Lipid and Nitrous Oxide Combination as Adjuvant for the Enhancement of the Efficacy of Vaccines

Abstract

The invention provides for a method of enhancing immunological responses to an antigen in a vaccine formulation, and for a vaccine formulation that provides for an enhanced immunological response to an antigen. In the method and formulation the antigen is administered with an adjuvant which adjuvant comprises a solution of nitrous oxide gas in a pharmaceutically acceptable carrier solvent for the gas and which adjuvant includes at least one fatty acid or ester or other suitable derivative thereof selected from the group consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid [C20: 5ω3], decosahexaenoic acid [C22: 6ω3], ricinoleic acid and derivatives thereof selected from the group consisting of the C1 to C6 alkyl esters thereof, the glycerol-polyethylene glycol esters thereof and the reaction product of hydrogenated natural oils composed largely of ricinoleic acid based oils, such as castor oil with ethylene oxide.

Description

FIELD OF THE INVENTION[0001]This invention relates to pharmaceutical preparations (which expression is herein intended to include veterinary preparations) for use in the prevention of disease by inoculation against infective organisms afflicting the animal body (which expression is herein intended to include the human body).BACKGROUND TO THE INVENTION[0002]In EP 93912877.3 and U.S. Pat. No. 5,633,284 and their equivalents there is disclosed that dermatological or topical compositions comprising the combination of nitrous oxide [N2O] and at least one fatty acid, or lower alkyl ester thereof, in a dermatologically acceptable carrier medium, are useful in the treatment of a variety of skin, muscle and joint disorders. It further disclosed therein that such combinations might beneficially also include additional active ingredients. The following active ingredients are specifically mentioned in this regard: coal tar solution, collagen, nicotinamide, nicotinic acid, lanolin, vitamin E, me...

AI Technical Summary

Benefits of technology

[0114]The high loading efficiency of the particles can be demonstrated by the high degree of entrapment of dipthteria toxoid (DT) and inactivated rabies viruses in particles according to the present invention as were illustrated by Confocal Laser Scanning Microscopy (CLSM). The inactivated viruses were a generous gift from the SA State Vaccine Institute, now the BIOVAC Institute.

[0116]The particles of the invention seem to act as an absorption mechanism in the case of nasal and oral administration and a transport mechanism in the case of parenteral administration to deliver antigens to immune competent cells. The delivery efficiency relates to tissue penetration, cell adsorption, interaction between the components of the cell membrane and the particles, internalisation of particles by cells, and intra-cellular stability.

[0118]The result of high delivery efficiency is the release of antigens not only at membrane sites, but also at intracellular sites, resulting in an enhanced efficacy of said vaccine. The particles act in synergism with the antigen to attain enhanced immunogenicity. The release rate of the particles is influenced by their composition. Prolonged and / or controlled release particles may be used with the aim of combining the prime and boost elements of vaccination.

[0121]The unsaturated long chain fatty acid component contributes to cell integrity by its contribution to membrane maintenance. The nitrous oxide component of the particles of the present invention enhances membrane fluidity, which presumably has a positive effect on adsorption, absorption and other membrane bound processes. The composition of the invention has been found to have beneficial effects on the immunogenecity of antigens.

[0124]It has been shown that particle inter-lipid and particle / cell relationships do exist. The particles can combine to resize themselves continuously without detriment to their stability. These interactive membrane characteristics make the movement of the vesicles through the cells optimal.

Problems solved by technology

While microbicides may usefully extend prevention options and serve as valuable prototypes for vaccine development, it is not clear that these can be delivered sustainably to everyone at risk.

A major hindrance that has prevented the development of effective mass immunization programs is the inability to induce an appropriate, protective, immune response.

Such a response can be extremely difficult to elicit, especially by recombinant, soluble protein subunits.

This deficiency is due to the inability of these antigens to access the machinery of the appropriate antigen-processing pathway.

Furthermore, products given by syringe are inherently more expensive than those which can be taken by mouth or—for example—as a nasal spray.

The danger of re-use of needles in underdeveloped countries is a compounding factor.

Despite the urge for an efficient mucosal vaccine, its introduction is still hindered by the degradation of antigens during transport to and low uptake by the mucosal associated lymphoid tissue (MALT).

Oral vaccination is firstly complicated due to degradation of antigens by both the acidic environment in the stomach and the enzymes in the gut.

Moreover, the soluble antigens are not always taken up efficiently by the M-cells of the gut associated lymphoid tissue (GALT).

Nasal vaccination is mainly complicated by the fast clearance of the antigen and the low uptake by the nasal associated lymphoid tissue (NALT).

These types of vaccines are not safe for use in some cases.b) Inactivated or ‘killed’ vaccines.

These have still not been fully evaluated for their ability to protect against pathogens.

Sub-unit vaccines researched to date have been strain-specific and have produced poor antibody responses.

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