Recombinant Vector Vaccines

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Genes that encode major antigens of especially virulent pathogens can be introduced into attenuated viruses or bacteria. The attenuated organism serves as a vector, replicating within the host and expressing the gene product of the pathogen. A number of organisms have been used for vector vaccines, including vaccinia virus, the canarypox virus, attenuated poliovirus, adenoviruses, attenuated strains of Salmonella, the BCG strain of Mycobacterium bovis, and certain strains of streptococcus that normally exist in the oral cavity.

Vaccinia virus, the attenuated vaccine used to eradicate smallpox, has been widely employed as a vector vaccine. This large, complex virus, with a genome of about 200 genes, can be engineered to carry several dozen foreign genes without impairing its capacity to infect host cells and replicate. The procedure for producing a vaccinia vector that carries a foreign gene from a pathogen is outlined in Figure 18-5. The genetically engineered vaccinia expresses high levels of the inserted gene product, which can then serve as a potent immunogen in an inoculated host. Like the smallpox vaccine, genetically engineered vaccinia vector vaccines can be administered simply by scratching the skin, causing a localized infection in host cells. If the foreign gene product expressed by the vaccinia is a viral envelope protein, it is inserted into the membrane of the infected host cell, inducing development of cell-mediated immunity as well as antibody-mediated immunity.

Other attenuated-vector vaccines may prove to be safer than the vaccinia vaccine. The canarypox virus has recently been tried as a vector vaccine. Like its relative vaccinia, the ca-narypox virus is large and easily engineered to carry multiple

Vector Vaccine
Cleavage and ligation

from the bacterium that causes cholera. The advantage of this vector vaccine is that Salmonella infects cells of the mucosal lining of the gut and therefore will induce secretory IgA production. Effective immunity against a number of diseases, including cholera and gonorrhea, depends on increased production of secretory IgA at mucous membrane surfaces. Similar strategies using bacteria that are a normal part of oral flora are in development. The strategy would involve introduction of genes encoding antigens from pathogenic organisms into bacterial strains that inhabit the oral cavity or respiratory tract. Eliciting immunity at the mucosal surface could provide excellent protection at the portal used by the pathogen.

Vaccinia promoter

TK gene

Gene from pathogen TK gene

Recombinant plasmid

Vaccinia virus Transfection Infection

1 fl Tissue-culture cells

Homologous recombination

BUdr selection

BUdr selection

Recombinant vaccinia vector vaccine

Recombinant vaccinia vector vaccine

FIGURE 18-5

Production of vaccinia vector vaccine. The gene that encodes the desired antigen (orange) is inserted into a plasmid vector adjacent to a vaccinia promoter (pink) and flanked on either side by the vaccinia thymidine kinase (TK) gene (green). When tissue-culture cells are incubated simultaneously with vaccinia virus and the recombinant plasmid, the antigen gene and promoter are inserted into the vaccinia virus genome by homologous recombination at the site of the nonessential TK gene, resulting in a TK~ recombinant virus. Cells containing the recombinant vaccinia virus are selected by addition of bromodeoxyuridine (BUdr), which kills TK+ cells. [Adapted from B. Moss, 1985, Immunol. Today 6:243.]

genes. Unlike vaccinia, the canarypox virus does not appear to be virulent even in individuals with severe immune suppression. Another possible vector is an attenuated strain of Salmonella typhimurium, which has been engineered with genes

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