What are some of the challenges in developing viral vector-based vaccine candidates and how are scientists trying to overcome these challenges?
Many of the current AIDS vaccine candidates that are being tested in clinical trials utilize viral vectors to shuttle HIV fragments into the body that can stimulate an immune response (see VAXSep. 2004 Primer on Understanding Viral Vectors). Some of the viral vector-based candidates are being tested in prime-boost combinations with other approaches (see Global News, this issue). Several different viruses have been used to develop vectors for HIV vaccine candidates, including adenovirus, a common cold virus, and pox viruses, such as modified vaccinia Ankara virus and canarypox, among others.
The viruses used as viral vectors are attenuated so that they cannot cause disease. They are also manipulated, so that in addition to containing their own genes they can carry HIV genes, referred to as antigens, which cannot cause an HIV infection.
The HIV genes that are placed into the viral vector are referred to as the vaccine insert. Once the vaccine candidate is injected into the body, HIV’s genetic material is taken up by cells and converted into protein that hopefully will trigger the immune system to respond to HIV. This sounds simple enough, but viral vector-based vaccine candidates present some unique design and manufacturing challenges. Because the manufacturing process is so complicated, additional effort is required to avoid delays in the clinical testing of viral vector-based vaccine candidates.
To develop viral vector-based candidates, scientists first need to design and generate the vector with the HIV insert in cells that can support virus growth. The virus vector is then amplified multiple times to produce hundreds of virus particles carrying the HIV genes, which are then subjected to extensive testing.
One of the major challenges in making viral vector-based vaccine candidates comes down to chemistry, or rather, a lack of chemistry between the vector and the insert. Sometimes the vector and the insert are simply incompatible. For instance, if the length of the insert is too long or its configuration is not suitable to the viral vector, the vector may simply reject the insert. In other cases, the virus acting as the vector may introduce mutations into the HIV genes that may prevent production of the complete protein once inside the body. These changes can ultimately impact the generation of a good immune response following vaccination. Sometimes the vector can even clip the insert, rendering it completely useless.
In some cases the vector will tolerate the insert for a while, at other times it will reject it outright. In either case it represents a setback in the production of the vaccine candidate. It is therefore important to analyze the stability of these vectors during the early stages of vaccine development. This is accomplished by subjecting these vector particles to a series of stress tests that assess whether they are stable enough to be tested in a clinical trial. The stress test evaluates the ability of these vectors to express the HIV proteins in cells and in small animals. Even after this vetting process is complete, the vector may still reject the inserts, so it is not uncommon for researchers to have to repeat this cycle several times prior to obtaining a stable vector that expresses the HIV protein and can be advanced into clinical trials.
Most of the inserts used in current viral vector vaccine candidates contain HIV gene sequences from a single virus found in a certain region of the world, or a consensus sequence generated from different viruses that are circulating in that region of the world. Because HIV replicates so rapidly, there is tremendous variation among viruses circulating in a population, and even within a single infected individual. To address this, scientists are also attempting to design HIV inserts known as mosaic antigens that are designed to address the overwhelming diversity of HIV (see VAXMarch 2009 Primer on Understanding How Inserts for Vaccine Candidates are Designed). Mosaic antigens are based on optimized genetic sequences of the many circulating strains of HIV globally and are meant to induce immune responses to a broad range of circulating strains.
To make mosaic antigens, scientists must stitch together different genetic sequences from multiple strains. These gene sequences do not exist in nature but rather are computer-generated. This makes designing and developing novel viral vector-based candidates that can carry these mosaic antigens even more challenging. Before advancing them into clinical trials, researchers will have to ensure that viral vectors carrying mosaic antigens can be obtained and manufactured at large scale, while maintaining their stability. Researchers are hoping to begin clinical trials with these vaccine candidates containing mosaic antigens soon.