The Virosomal Vaccine Approach

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Vaccines Have Serious Side Effects

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The most significant impediment to the use of synthetic peptides as vaccines has been that they are only weak or nonimmunogenic when injected by themselves into animals (3,4). This property has necessitated the use of carriers, usually large, highly "immunogenic" proteins, to which the peptides are covalently coupled. These carriers, although helpful in producing an initial antibody response, have no relationship to the pathogen against which the vaccine is designed and therefore do not elicit pathogen-specific T-cell help. Therefore, when an individual who has been vaccinated with a peptide-carrier complex is challenged with the pathogen, a primary rather than a secondary (faster, stronger, higher affinity) response results. Also, booster immunizations often lead to a stronger antibody response to the carrier and a diminishing one to the peptide. In addition, these peptide-carrier complexes must usually be combined with other adjuvants (for example, Freund's) to enhance the response to the peptide. These adjuvants frequently induce undesirable side effects which make them unacceptable for use in humans (3-14).

It has been hypothesized that anchorage of a peptide in a liposomal bilayer might mimic the normal presentation of antigen on an infectious agent (i.e., multivalent and projecting outward from an anchor on the surface of the cell) and thereby potentiate the immune response to the peptide. To test this hypothesis, peptides were covalently linked to a phospholipid, providing a hydropho-bic anchorage into the phospholipid bilayer.

It has been found that when molecules capable of stimulating T-helper cells (either viral envelope proteins or peptides representing defined Th cell epitopes) are integrated into the same phospholipid matrix as a B-cell epitope, a highly efficient immunogen is produced (15,16). Sequences not recognized by T-helper cells do not elicit antibody responses, even when formulated into peptide-phospholipid complexes (17).

Current concepts regarding the mechanisms through which peptide epitopes are presented to CD8+, major histocompatibility complex (MHC) Class I -restricted cytotoxic T lymphocytes (CTL) indicate that a crucial aspect of this process is the capacity to introduce antigen into the cytoplasm (but not endosomes) of antigen-presenting cells (18). This explains, at least in part, the success of live-attenuated and live-vector vaccines for stimulating cell-mediated immune responses.

In order to obtain a similar mechanism, methods have been introduced for integrating lipid-linked peptides (membrane proteins) into the lipid bilayer of large, mainly unilamellar liposomes (19). For example, glycoproteins of influenza and parainfluenza type I (Sendai) viruses maintain their receptor-binding activities and receptor-induced endocytosis when reconstituted into protein lipid vesicles (virosomes) (20,21). In addition, water-soluble materials can be encapsulated within the aqueous interior of such vesicles at high efficiency. It could even be shown that these vesicles act as effective delivery vehicles for drugs, proteins, and DNA. Using a liposome based system they were employed to achieve the first stable gene transfer in animals (22,20).

Virosomes proved to also be highly effective immunogens in mice, rabbits, and monkeys (23,24). This included the ability to stimulate strong CD8+ CTL responses to lipid bilayer-integrated glycoproteins or lipid-linked peptides, as well as to encapsulated peptides, proteins, and formalin-fixed whole viruses (17,23,24).

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