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Interleukin-12 as an adjuvant for paramyxoviridae vaccines

a vaccine and interleukin-12 technology, applied in the field of interleukin-12 as an adjuvant for paramyxoviridae vaccines, can solve the problems of increased hospitalization rate, rsv-sensitive mutants, and vaccine elicited complement-binding antibodies but failed to protect against infection in children, so as to reduce the replication rate of respiratory syncytial virus (rsv), the effect of potent adjuvant effect and reducing viral replication

Inactive Publication Date: 2007-04-19
VANDERBILT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006] The present invention is based on the discovery that IL-12 has a potent adjuvant effect for immunizing against Paramyxoviridae virus infection. In one embodiment, the invention comprises a method of reducing viral replication of a virus of the paramyxoviridae family in a host (e.g., mammalian, including human, and avian) comprising administering to the host an antigen of the virus in combination with an effective adjuvant amount of interleukin-12 (IL-12). Human viruses of the Paramyxoviridae family include paramyxoviruses (e.g., parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4 and mumps virus), morbilliviruses (e.g., measles virus) and pneumoviruses (e.g., respiratory syncytial virus); other non-human viruses of the Paramyxoviridae family include canine distemper virus, bovine RSV, Newcastle disease virus and rhinderpest virus. In one embodiment, the invention relates to a method of reducing replication of the respiratory syncytial virus (RSV) in a host comprising administering to the host an antigen of RSV in combination with an effective adjuvant amount of IL-12. Thus, the present invention also relates to a method of eliciting an immune response against viruses of the Paramyxoviridae family in a host, comprising administering to the host an antigen of a virus of the Paramyxoviridae family in combination with an effective adjuvant amount of IL-12. The present invention also relates to a method of immunizing a host against RSV comprising administering to the host a mixture comprising an antigen of respiratory syncytial virus in combination with an effective adjuvant amount of interleukin-12.

Problems solved by technology

The major impediment to advancing new candidate vaccines directed against RSV to clinical trials is an incomplete understanding of the vaccine-enhanced illness caused by formalin-inactivated RSV vaccines in the 1960's.
Clinical trials of a formalin-activated alum-precipitated RSV vaccine in the 1960's showed that the vaccine elicited complement-binding antibodies but failed to protect against infection in children.
In addition, the illness after subsequent infection was unusually severe with some deaths, and an increased rate of hospitalization (Kapikian, A. Z., et al.
Temperature-sensitive mutants of RSV, cold-adapted RSV or live RSV given parenterally have been considered unsuccessful as vaccines because of high rates of reversion to wild-type, unacceptable virulence or lack of immunogenicity in the appropriate age group (Graham, B. S., et al., J. of Immun., 151:2032-2040 (1993).

Method used

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  • Interleukin-12 as an adjuvant for paramyxoviridae vaccines
  • Interleukin-12 as an adjuvant for paramyxoviridae vaccines
  • Interleukin-12 as an adjuvant for paramyxoviridae vaccines

Examples

Experimental program
Comparison scheme
Effect test

example 1

Immunization of Mice with RSV and IL-12

[0033] Mice: Pathogen-free female BALB / c mice, 8 to 10 months old, were purchased from Charles River Laboratories (Raleigh, N.C.) and cared for according to the “Guide for the Care and Use of Laboratory Animals” as previously described (Graham, B. S., et al, J. Med. Virol. 26:153 (1988)).

[0034] RSV Immunogen and Virus: Preparation of the formalin-inactivated alum-precipitated RSV and preparation of stock of the A2 strain of RSV have been previously reported (Graham, B. S., et al, Immunol. 151:2032 (1993)). Both the vaccine preparation and the challenge stock were derived from the A2 strain of RSV.

