Understanding Replicating Viral Vectors
What are the advantages of using replicating viral vectors in AIDS vaccine research?
Many of the already licensed vaccines are based on either a weakened or killed version of the disease-causing virus or bacteria against which the vaccine is designed to protect. The vaccine against measles, for example, is a weakened version of the measles virus. This is a common approach in vaccine development and usually stimulates strong and varied immune responses.
However, this approach is not being pursued in AIDS vaccine research because of safety concerns. HIV can mutate rapidly and extensively and researchers are concerned that an attenuated or killed version of HIV may recover or retain its ability to cause disease once inside the body. As it is not feasible to develop a preventive AIDS vaccine using this approach, researchers have explored alternative strategies. One of these is using other viruses as delivery systems or vectors (see VAX September 2004 Primer on Understanding Viral Vectors). The virus particles used as vectors are weakened, or attenuated, by researchers so that they can't cause disease, and are also manipulated so that instead of containing their own genes, they carry fragments of HIV. These virus vectors shuttle the HIV fragments or immunogens into human cells, where they are then presented to the immune system. This triggers an immune response against HIV. These viral vector-based AIDS vaccine candidates include only parts of the virus and therefore can not cause HIV infection.
Most of the current AIDS vaccine candidates in clinical trials utilize viral vectors to induce cellular immune responses against HIV. The STEP and Phambili trials both used a candidate based on adenovirus serotype 5 (Ad5; see VAXOctober-November 2007 Spotlight article, A STEP back?). The naturally-circulating form of this virus is one of many that cause the common cold, but the version used as a vector is intentionally attenuated so that it can not cause disease. The Ad5-based vector tested in these trials, as well as others being tested, was also modified by researchers to carry HIV immunogens and was further attenuated by genetic modification so that it could not replicate or multiply. All viruses cause infection and disease by infecting cells and then using the cell's machinery to churn out multiple copies of the virus. This is referred to as replication. Copies of the virus that are produced can then infect other cells—setting off an infectious cycle. Researchers prevent the Ad5 vector from replicating once it enters the body by removing a single gene from the virus.
This means that each Ad5 particle used as a vector could infect only a single cell and present the HIV immunogens it carries only once before the vector is processed and the infected cells are destroyed by the immune system. Each dose of the vaccine candidate contains a billion or more Ad5 particles, meaning an equivalent number of cells could be infected. This may sound like a large number, but using non-replicating vectors substantially limits the immune system's exposure to HIV and therefore the magnitude of HIV-specific immune responses that can be induced. The outcome of the STEP trial showed that this specific Ad5 vector was not effective at providing any level of protection against HIV. It is still unclear why this vaccine candidate failed, but even before these disappointing results, researchers had started exploring alternative strategies for developing AIDS vaccine candidates.
One of these strategies is using viral vectors that retain their ability to replicate. This type of vector could greatly increase the amount of cellular immune responses generated against HIV. With a replicating virus as a vector, many more cells would be infected, increasing the immune system's exposure to the HIV immunogens included in the vector and potentially increasing the immunogenicity of the vaccine candidate (see VAX August 2007 Primer onUnderstanding Immunogenicity).
To develop a replicating viral vector, researchers manipulate the viruses so that they are unable to replicate at their full capacity and therefore can't cause disease. For some viruses, researchers remove some of their genetic material, which in turn slows down their replication rate and minimizes their ability to cause disease. This allows the immune system to eventually catch up, typically within a few weeks, and rid the body of the viral vector. AIDS vaccine researchers are also studying several animal viruses that do not naturally infect humans and therefore do not replicate as well in human cells.
Some of the replicating viral vectors that are currently being studied include vesicular stomatitis virus or VSV, which primarily infects cattle; sendai virus, which infects rodents; and an attenuated strain of measles virus. Some research groups are also studying serotypes of adenoviruses that retain their ability to replicate.
So far no AIDS vaccine candidates based on replicating viral vectors have entered clinical trials, but many researchers are hopeful that replicating viral vectors will improve the efficacy of AIDS vaccine candidates that induce primarily cellular immune responses. Although it is unlikely that cellular immune responses alone will be sufficient to protect against HIV infection, after the recent results of the STEP trial researchers are looking for vaccine candidates that will induce more robust immune responses that can provide some level of partial protection against HIV infection (see VAX May 2007 Primer on Understanding Partially Effective AIDS Vaccines).
But safety is also a concern. Although replicating viral vectors will be attenuated so that they are unable to cause disease, there is still some concern amongst regulatory agencies about the potential risks associated with this approach. Further study of these vectors will be essential to sorting out any possible safety issues.