Researchers have created a successful vaccine strategy in mice that uses the immune system's typical antibody response to adenoviruses—which can prevent modified viruses from expressing their payloads and thus diminish the vaccine's efficacy—to actually boost the antibody response to the vaccine, they report in the current issue of the
By attaching 720 copies of an immunogenic polypeptide from
"It's a dual Trojan horse," said study coauthor Ron Crystal, whose earlier work helped pioneer the use of adenovirus for gene transfer.
When DNA for an epitope from the pathogen is inserted into the viral genome in typical adenovirus vaccines, antigen-presenting cells such as dendritic cells are stimulated into a cellular immune response by the expression of that DNA. An adenovirus vaccine for HIV, for example, has been developed by Merck and entered phase II trials in January.
One problem with using adenovirus for gene transfer is that "you not only get immunity against the gene that you put in, but you get immunity against the capsid of the adenovirus," Crystal said. As a result, expression of transgenes inserted into the viral DNA is shut down within a week or two, and subsequent administration of the same serotype of virus doesn't boost the response. Moreover, adenovirus capsid proteins, especially the hexone that covers most of the surface, act as potent adjuvants, spurring the immune response into high gear.
In the current study, "we're taking advantage of the immunogenicity" of the capsid by building it out of a modified hexone protein that also displays the epitope, Crystal told
After administering their doubly-modified virus, the researchers detected a cellular immune response to OprF, which varied with the haplotype of the mice. When exposed to a pulmonary infection with
John Staczek and his colleagues from Louisiana State University had also used other viruses as vectors to express Epi8 as a vaccine for
"What is so clever about this approach is that they exploited the anti-capsid response [that is usually a problem]," James Wilson, of the University of Pennsylvania, told