HIV vaccine
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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.
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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 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, as work with monoclonal antibodies (MAb) has proven. 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.
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 temporarily.
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. 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.
On November 16, 2004, researchers at the French Institut Pasteur announced that they had been able to induce antibodies to significantly block HIV from infecting human cells, an achievement hailed as an important step towards an HIV vaccine. (365gay.com) (http://www.365gay.com/newscon04/11/111604AIDS.htm)
On December 1, 2004, Swedish media announced that a new vaccine will be tested on 40 volunteers. If the new method is successful, vaccines will be performed in Tanzania next year.
On March 13. 2005, China announced it began human trials for an AIDS vaccine. 49 volunteers between the ages of 18 and 50 would receive the vaccine.
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. 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.
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. As canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses,
Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, lipopeptides, p24, etc. 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.
Economics of vaccine development
External links
- NIAID HIV vaccine site (http://www.niaid.nih.gov/daids/vaccine/default.htm)
- Global Alliance for Vaccines and Immunization (GAVI) (http://www.vaccinealliance.org)
- International AIDS Vaccine Initiative (IAVI) (http://www.iavi.org)
- AIDS Vaccine Advocacy Coalition (AVAC) (http://www.avac.org)
- Investigation of first candidate vaccine (http://briandeer.com/vaxgen-aidsvax.htm)
- Vaccines for Development (http://blogs.cgdev.org/vaccine)