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HIV vaccine

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There is no known cure for AIDS and so 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 has been limited to the generation of huge volumes of research data.

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Problems with HIV vaccine research

Research into HIV vaccines has a number of problems. There are two key issue 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.

Other problems are 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 usually 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 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 ealier results were discouraging. Research has identified certain HIV glycoproteins as potentially valuble 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 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 gp140[?]/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 is 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.

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-na´ve 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 peripheral blood mononuclear cells[?] infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. In addition, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. A phase II trial of vCP205 and gp120 (SF2) was concluded last summer and demonstrated the safety and immunogenicity of that combination in individuals at higher risk of HIV infection. This trial also demonstrated that risk taking behavior did not increase overall among trial volunteers, all of whom had received repeated counseling on how to minimize their risk of HIV infection.

As canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses, the first phase I trial of a candidate vaccine in Africa was launched early in 1999 in Ugandan volunteers, and determine the extent to which Ugandan volunteers have CTL that are active against the subtypes of HIV prevalent in Uganda, A and D.

Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, lipopeptides, p24, etc. (Table 2). To date, none has proven as effective in eliciting human CTL and/or antibody as the recombinant canarypox-envelope combination. Other approaches to improve the immunogenicity of DNA vaccines are being pursued and may enter phase I trials over the next few years.

In summary, clinical trials of candidate HIV vaccines have been informative. In the absence of validated correlates of immune protection, larger trials of the most promising candidates will be needed.

At the same time as promising candidates advance to efficacy trials, there does appear to be room for improvement. Specifically, candidate vaccines that induce one or more of the following are being sought:

  • broadly neutralizing antibody against HIV primary isolates;
  • cytotoxic T cell responses in a vast majority of recipients;
  • strong mucosal immune responses.

Novel approaches, including modified vaccinia Ankara[?] (MVA), adeno-associated virus[?], Venezuelan Equine Encephalitis[?] (VEE) replicons, and codon-optimized DNA have proven to be strong inducers of CTL in macaque models, and have provided at least partial protection in some models. Most of these approaches are, or will soon, enter clinical studies.

New information on the nature of the interaction of the HIV envelope with the cell surface during the binding, entry and fusion process has led to new ideas about how to improve envelope immunogenicity.

Other strategies being pursued include:

  • envelope interacting with one or both receptors, either in the form of a fusion protein or complexes or co-expressed proteins;
  • oligomeric envelope;
  • disulfide stabilized envelope;
  • envelope in which one or more variable regions are deleted;
  • partially de-glycosylated envelope;
  • truncated forms to increase expression on the cell surface.

Some of the text above was taken from the NIAID document "HIV Vaccine Development Status Report May 2000" taken from http://www.niaid.nih.gov/daids/vaccine/whsummarystatus.htm which, as a work of a US Federal Government agency without any other copyright notice, should be in the public domain

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