Since the discovery of HIV in 1982, more than 30 vaccine candidate's have been tested in humans. The first trial started in the late 1980's in the US. All vaccines tested appeared to be generally safe and well tolerated. Only two vaccines have been tested in efficacy trials and they failed to demonstrate efficacy. Two other vaccines are currently in efficacy trials (canary pox + gp120 prime – boost in Thailand and Adeno-5 Merck in the US). This long and so far deceptive vaccine development process faces unprecedented scientific and organizational challenges, which include:
- The genetic hypervariability of the virus
- Persistence of latent proviral DNA that is invisible to the immune system
- Camouflaged conserved targets of the viral envelope glycoprotein, able to induce neutralizing antibodies against primary isolates
- Transmission of the disease by mucosal route
- Immune correlates of protection are still unknown
- Transmission of HIV by infected cells
- Animal models are of limited guidance and relevance
- Time consuming and costly clinical trials, especially efficacy trials
In the normal course of events, it takes a minimum of 10-15 years to go from basic science and design to the preclinical and clinical research process and bring the vaccine to the stage of marketing.
The clinical research can be divided into the following phases, all of which are randomised, double blinded and placebo controlled.
Phase I trials
These represent the first human trials of the candidate vaccine and are generally conducted on small numbers (10-30) of healthy adult volunteers. The safety (how the body will tolerate the vaccine), immunogenicity (how the body's immune system will respond to the vaccine to fight against HIV) of the vaccine, preliminary dose escalation and schedules of immunization are evaluated in this phase. Phase I trials generally take 12-18 months for completion.
Phase II trials
These are carried out in a larger number (50-500) of volunteers who are healthy adults at risk for HIV infection. The goals of Phase II trials are to obtain additional safety data and refine the dosing and scheduling regimens of the vaccine. These trials generally take two years for completion. Phase II b are considered efficacy trials on a smaller scale (2000-3000). They allow to draw preliminary conclusions on efficacy (with a large confidence interval) and to study the immune correlates of protection. Successful Phase II b trials would pave the way to full blown Phase III trials.
Phase III trials
Large scale efficacy trials are conducted in thousands of subjects, in which the vaccine is compared with a placebo in geographic areas where the incidence of HIV transmission is high. The efficacy of the vaccine is determined in preventing HIV infection or preventing disease. Phase III trials take an average of 3-4 years. Successful demonstration of efficacy in a Phase III trial will lead to an application for licensure of the vaccine for marketing and distribution.
It is necessary to ensure that the timelines for vaccine development are compressed to 8-10 years and parallel rather than sequential Phase III trials are conducted. This can be done by accelerating the development of new and innovative AIDS vaccine designs, engaging and preparing communities for this development and prioritising the best candidate vaccines for large scale efficacy testing.
The trials have to be conducted among populations where the vaccine is eventually to be used, in order to determine its efficacy against the prevalent circulating subtypes. The recruitment of volunteers, especially women, will be a challenge in a country where stigma and discrimination of HIV-infected people is still predominant. In this regard, transparent information provision and the active participation of the communities will be essential.
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