Vaccines containing non-ionic surfactant vesicles

Details Vaccines containing non-ionic surfactant vesicles Vaccines containing non-ionic surfactant vesicles

1995-01-05

1997-10-21

Housel, James C.

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

4242801, 424450, 4284022, A61K 4500, A61K 910, A61K 4505, A61K 4700

Patent

active

056793553

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention concerns improvements in or relating to vaccines and more particularly relates to a novel adjuvant for use e.g. in vaccines containing synthetic antigens.
Many successful human and veterinary vaccines employ attenuated living pathogens. However, recent studies with a whole range of pathogenic infections have identified potentially protective, species-specific antigens which can be produced in bulk using recombinant DNA technology and improved culturing, harvesting and purifying techniques. It is also now feasible to produce wholly synthetic peptide antigens which mimic significant epitopes of a natural antigen. Subunit vaccines are vaccines which contain only certain antigenic parts of the pathogen ie. can include antigenic proteins or individual peptide epitopes. Suitable peptides may be designed by computer modelling techniques. Such synthetic antigens have many potential advantages, including purity, stability, a high level of protection, specificity and a guaranteed lack of any pathogenic properties as are sometimes seen with vaccines containing attenuated pathogens.
Unfortunately, antigens of low molecular weight, whether made by chemical synthesis or by recombinant means, exhibit an inherently low antigenicity; in general, they are weak stimulators of the immune response. Even after conjugation to a carrier protein such as purified protein derivative of tuberculin (PPD) their immunogenicity is often inadequate to elicit an adequate response.
This problem can be overcome by the use of adjuvants, but such adjuvants introduce further difficulties. The only adjuvant currently licensed for use in man is aluminium hydroxide. However aluminium hydroxide is not considered to be an adequate adjuvant for all antigens as it does not boost cell-mediated immunity (CMI), an essential property if a vaccine is to be successful against intracellular pathogens such as Leishmania and Toxoplasma. Freund's Complete Adjuvant (FCA) does stimulate cellular immunity but is unsuitable for human or veterinary use as it promotes granuloma formation, adhesions, and other toxic side effects. FCA also produces a local inflammatory reaction which can persist for months. There is an urgent need for new non-toxic adjuvants which promote cell-mediated immunity (CMI), preferably to a level comparable with that seen with FCA. Indeed, such adjuvants will be essential if the full potential of subunit vaccines is to be realised.


SUMMARY OF THE INVENTION

We have now discovered that non-ionic surfactant vesicles (NISV) with entrapped antigen act as potent immunological adjuvants, even with shorter peptide antigens which inherently provoke a weak immune response. Indeed we have observed antibody titres of the same order of magnitude as and T cell stimulation indices greater than those using FCA as the adjuvant with, however, no evident toxicity. Also, the immune response may be altered qualitatively as well as quantitatively, as discussed more fully later herein.
The best known vesicles are liposomes having a phospholipid bi-layer. However other amphipathic molecules can be made to form vesicles, including non-ionic surfactants (NIS). Indeed such NISV have already been proposed as drug carriers, e.g. for anti-neoplastic agents such as methotrexate and doxorubicin. However, we are not aware of any recognition that NISV are able greatly to potentiate the immunological response to antigens, even when the antigen alone elicits a minimal response, as is the case with peptide antigens.
Thus in one aspect our invention provides a vaccine comprising at least one antigen, especially a peptide of synthetic or recombinant origin, entrapped in NISV.
Another aspect of our invention is a method of potentiating the immunological response, to at least one antigen in a mammalian or non-mammalian subject which comprises administering said at least one antigen entrapped in NISV.
A still further aspect of our invention is a method for preparing a vaccine which comprises entrapping at least one antigen, e.g. a peptid

REFERENCES:
patent: 4772471 (1988-09-01), Vanlerberghe et al.
patent: 4830857 (1989-05-01), Handjani et al.
patent: 5171577 (1992-12-01), Griat et al.
Gregory Gregoriadis, "Immunological adjuvants: a role for liposomes", Immunology Today, vol. 11, No 3 1990, p. 89.
Gregory Gregoriadis, Ph.D. "Medical Progress--The Carrier Potential of Liposomes in Biology and Medicine (First of Two Parts)", The New England Journal Of Medicine, Sep. 23, 1976, pp. 704-710.
A. Yekta Ozer et al., "A Novel Drug Delivery System: Non-Ionic Surfactant Vesicles" Eur J. Pharm. Biopharm 37/2 75-79 (1991).
Ruth Lifshitz, et al., "Liposomes as immunological adjuvants in eliciting antibodies specific to the synthetic polypeptide poly (LTyr, LGlu)-poly (DLAla)--poly (LLys) with high frequency of site-associated idiotypic determinants", Eur. J. Immunol. 1981 11:398-404.
A.J. Baillie, et al., "The Preparation and Properties of Niosomes--Non-ionic Surfactant Vesicles", J. Pharm. Pharmacol. 1985, 37:863-868, Received Aug. 29, 1985.

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