Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1995-02-17
1998-05-12
Smith, Lynette F.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4241841, 4241881, 4242041, A61K 3900, A61K 3921, A61K 3938
Patent
active
057501106
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel vaccine formulations, to methods for their production and to their use in medicine. In particular, the present invention relates to vaccines containing QS21, an Hplc purified non-toxic fraction derived from the bark of Quillaja Saponaria Molina, and 3 De-O-acylated monophosphoryl lipid A (3 D-MPL).
3 De-O-acylated monophosphoryl lipid A is known from GB2220 211 (Ribi). Chemically it is a mixture of 3-deacylated monophosphoryl lipid A with 4, 5 or 6 acylated chains and is manufactured by Ribi Immunochem Montana.
QS21 is a Hplc purified non-toxic fraction of a saponin from the bark of the South American tree Quillaja saponaria molina and a method for its production is disclosed (as QA21) in U.S. Pat. No. 5,057,540.
The present invention is based on the surprising discovery that formulations containing combinations of QS21 and 3 D-MPL synergistically enhance immune responses to a given antigen.
For example, a vaccine formulation of the malarial antigen, RTS, S in combination with 3D-MPL and QS21 results in a powerful synergistic induction of CS protein-specific cytotoxic T lymphocyte (CTL) response in the spleen.
RTS is a hybrid protein comprising substantially all the C-terminal portion of the circumsporozoite (CS) protein of P. falciparum linked, via four amino acids of the preS.sub.2 portion of Hepatitis B surface antigen, to the surface (S) antigen of hepatitis B virus. Its full structure is disclosed in co-pending International Patent Application No. PCT/EP92/02591, published under Number WO 93/10152 claiming priority from UK patent application No.9124390.7. When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S.
The observation that it is possible to induce strong cytolytic T lymphocyte responses is significant as these responses, have been shown to induce protection against disease in certain animal models.
The present inventors have shown that the combination of the two adjuvants QS21 and 3D-MPL with the recombinant particulate antigen RTS,S results in a powerful induction of CS protein-specific CTL in the spleen. QS21 also enhances induction of CTL on its own, while 3D-MPL does not. The combination can be said to act in a synergistic way, because it has an effect that is larger than the sum of the separate effects of each adjuvant. The synergy between these two adjuvants for CTL induction is a surprising observation which has important implications for the use of recombinant molecules as vaccines for induction of CTL-mediated immunity.
Induction of CTL is easily seen when the target antigen is synthesised intracellularly (e.g. in infections by viruses, intracellular bacteria, or in tumours), because peptides generated by proteolytic breakdown of the antigen can enter the appropriate processing pathway, leading to presentation in association with class I molecules on the cell membrane. However, in general, pre-formed soluble antigen does not reach this processing and presentation pathway, and does not elicit class I restricted CTL. Therefore conventional non-living vaccines, while eliciting antibody and T helper responses, do not generally induce CTL-mediated Immunity. The combination of the two adjuvants QS21 and 3D-MPL can overcome this serious limitation of vaccines based on recombinant proteins, and induce a wider spectrum of immune responses.
CTLS specific for CS protein have been shown to protect from malaria in mouse model systems (Romero et al. Nature 341:323 (1989)). In human trials where volunteers were immunised using irradiated sporozoites of P. falciparum, and shown to be protected against subsequent malaria challenge, induction of CTL specific for CS epitopes was demonstrated Malik et al. Proc. Natl. Acad. Sci. U.S.A. 88:3300 (1991)),.
The ability to induce CTLs specific for an antigen administered as a recombinant molecule is relevant to malaia vaccine development, since the use of irradiated sporozoites would be impractical, on the groun
REFERENCES:
patent: 4877611 (1989-10-01), Cantrell
patent: 4912094 (1990-03-01), Myers et al.
patent: 5057540 (1991-10-01), Kensil et al.
Allison, et al., "Immunological Adjuvants and Their Mode of Action", Biotechnology 20, pp. 431-449 (1992).
Roberts, et al., "Active Immunization of Beef Heifers Against Luteinizing Hormone . . . " J. Animal Science, 68, pp.:3742-3746 (1990).
Butini, et al, 1994, "Comparitive Analysis of . . . " J. Cell Biochem. Suppl. 18B, Abstract J306.
Cohen, 1993, "Jitters Jeopardize AIDS . . . " Science 262:980-981.
Long, et al, 1984, "Glycoprotein D protects M16 . . . " Infection and Immunity 37(2):761-764.
Schneerson, et al, 1991, "Evaluation of mono . . . " J. Immunol. 147(7):2136-2140.
Weiss, et al, 1988, "CD8+T cells . . . are . . . " PNAS 85:573-576.
Schofield, et al, 1987, "r Interferon CD8+ T Cells . . . " Nature 330:664-666.
Garcon-Johnson Nathalie Marie-Josephe Claude
Pala Pietro
Prieels John Paul
Slaoui Moncef
Kerekes Zoltan
Lentz Edward T.
Smith Lynette F.
SmithKline Beecham Biologicals, s.a
Venetianer Stephen
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