HIV vaccines: education key to partial efficacy success
Recent research by Datamonitor has found that despite the immense need for an HIV vaccine, an 'ideal' vaccine may not be achievable. Instead, attributes such as 'partial efficacy' and 'limited protection' are being seen as more realistic goals. However, according to Datamonitor's Laura Harris, there are various issues to confront in the development of a partially effective HIV vaccine.

Gordon Brown recently announced that he will be promoting the establishment of worldwide infrastructure to co-ordinate research into AIDS, including further funding for the development of an effective HIV vaccine. While an increase in funding would undoubtedly aid the development of a vaccine, there remain fundamental challenges within HIV virology and human immunology that need to be addressed.

In December 2004, UNAIDS released a global summary of the HIV/AIDS epidemic reporting that 35.9-44.3 million individuals were currently living with the disease. During 2004, 2.8-3.5 million had reportedly died with a further 4.3-6.4 million new infections. Furthermore, new dynamics within the epidemic suggested that rapid spread will continue within east Asia, and in eastern Europe and central Asia, where in some regions, the number of people living with the disease has increased by almost 40-50%.

While antiretroviral therapy has led to the possibility of a life expectancy equivalent to that of the uninfected population for some HIV-infected individuals, the limited access to pharmacological therapy in areas worst affected by the HIV pandemic has boosted calls for an effective preventative vaccine to halt the continued spread of the disease.

Positive start but limited progress

The quest for an HIV vaccine began shortly after the causative virus for AIDS was first characterized in 1984, with the first human trials conducted as early as 1987 using Chiron and Genentech's gp120 candidates. This seemingly rapid response not only raised hope but also signaled prompt commitment from the scientific community. However almost 20 years later it is clear that the worldwide efforts are only marginally closer to a safe and effective HIV vaccine.

The approaches taken during the R&D of HIV vaccines have varied enormously due to three primary interrelated issues: the variability of the HIV virus, the lack of one single predictive animal model and the difficulty in identifying the appropriate immune response necessary for protection. Despite the existence of some cohorts of HIV-infected patients who remain seronegative and apparently uninfected, there is still little evidence that HIV infection can ever be cleared.

Numerous safety and efficacy issues abound, with researchers reluctant to use the traditional vaccine approach of a live attenuated (weakened) virus due to the possibility that the attenuated vaccine itself could cause AIDS in some individuals after a period of time. Since the weakened version of the virus would remain in the vaccinated individual's body, it is feared that factors such as age or other illness may induce the development of AIDS. Other concerns include that the virus included in the vaccine could revert to the wild-type and rapidly cause disease, or long-term persistence of the attenuated vaccine could cause autoimmune or malignant disease.

Similar concerns have prevented the development of whole killed or inactivated HIV vaccines, since it is unclear whether complete inactivation of the virus could be achieved or demonstrated.

Researchers have instead focused on more novel approaches, with prime-boost vaccines, DNA vaccines and pseudovirion vaccines being investigated. Currently some promising data has been gathered from trials with adenovirus vector vaccines and prime-boost strategies targeting several different immune responses. This is the case with the combination of Aventis-Pasteur's vCP1521 ALVAC vaccine, which induces cellular immunity, and with VaxGen's AIDSVAX B/E, which targets the humoral immune response. This combination recently entered phase III trials, although it will be several years before final data is obtained.

Partial efficacy: a shorter term solution?

Currently the IAVI database lists 65 HIV vaccines, which have been tested with approximately half currently in clinical trials. Of the HIV vaccines in the pipeline, only three have progressed to phase III trials - the two AIDSVAX vaccines and Aventis-Pasteur's vCP1521 from the ALVAC group of vaccines. However while there are numerous phase I and phase II trials underway, there is a lack of optimism regarding the eventual outcome of these. Indeed, expectations appear to be shifting, with endpoints such as partial efficacy and limited protection being viewed as more realistic goals.

Few vaccines that are currently in use are 100% effective, with a key example being the BCG (Bacillus Calmette-Guerin) vaccine, first introduced in 1921 to protect against tuberculosis, which has been shown in various studies to have approximately 50% efficacy in preventing infection. However the recent development of newer more effective vaccines that confer a greater degree of protection has led to an increase in expectation from the public, as highlighted in a recent article published in JAIDS where participants in a focus group commented: "I would get vaccinated only if they tell me that it is 100% effective". Despite this, several studies have highlighted the benefits a partially effective vaccine would provide - a vaccine with 50% efficacy over 10 years given to 65% of all adults could reduce HIV incidence by 25 to 60%.

A second idea being floated is that of a vaccine that only protects against a specific subset of the population. Although a vaccine that only protects certain groups of the population would undoubtedly encounter opposition on the grounds of discrimination and ethical obligations, data from recent trials has highlighted the possibility of this approach. The AIDSVAX B/B trial, which was completed in early 2003, found that certain racial subgroups did appear to be protected against infection, although this trend has to be explored more fully. Moreover some vaccines can be designed to specifically target certain populations, such as risk-groups or HIV subtypes.

Education is key

With continued compromise to the concept of an 'ideal' HIV vaccine it is clear that more and more non-clinical challenges with regard to vaccine adoption present themselves. While it is universally agreed that a prophylactic vaccine that protects against HIV infection would have led to a significant decline in the incidence and eventual prevalence of the disease, the potential impact of a partially effective vaccine is less clear. For example, a study conducted in Thailand investigated how partially effective vaccines would impact on the transmission of the virus. It was found that a 75% effective vaccine led to a 40-year HIV prevalence of 37% with vaccination but 50% without vaccination. While these trends are not disputed, what is causing concern is the possibility that risk behavior may increase as a result of the mistaken belief that a partially vaccinated individual can not pass on nor acquire HIV.

Indeed another study found that the change in post vaccination behavior varied depending on the efficacy of the vaccine. For example it had a limited effect on the prevalence results with a 75% effective vaccine, but a significant effect with a 30% effective vaccine. The implication being that if 90% of low-risk individuals responded to a 30% effective vaccine with increased high-risk behavior, the benefit of vaccination disappeared.

Consequently, extensive patient education and awareness campaigns will have to be undertaken should partial vaccination become a realistic prospect:

One French opinion leader explained: "I think we have some papers showing that with a vaccine with partial efficacy we may have an increase of the spread of the epidemic rather than something which might contain the epidemic. So, I think if the world and the scientists want to go to the development of vaccines with partial efficacy, I think [we must know] how to explain that and how to use that."

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