TYPES OF HIV VACCINES

Whole virus vaccines

The advantage of using an inactivated whole virus preparation for a vaccine rather than a subunit preparation is that in a case like HIV-1 where the parameters of immunity aren’t clearly delineated, you don’t risk leaving out any antigens that are critical to mounting a protective immune response against the virus. However, vaccine safety has been prioritized over efficacy in the case of the HIV, because there is tremendous fear that the virus particles may not be wholly inactivated and will retain infectious genetic material, thereby helping to transmit rather than protect against this pathogen. The second issue is that even though techniques have been developed to fully inactivate any remaining nucleic acids, the lack of a suitable animal model in which we can prove that the preparation is free of any infectious HIV prevents such a vaccine from ever being licensed.

Envelope Proteins

Envelope proteins have been a real focal point in vaccine development because important T-cell epitopes and neutralizing epitopes have been found to be located on the envelope proteins. Envelope HIV vaccines have been developed through recombinant DNA expression systems since they provide an easy means to produce mass quantities of purified proteins without the risk of contamination with other HIV products.

Synthetic Peptides

Another approach is to generate synthetic peptides that only contain the epitopes of interest rather than the whole gp160 or gp 120 proteins themselves. This allows vaccine developers to only include the epitopes that are important for a protective response and to exclude minor or even potentially deleterious epitopes (eg. epitopes involved with the enhancement of infection of immunopathogenesis). One setback, however, is that synthetic peptides tend not to be as immunogenic as the whole proteins, and so more potent adjuvants will need to be investigated. Also, these peptides won’t stimulate immune responses to noncontiguous epitopes, or epitopes that are dependant on molecular confirmation.

Internal or Core Proteins

These have received far less attention from researchers even though they are probably very important in the generation of cell-mediated immune responses, particularly with CTLs and neutralizing antibodies.

Attenuated Virus Vaccines

Live, attenuated virus vaccines mimic natural exposure while avoiding disease, in the expectation that immunologic memory and lifelong immunity will be induced, just as in youngsters who recover from the usual childhood infections. These vaccines effectively induce both humoral and cell-mediated immunity, and generally require only one or two immunizations, since the immune responses they induce are very durable. While most licensed vaccines in use today for other diseases are based on this concept, formidable safety concerns have limited research on live, attenuated HIV vaccines in humans. Safety issues include the possibilities that: a] the attenuated vaccine itself could cause AIDS after a long time, at least in some individuals; b] the vaccine could revert to the wild-type, rapidly causing disease; c] long-term persistence of the attenuated vaccine could cause autoimmune or malignant disease. Extensive experimentation with the live-attenuated vaccine concept for AIDS has been done using SIV in macaques. These studies have shown that either naturally-occurring attenuated viruses or ones created by deletion of one or more genes can serve as vaccines. In the SIV macaque model, protection is effective against rectal as well as intravenous routes of transmission, but efficacy appears to vary inversely with the level of attenuation of the vaccine. Despite extremely low levels of replication of the vaccine, the vaccine genome evolves. Larger deletions develop, and a duplication of an LTR element has been observed.

Nucleic Acid Vaccines

DNA immunization uses the genes for viral antigens, rather than the antigens themselves, as the source of immunogen. In DNA immunization, the host is immunized by direct administration of viral genes; the genes are composed of DNA that encode for the antigen that would normally be produced by the cell infected with the virus. The vaccinee's cells take up the DNA and produce viral antigen by normal cellular mechanisms. The newly-formed antigen is then presented on the cell surface with host MHC class I and class II molecules where contact with immunocompetent cells evokes an immune response. Several experimental DNA vaccines for HIV/AIDS have been produced and tested in small animals and non-human primates. In general, the results of these studies have been quite promising. DNA vaccines delivered intramuscularly or by gene gun have been shown to induce both neutralizing antibodies and CTL responses against HIV and SIV antigens.

Live Vectors

Live recombinant vector vaccines are constructed by inserting HIV or SIV genes into live, infectious, but non-disease-causing viruses or bacteria such as vaccinia virus or Bacille Calmette-Guerin (BCG). These vaccines are produced by engineering viral or bacterial genomes to express the desired HIV antigen. Recombinant viral vectors enter cells and allow the HIV or SIV proteins to be generated inside the cells; these proteins are then presented to the immune system in the same way that proteins from a virus-infected cell would be. As a result, vector-based vaccines induce both humoral and cellular immune responses. Some live vectors such as vaccinia virus are also resistant to environmental inactivation, which is a real advantage since most of these vaccines are needed in field conditions in developing countries.
The poxviruses vaccinia and canarypox are two of the most highly favored vector viruses since they are well characterized, have large DNA genomes for the incorporation of multiple target antigens, and can infect many different cell types. Stable constructs have been produced carrying various permutations of the HIV-1 gag, pol and env genes, and are currently undergoing clinical trials. Other vectors that are being considered include adenovirus, poliovirus, salmonella and BCG (bacilli Calmete-Guerin). The Venezuelan equine encephalitis virus is also up for special consideration because it has a tropism for dendritic cells and can stimulate high titers of both systemic immunity and local IgA production.
The antibody response to some live vector experimental vaccines can be substantially augmented by subsequent boost with recombinant subunit protein vaccines. In addition, some live vector vaccines may be capable of generating a mucosal immune response. One of the drawbacks however is that since immune responses are generated to both the vector and the incorporated antigens, immune responses to the vector could limit the effectiveness of subsequent immunizations using the same vector. Another big concern is that vaccinia can cause serious illness in immuosuppressed persons or those with eczematoid skin disorders, either if they are directly immunized or through spread from immunization of people around them. Canarypox, on the other hand, is a better candidate since it only ever undergoes a single non-infectious replicative cycle in human hosts, and so cannot cause either disease or transmission. The trade-off is that is is significantly less immunonogenic than the vaccinia vector.

Live recombinant vector vaccines are constru