Multivalent Subunit Vaccines

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One of the limitations of synthetic peptide vaccines and recombinant protein vaccines is that they tend to be poorly immunogenic; in addition, they tend to induce a humoral antibody response but are less likely to induce a cell-mediated response. What is needed is a method for constructing synthetic peptide vaccines that contain both immunodominant B-cell and T-cell epitopes. Furthermore, if a CTL response is desired, the vaccine must be delivered intra-cellularly so that the peptides can be processed and presented together with class I MHC molecules. A number of innovative techniques are being applied to develop multivalent vaccines that can present multiple copies of a given peptide or a mixture of peptides to the immune system (Figure 18-7).

VISUALIZING CONCEPTS

T-cell epitope

VISUALIZING CONCEPTS

T-cell epitope

B-cell epitope

B-cell epitope

-Monoclonal

Solid matrix-Ab-Ag complex

-Monoclonal

Solid matrix-Ab-Ag complex

(b) Detergent extracted membrane antigens or antigenic peptides

Detergent + Quil A

(b) Detergent extracted membrane antigens or antigenic peptides

Detergent + Quil A

Solid Matrix Complex

Phospholipid Detergent

ISCOM

Liposome

Phospholipid Detergent

Micelle

Micelle

ISCOM

Liposome

Phospholipid bilayer

FIGURE 18-7

Multivalent subunit vaccines. (a) Solid matrix-antibody-antigen complexes can be designed to contain synthetic peptides representing both T-cell epitopes and B-cell epitopes. (b) Protein micelles, liposomes, and immunostimulating complexes (ISCOMs) can all be prepared with extracted antigens or antigenic peptides. In micelles and liposomes, the hydrophilic residues of the antigen molecules are oriented outward. In ISCOMs, the long fatty-acid tails of the external detergent layer are adjacent to the hydrophobic residues of the centrally located antigen molecules. (c) ISCOMs and liposomes can deliver antigens inside cells, so they mimic endogenous antigens. Subsequent processing by the cytosolic pathway and presentation with class I MHC molecules induces a cell-mediated response.

(c) ISCOM delivery of antigen into cell

(c) ISCOM delivery of antigen into cell

Multivalent Subunit Vaccine

One approach is to prepare solid matrix-antibody-antigen (SMAA) complexes by attaching monoclonal antibodies to particulate solid matrices and then saturating the antibody with the desired antigen. The resulting complexes are then used as vaccines. By attaching different monoclonal antibodies to the solid matrix, it is possible to bind a mixture of peptides or proteins, composing immunodominant epi-topes for both T cells and B cells, to the solid matrix (see Figure 18-7a). These multivalent complexes have been shown to induce vigorous humoral and cell-mediated responses. Their particulate nature contributes to their increased immuno-genicity by facilitating phagocytosis by phagocytic cells.

Another means of producing a multivalent vaccine is to use detergent to incorporate protein antigens into protein micelles, lipid vesicles (called liposomes), or immunostimulat-ing complexes (see Figure 18-7b). Mixing proteins in detergent and then removing the detergent forms micelles. The individual proteins orient themselves with their hydrophilic residues toward the aqueous environment and the hydropho-bic residues at the center so as to exclude their interaction with the aqueous environment. Liposomes containing protein antigens are prepared by mixing the proteins with a suspension of phospholipids under conditions that form vesicles bounded by a bilayer. The proteins are incorporated into the bilayer with the hydrophilic residues exposed. Immunostimu-lating complexes (ISCOMs) are lipid carriers prepared by mixing protein with detergent and a glycoside called Quil A.

Membrane proteins from various pathogens, including influenza virus, measles virus, hepatitis B virus, and HIV have been incorporated into micelles, liposomes, and ISCOMs and are currently being assessed as potential vaccines. In addition to their increased immunogenicity, liposomes and ISCOMs appear to fuse with the plasma membrane to deliver the antigen intracellularly, where it can be processed by the cytosolic pathway and thus induce a cell-mediated response (see Figure 18-7c).

SUMMARY

■ A state of immunity can be induced by passive or active immunization a) Short-term passive immunization is induced by transfer of preformed antibodies.

b) Infection or inoculation achieves long-term active immunization.

■ Three types of vaccines are currently used in humans: attenuated (avirulent) microorganisms, inactivated (killed) microorganisms, or purified macromolecules.

■ Protein components of pathogens expressed in cell culture may be effective vaccines.

■ Recombinant vectors, including viruses or bacteria, engineered to carry genes from infectious microorganisms, maximize cell-mediated immunity to the encoded antigens.

■ Plasmid DNA encoding a protein antigen from a pathogen can serve as an effective vaccine inducing both humoral and cell-mediated immunity.

■ Realizing the optimum benefit of vaccines will require cheaper manufacture and improved delivery methods for existing vaccines.

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