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Use of hyaluronic acid polymers for mucosal delivery of vaccine and adjuvants

a technology of hyaluronic acid and polymer, which is applied in the field of bioadhesive polymer systems, can solve the problems of few bioadhesive delivery systems commercially available, local irritation, and inability to duplicate the performance of these bioadhesives in vivo, and achieves the effects of enhancing the immunogenicity of the antigen coadministered, reducing the rate of mucociliary clearance, and effective methods of elici

Inactive Publication Date: 2005-10-13
CHIRON CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The present invention provides an effective method for eliciting an immune response in a mammalian subject using mucosal immunization and hyaluronic acid delivery techniques. The present invention is based on the discovery that the mucosal delivery of hyaluronic acid derivatives, such as esterified hyaluronic acid polymers and auto-crosslinked hyaluronic acid polymers, in combination with an antigen of interest, and optionally an adjuvant, acts to enhance the immunogenicity of the antigen coadministered therewith. While not wishing to be bound by a particular theory, it is believed that the bioadhesive properties of the hyaluronic acid polymers decrease the rate of mucociliary clearance from the nasal cavity and thus allow a longer contact time between the antigen and the absorbing membrane. Additionally, a transient widening occurs at the tight junctions between the cells of the mucosal epithelia allowing more efficient transport of the antigen of interest. The use of hyaluronic acid polymers provides a safe and effective approach for enhancing the immunogenicity of a wide variety of antigens.

Problems solved by technology

However, performance of these bioadhesives has not been duplicated in vivo.
Additionally, such bioadhesives may cause local irritation.
Hence, few bioadhesive delivery systems are commercially available.
However, the use of hyaluronic acid derivatives to deliver vaccine antigens has not heretofore been described.

Method used

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  • Use of hyaluronic acid polymers for mucosal delivery of vaccine and adjuvants
  • Use of hyaluronic acid polymers for mucosal delivery of vaccine and adjuvants
  • Use of hyaluronic acid polymers for mucosal delivery of vaccine and adjuvants

Examples

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example 1

Preparation and Use of HYAFF Formulations Including Influenza Antigen

[0089] Placebo (Blank) microparticles of HYAFF11 polymer, approximately 100% esterified with benzyl alcohol, were supplied by Fidia Advanced Biopolymers Srl (Abano Terme, Italy). The average size of these microparticles was about 8 microns (with a portion of the size distribution being less than 1 micron and a portion above 10 microns), as determined by a Malvem Mastersizer Instrument.

[0090] In order to achieve a dose of 10 μg influenza antigen H3N2 (“HA”) (Chiron Vaccines, Sienna, Italy) and 10-25 μg LT-K63 (International Publication No. WO 93 / 13202), a 1% w / w loading of HA / LT-K63 to microparticles was targeted. To do so, 1 mg of HA and 1 mg of LT-K63, in 84 mM Na2HPO4, 11 mM KH2PO4, 82 mM NaCl, was incubated with 100 mg of blank microspheres in PBS at 4° C. for three hours. The suspension was then frozen at −80° C. and freeze-dried overnight.

[0091] Actual antigen / adjuvant load was confirmed by hydrolyzing the ...

example 2

Preparation and Use of ACP Formulations Including Influenza Antigen

[0095] Auto-crosslinked polysaccharide (ACP) hyaluronic acid gel was obtained from Fidia Advanced Biopolymers Srl (Abano Terme, Italy) and used as shipped. To the gel was added 10 μg of HA and 10-25 μg LT-K63, in an aqueous solution to make a gel-to-water ratio of 1:30.

[0096] 50 μl of the viscous solution was administered intranasally using a micropipette to three groups of Balb / C mice each with five animals,.as shown in Table 2 below. Formulations were administered within 60 minutes of preparation. Animals were boosted 28 days later, bled on day 42 and anti-HA titers determined by ELISA. IgA titers from a nasal wash were also assayed.

[0097] As shown in Table 2, animals administered antigen in combination with ACP and adjuvant had higher antibody titers than those administered antigen alone.

TABLE 2Serum anti-HAIgA Titers in theGroupsFormulationELISA TitersNasal Wash1ACP (1:30) +449 + / − 84 1836 + / − 630LT-K63 (25 ...

example 3

Comparison of HYAFF and ACP Formulations

[0099] The immunogenicity of the HA antigen in HYAFF and ACP gel was evaluated in micro pigs (Yucatan). 12 pigs were divided into three groups of four pigs each, as shown in Table 4. In order to achieve the proper dose, pigs were administered intranasally using a gauge 16 Teflon catheter, 500 μl of the ACP formulation or 50 mg of the HYAFF formulation. Control pigs were given 500 μL of antigen alone. Pigs were boosted at 28 days and sera collected and assayed for anti-HA serum IgG levels using an ELISA.

[0100] As can be seen in Table 4, groups of pigs administered antigen with HYAFF or ACP both had higher titers than pigs administered antigen alone, with pigs administered the HYAFF formulations having the highest titers.

TABLE 4Serum Anti-HAGroupsFormulationELISA Titers1LT-R72 (100 μg) + HA (100 μg) 505 + / − 1832LT-R72 (100 μg) + HA (100 μg) − HYAFF1919 + / − 6023LT-R72 (100 μg) + HA (100 μg) + ACP 871 + / − 155

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Abstract

Compositions are provided which include hyaluronic acid derivatives in combination with vaccine antigens, and optionally adjuvants, for mucosal delivery. Also provided are methods of making the compositions, as well as methods of immunization using the same.

Description

TECHNICAL FIELD [0001] The present invention relates generally to bioadhesive polymer systems. In particular, the invention relates to the use of hyaluronic acid polymers for mucosal delivery of vaccine antigens and adjuvants. BACKGROUND OF THE INVENTION [0002] Mucosal immunity provides an important defense mechanism against a wide variety of pathogens. In this regard, the mucosal surfaces of the gastrointestinal, respiratory and genitourinary tracts are continuously exposed to foreign antigens, including potentially infectious bacterial, viral and sometimes parasitic organisms. Mucosal immune responses protect against such challenges and have distinct and specialize characteristics. [0003] For example, the principal immunoglobulin produced by the mucosal immune system is secretory IgA. Specialized antigen uptake cells in the Peyer's Patches of intestinal tract or nasopharyngeal lymphoid tissues, termed microfold or M cells, transport antigen to the underlying mucosal associated lym...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K9/16A61K39/00A61K39/145A61K39/39A61K47/36
CPCA61K9/0043A61K9/1652A61K39/00A61K39/145C12N2760/16134A61K47/36A61K2039/543A61K2039/55544A61K2039/55555A61K39/39A61K39/12
Inventor O'HAGAN, DEREKPAVESIO, ALESSANDRA
Owner CHIRON CORP
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