HIV vaccine
There is no known cure for AIDS and so the search for a vaccine against the causative agent, HIV, has become part of the struggle against the disease. Like the curative research there has been considerable hype over individual efforts, changing fashionable fields. Real achievements to date have been limited to the generation of huge volumes of research data.
Problems with HIV vaccine research
Research into HIV vaccines has a number of problems. There are two key issues that protect HIV from vaccines. First is that of selective pressure quickly neutralising early promise, the falling off of immune response is called anergy. HIV responds rapidly to these pressures, as is recorded by the HIV Variation Project. From human isolates it has been discovered that HIV currently has three groups of clades, M, N and O. Nine clades have been identified in M but less in the others. The earliest vaccine were based on the LAI clade, which was discovered to be rare in human infections. The second problem with HIV is its attack on the immune system itself which means that, to date, no effective cell-mediated immune response has been determined.
The lack of a quality animal model has also impacted research, as has the multi-path internal transmission method of HIV which requires the immune response to be stimulated at a number of levels.
The typical animal model for vaccine research is the monkey, often the macaque. The monkeys can be infected with SIV or the chimeric SHIV for research purposes.
The human body can defend itself against HIV, work on monoclonal antibodies (MAb) proved that. That certain individuals can be asymptomatic for decades after infection is encouraging.
Research achievements
Research supports the contention that a safe and effective vaccine is possible. Vaccines against other diseases where correlates were not known and where there were no ideal animal model have been developed. Experimental HIV/AIDS vaccines have proven efficacious to varying degrees in stringent animal model tests that use virus challenges that are significantly higher than what is believed to occur in most human exposures. Third, most HIV is transmitted heterosexually, which is known to be less efficient than parenteral exposure. Finally, individuals who become infected with HIV do not succumb to the disease for years even in the absence of anti-retroviral therapy, suggesting that the human immune system is capable of controlling HIV infection partially or temporally.
Enormous effort has been put into understanding how HIV works, it has produced a number of approaches to vaccination, none of which have been effective. Methods attempted include recombinant proteins, synthetic peptides, recombinant viral vectors, recombinant bacterial vectors, recombinant particles, DNA vaccines to induce production of a specific antigen, and whole-killed and live-attenuated HIV, though these latter two have not progressed into clinical trials in uninfected individuals due to an unfavorable benefit/risk ratio. The role of broadly neutralising antibodies (NAb) is under investigation, although earlier results were discouraging. Research has identified certain HIV glycoproteins as potentially valuable in detecting the effect of antibodies (ELISA) or as binding points or as key in the workings of HIV. Recombinant subunit vaccines are used to investigate the HIV glycoproteins. Attacks on particular parts of the RNA code of the virus have shown some promise, such as those against the nef gene which regulates viral replication.
Clinical Trials to Date
Up to May 2000 over 60 phase I/II trials of candidate vaccines had been conducted worldwide. Most initial approaches focused on the HIV envelope protein. At least thirteen different gp120 and gp160 envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as the latter are generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced [[CD8+ cytotoxic T lymphocytes]] (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. The antibodies induced by these early envelope preparations were relatively specific for clade B isolates and rarely neutralized primary isolates of HIV.
However, as low levels of neutralizing antibody titers in some circumstances may provide protection from viral infection, bivalent preparations of gp120, based on one lab (B) and one primary isolate (B or E) of HIV, were developed by VaxGen, who sponsored phase III trials of these candidates in the U.S. and Thailand. The first large scale human trial of VaxGen's AIDSVAX®, was completed in February 2003. Although this gp120 subunit vaccine appears to be safe, it failed to work. Although the vaccination process involved many repeated "booster" injections, it was very difficult to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an HIV exposure.
In an effort to induce both CTL and antibody responses, attention has turned to evaluating a combination vaccine approach in which two types of vaccines are used. Most commonly referred to as "prime-boost", this has involved an immunization (priming) with a recombinant viral vector followed by or combined with boosting doses of recombinant protein. Three recombinant attenuated vaccinia vectors and five recombinant canarypox vectors were evaluated in phase I trials alone and in combination with a recombinant protein envelope boost. In general, vaccinia-immune individuals have not responded as well as vaccinia-naïve individuals to vaccinia vectors, although there has been no difference in the response of these groups to recombinant canarypox vectors. All recombinant viral vectors have been safe and immunogenic to date and have been shown to prime the immune response to an envelope boost, thereby necessitating fewer doses of recombinant protein to reach maximum antibodies titers. However, the antibodies elicited in prime-boost protocols so far have a limited breadth of reactivity. One exception to this may be gp160 formulated in polyphosphazine adjuvant, which in preliminary experiments conducted by WRAIR induced antibodies with an increased ability to neutralize primary isolates. However, the technical difficulties in producing large amounts of gp160 may make it impractical to evaluate this candidate in an efficacy trial in the near future.
The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors. Increasing the complexity of the canarypox vectors by inclusion of more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increasing the dose of the viral vector. Importantly, CTLs from volunteers were able to kill modified vaccinia Ankara (MVA), adeno-associated virus, public domain
