated and expensive [7]. An influenza vaccine that is stable at ambient temperatures and not sensitive to freezing stresses would reduce the dependency on coldchain facilities and would therefore allow the integration of the vaccine logistics with general drug distribution; especially in developing countries this would be attractive. Moreover, this would reduce the risk of vaccine losses caused by "off-label" storage. Overall this would result in enormous annual savings. In addition, a stable vaccine formulation would facilitate stockpiling of potential vaccines against pandemic viruses, which provides an immediate availability and simple distribution of vaccine in a pandemic situation. A potentially successful strategy to stabilize biopharmaceuticals, such as proteins, vaccines and gene delivery systems, is to convert them into a dry-powder formulation. However, during drying and subsequent storage stabilizers are required to prevent damage to these substances. It is well known that sugars can stabilize various biopharmaceuticals during drying [8-15]. If dried properly, the biopharmaceutical is incorporated in a glassy matrix of amorphous sugar and thereby stabilized during subsequent storage. Only limited research has been done on the stabilization of influenza vaccines by incorporating them in a glassy matrix of amorphous sugar. Therefore, more research is required to get a complete understanding of the formulation and process design. Especially the dependence of the integrity and stability of the (dried) vaccine on factors such as type of vaccine, used excipients and the drying process are unknown. 2
4 INTRODUCTION Needle-free dosage forms Current inactivated influenza vaccines are generally administered via the intramuscular (i.m.) or subcutaneous (s.c.) route using needles and syringes. Despite its common use, needle-based immunization has several disadvantages. Needle-phobia along with limited ease of use for vaccination programs are typical shortcomings of injections [16]. Needlefree delivery, such as mucosal delivery via the respiratory or gastro-intestinal tract, may provide several potential advantages in vaccine delivery, such as eliminated pain at the injection site, easier and faster vaccine distribution and administration, and reduced costs [17-19]. In addition, an important and promising advantage of mucosal vaccination is that it, in contrast to i.m. vaccines, may result in a local immune response in the respiratory tract. As a result antibodies in the respiratory tract might give protection against influenza infection at the port of entry. In addition, since mucosal IgA responses have been shown to exhibit cross-protective immunity against antigenically distinct viruses [20, 21], such a mucosal immune response might offer broader protection against drifted, heterologous strains. Unfortunately, despite these potential advantages, until now mucosal vaccination approaches have suffered from several limitations or practical problems related to the use of inadequate or old-fashioned delivery technologies, and thus have frequently resulted in inadequate antibody responses or even in a state of immunological tolerance [22]. Therefore, marketed influenza vaccines, being in the liquid state, are still mainly administered through injection. However, recent developments in the area of vaccine formulation and delivery technologies now allow efficient delivery of vaccines to specific sites in the human body and therefore provide new opportunities for the use of alternative needle-free dosage forms of influenza vaccines. This thesis addresses some of the issues involved in this development. Scope of this thesis The first objective of the studies described in this thesis was to study and develop stable influenza vaccine formulations. Dry-powder formulations, which are not dependent on a cold chain, of two vaccine types (a subunit and a virosomal vaccine) were investigated. The second objective of the studies described in this thesis was to study administration strategies for the development of needle-free dosage forms of influenza vaccines. Administration strategies that may lead to needle-free dosage forms of influenza vaccines via the oral or pulmonary route were investigated. Outline of this thesis In Chapter II, several aspects of influenza vaccine formulation and administration were reviewed: the different vaccine types used today; the rationale and need for stabilized vaccines; strategies by which influenza vaccines can be stabilized; the current status of stabilized solid vaccines and the current developments in the field of needle-free dosage forms for influenza vaccination. This review also contains a brief discussion of the research described in the following chapters. 3