[0035] Murine Cytokine IL-12: Murine recombinant IL-12 was expressed from cloned cDNAs (Schoenhaut, D. S., et al, J. Immunol. 148:3433 (1992)). The lot used in this paper was MRB021693-1.2 (Genetics Institute, Cambridge, Mass.) with a specific activity of 5.6×106 units / mg as determined by PHA blast assay (Wolf, S. F., et al, J. Exp. Med. 146:3074 (1...

example 2

Effect of Delivery Route of IL-12 on its Adjuvant Ability

[0040] The effect of a different delivery route of the adjuvant IL-12 was assessed. IL-12 was administered intraperitoneally as described in Example 1 to one group of mice. To another group of mice, IL-12 was administered intramuscularly mixed with the RSV antigen. The control mice were either mock immunized or treated with IL-12 alone without antigen. Table 1 summarizes the results of the experiment which show that a single dosage of IL-12 given simultaneously with immunogen had the same effect on the reduction of viral replication compared to the 5-dosage intraperitoneal regimen. IL-12 as a specific immunomodulator only worked in RSV immunized mice, having no effects on the unprimed mice. See FIG. 1 and Table 1. These data demonstrate that IL-12 exerted a potent adjuvant effect on the inactivated RSV immunogen.

example 3

Assay of Immunoglobulin Isotype Titers in RSV-immunized Mice Receiving IL-12

[0041] The patterns of immunoglobulin isotypes produced in RSV-immunized mice receiving IL-12 was examined. Mouse serum samples were collected on the day of and two weeks after live RSV challenge.

[0042] RSV-Specific Immunoglobulin Isotype ELISA: All serologic assays were performed by a person blinded to the experimental groups. BCH4 and BC cells were bound to the solid phase on Immulon II 96-well plates (NUNC, Denmark). Serial diluted mouse serum samples were added to each well. Plates were incubated, washed, and goat anti-murine IgG1 or IgG2a conjugated to alkaline phosphatase (Southern Biotechnology, Birmingham, Ala.) diluted 1:1000 was added, respectively. After another incubation, plates were washed and substrate was added for 30 minutes at room temperature and OD405 was determined (Graham, B. S., et al, Immunol. 151:2032 (1993); Tang, Y.-W., et al, J. Clin. Invest. (1994)). A serum dilution was consid...

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Abstract

A method is disclosed of reducing viral replication of a virus of the paramyxoviridae family in a host, comprising administering to the host an antigen of the virus in combination with an effective adjuvant amount of interleukin-12 (IL-12). Human viruses of the paramyxoviridae family include paramyxoviruses (e.g., parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3 and parainfluenza virus 4), morbilliviruses (e.g., measles virus) and pneumoviruses (e.g., respiratory syncytial virus); other non-human viruses of the paramyxoviridae family include canine distemper virus, bovine respiratory syncytial virus, Newcastle disease virus and rhinderpest virus. A composition is also disclosed comprising a mixture of an antigen of a virus of the Paramyxoviridae family and an effective adjuvant amount of interleukin-12 (IL-12).

Description

RELATED APPLICATION(S) [0001] This application is a Continuation of U.S. application Ser. No. 08 / 980,160 filed on Nov. 26, 1997, which is a Continuation of U.S. application Ser. No. 08 / 318,480 filed on Oct. 5, 1994. The entire teachings of U.S. application Ser. No. 08 / 980,160 and U.S. application Ser. No. 08 / 318,480 are incorporated herein by reference.GOVERNMENT SUPPORT [0002] The invention was supported, in whole or in part, by a grant ROA-AI-33933 from the National Institutes of Health. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] Respiratory syncytial virus (RSV), a member of the Pneumovirus genus of the Paramyxoviridae family, is an important cause of respiratory disease in infants and children (Connors, M., et al., J. of Virol., 66:7444-7451 (1992). The immunological basis for the differing susceptibility among individuals, and for the limited age range at which severe illness occurs, remains unclear. [0004] The major impediment to adva...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K39/12A61K38/00A61K39/155A61K39/165A61K39/17A61K39/175A61K39/39
CPCA61K39/155A61K39/39A61K2039/55538A61K2039/5252C07K16/1027C12N2760/18534C07K2317/52A61K2039/57A61K39/12A61P31/14
Inventor GRAHAM, BARNEY S.TANG, YI-WEI
Owner VANDERBILT UNIV
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