Most antiviral vaccines currently in use consist of either live attenuated or inactivated viruses. Inactivated, or ‘killed,’ viral vaccines consist of viruses treated so that they are unable to replicate. Inactivated viruses therefore cannot produce proteins in the cytosol of infected cells, so peptides from the viral antigens are not presented by MHC class I molecules. Thus, CD8 T cells are neither efficiently generated nor needed with killed virus vaccines. Live-attenuated viral vaccines are generally far more potent: they elicit a greater number of effector mechanisms, including the activation of CD4 T cells and cytotoxic CD8 T cells. CD4 T cells help in shaping the antibody response, which is important for a vaccine’s subsequent protective effect. Cytotoxic CD8 T cells provide protection while infection by the virus itself is under way, and, if maintained, may contribute to protective memory. Attenuated viral vaccines include the routine childhood vaccines in use for polio, measles, mumps, rubella, and varicella. Other attenuated live viral vaccines that are licensed for special circumstances or for use in high-risk populations include influenza, poxvirus (vaccinia), and yellow fever virus.
Traditionally, attenuation is achieved by growing the virus in cultured cells. Viruses are usually selected for preferential growth in nonhuman cells and, in the course of selection, become less able to grow in human cells (Fig. 16.24). Because these attenuated strains replicate poorly in human hosts, they induce immunity but not disease. Although attenuated virus strains contain multiple mutations in genes encoding several of their proteins, it might be possible for a pathogenic virus strain to reemerge by a further series of mutations. For example, the type 3 Sabin polio vaccine strain differs from a wild-type progenitor strain at only 10 of 7429 nucleotides. On extremely rare occasions, reversion of the vaccine to a neurovirulent strain can occur, causing paralytic disease in the unfortunate recipient.
Attenuated viral vaccines can also pose particular risks to immunodeficient recipients, in whom they often behave as virulent opportunistic infections. Immunodeficient infants who are vaccinated with live attenuated polio virus before their inherited immunoglobulin deficiencies have been diagnosed are at risk because they cannot clear the virus from their gut, and there is therefore an increased chance that mutations associated with the continuing uncontrolled replication of the virus in the gut will revert the virus to a virulent form and lead to fatal paralytic disease.
An empirical approach to attenuation is still in use but might be superseded by two new approaches that use recombinant DNA technology. One is the isolation and in vitro mutagenesis of specific viral genes. The mutated genes are used to replace the wild-type genes in a reconstituted virus genome, and this
Fig. 16.24 Viruses are traditionally attenuated by selecting in cells of a different species, until it grows only poorly in human for growth in nonhuman cells. To produce an attenuated virus, cells. The adaptation is a result of mutation, usually a combination the virus must first be isolated by growing it in cultured human cells. of several point mutations. It is usually difficult to tell which of the The adaptation to growth in cultured human cells can cause some mutations in the genome of an attenuated viral stock are critical to attenuation in itself; the rubella vaccine, for example, was made in attenuation. An attenuated virus will grow poorly in the human host this way. In general, however, the virus is then adapted to growth and will therefore produce immunity but not disease.
Resulting virus is viable, immunogenic but avirulent. It can be used as a vaccine Isolate virulence gene Isolate pathogenic virus Mutate virulence gene Delete virulence gene receptor-binding protein virulence core proteins