5 In Chapter III, a stable dry-powder subunit vaccine formulation was developed. Influenza subunit vaccine was incorporated in a glassy matrix of carbohydrate using lyophilization. The influence of freezing rate, buffer composition, and type of carbohydrate (disaccharide, oligosaccharide or polysaccharide) on the structure and antigenic activity of HA after freezing and freeze-drying respectively was studied. The structural integrity of HA was investigated with a proteolytic assay, fluorescence spectroscopy and circular dichroism spectroscopy. The antigenic properties of the subunit vaccine powder were determined by a single radial immunodiffusion assay in vitro. The antigenic properties of the subunit vaccine powder after reconstitution were further evaluated in an in vivo study in BALB/c mice. In Chapter IV, the aim of the presented work was to develop a stable dry-powder formulation of influenza virosomes with the objective to preserve the structural integrity and biological activity of the virosomes. To this end virosomes and pdna-virosomes were lyophilized with inulin as a stabilizer. The physical and functional properties of freezedried virosomes were studied and followed during storage. Freeze-dried virosomal vaccine was evaluated for the preservation of its immunological properties, while freezedried pdna-virosomes were investigated for preservation of their delivery properties by studying their fusion capacity and transfection efficiency. In Chapter V, a strategy for an oral influenza vaccine is presented. It was assessed to which part of the gastro-intestinal (GI) tract (the upper part or the lower part) an oral influenza vaccine should be targeted to result in an effective immune response. For this purpose BALB/c mice were immunized with a liquid influenza subunit vaccine via different routes. Intragastric delivery was used to target to the upper GI-tract and intracolonic delivery was used to target to the lower GI-tract. Furthermore, the effect of an adjuvant, E.coli heat-labile enterotoxin, on the immune responses elicited by the differently delivered vaccines was investigated. In Chapter VI, pulmonary vaccination with an inulin stabilized influenza subunit vaccine powder, produced by spray-freeze drying, was evaluated. Immune responses after pulmonary vaccination of BALB/c mice with vaccine powder were determined and compared to those induced by intramuscular vaccination with a conventional liquid subunit vaccine and pulmonary administered liquid subunit vaccine. In Chapter VII, the findings of this thesis and the perspectives of solid influenza vaccines and needle-free delivery strategies are discussed. 4
6 INTRODUCTION REFERENCES [1] WHO. WHO Media Influenza Factsheet N [2] Wilschut J, McElhaney JE, Palache AM. Rapid Reference Influenza. 2nd ed. London: Mosby/Elsevier Science, [3] Abramson JS. Intranasal, cold-adapted, live, attenuated influenza vaccine. Pediatr Infect Dis J 1999;18(12): [4] Coenen F, Tolboom JT, Frijlink HW. Stability of influenza sub-unit vaccine. Does a couple of days outside the refrigerator matter? Vaccine 2006;24(4): [5] WHO Department of Immunization Va, Biologicals. Temperature sensitivity of vaccines [6] Luykx DM, Casteleijn MG, Jiskoot W, Westdijk J, Jongen PM. Physicochemical studies on the stability of influenza haemagglutinin in vaccine bulk material. Eur J Pharm Sci 2004;23(1): [7] Zweig SE. Advances in vaccine stability monitoring technology. Vaccine 2006;24(33-34): [8] Randolph TW. Phase separation of excipients during lyophilization: effects on protein stability. J Pharm Sci 1997;86(11): [9] Slade L, Levine H. Non-equilibrium behavior of small carbohydrate-water systems. Pure Appl Chem 1988;60: [10] Hinrichs WL, Prinsen MG, Frijlink HW. Inulin glasses for the stabilization of therapeutic proteins. Int J Pharm 2001;215(1-2): [11] Sun WQ, Leopold AC, Crowe LM, Crowe JH. Stability of dry liposomes in sugar glasses. Biophys J 1996;70(4): [12] Crowe JH, Crowe LM, Carpenter JF, Aurell Wistrom C. Stabilization of dry phospholipid bilayers and proteins by sugars. Biochem J 1987;242(1):1-10. [13] Levy JA, Fieldsteel AH. Freeze-drying is an effective method for preserving infectious type C retroviruses. J Virol Methods 1982;5(3-4): [14] Bieganski RM, Fowler A, Morgan JR, Toner M. Stabilization of active recombinant retroviruses in an amorphous dry state with trehalose. Biotechnol Prog 1998;14(4): [15] Croyle MA, Roessler BJ, Davidson BL, Hilfinger JM, Amidon GL. Factors that influence stability of recombinant adenoviral preparations for human gene therapy. Pharm Dev Technol 1998;3(3): [16] Mitragotri S. Immunization without needles. Nat Rev Immunol 2005;5(12): [17] Giudice EL, Campbell JD. Needle-free vaccine delivery. Adv Drug Deliv Rev 2006;58(1): [18] Freytag LC, Clements JD. Mucosal adjuvants. Vaccine 2005;23(15): [19] Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med 2005;11(4 Suppl):S [20] Liew FY, Russell SM, Appleyard G, Brand CM, Beale J. Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity. Eur J Immunol 1984;14(4): [21] Tumpey TM, Renshaw M, Clements JD, Katz JM. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection. J Virol 2001;75(11): [22] Smith DJ, Bot S, Dellamary L, Bot A. Evaluation of novel aerosol formulations designed for mucosal vaccination against influenza virus. Vaccine 2003;21(21-22):
7 6
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